Details of a Researcher - Mikami, Yohei

Papers - Mikami, Yohei

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Radiomics prediction of surgery in ulcerative colitis refractory to medical treatment

Sakamoto K., Okabayashi K., Seishima R., Shigeta K., Kiyohara H., Mikami Y., Kanai T., Kitagawa Y.

Techniques in Coloproctology 29 ( 1 ) 113 2025.12

ISSN 11236337

Background: The surgeries in drug-resistant ulcerative colitis are determined by complex factors. This study evaluated the predictive performance of radiomics analysis on the basis of whether patients with ulcerative colitis in hospital were in the surgical or medical treatment group by discharge from hospital. Methods: This single-center retrospective cohort study used CT at admission of patients with US admitted from 2015 to 2022. The target of prediction was whether the patient would undergo surgery by the time of discharge. Radiomics features were extracted using the rectal wall at the level of the tailbone tip of the CT as the region of interest. CT data were randomly classified into a training cohort and a validation cohort, and LASSO regression was performed using the training cohort to create a formula for calculating the radiomics score. Results: A total of 147 patients were selected, and data from 184 CT scans were collected. Data from 157 CT scans matched the selection criteria and were included. Five features were used for the radiomics score. Univariate logistic regression analysis of clinical information detected a significant influence of severity (p < 0.001), number of drugs used until surgery (p < 0.001), Lichtiger score (p = 0.024), and hemoglobin (p = 0.010). Using a nomogram combining these items, we found that the discriminatory power in the surgery and medical treatment groups was AUC 0.822 (95% confidence interval (CI) 0.841–0.951) for the training cohort and AUC 0.868 (95% CI 0.729–1.000) for the validation cohort, indicating a good ability to discriminate the outcomes. Conclusions: Radiomics analysis of CT images of patients with US at the time of admission, combined with clinical data, showed high predictive ability regarding a treatment strategy of surgery or medical treatment.

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Gut Microbiota and Interorgan Communication among the Gut, Brain, and Beyond.

Shigehara A, Kiyohara H, Teratani T, Nakamoto N, Mikami Y, Kanai T

Internal medicine (Tokyo, Japan) 2025.05

ISSN 0918-2918

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Post-marketing surveillance of tofacitinib in patients with ulcerative colitis in Japan: a final report of safety and effectiveness data

Matsuoka, K; Motoya, S; Yamamoto, T; Matsuura, M; Fujii, T; Shinzaki, S; Mikami, Y; Arai, S; Oshima, J; Endo, Y; Yuasa, H; Hoshi, M; Sato, K; Hisamatsu, T

JOURNAL OF GASTROENTEROLOGY 2025.04

ISSN 0944-1174

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First-line biologics as a treatment for ulcerative colitis: a multicenter randomized control study

Naganuma M., Shiga H., Shimoda M., Matsuura M., Takenaka K., Fujii T., Yamamoto S., Matsubayashi M., Kobayashi T., Aoyama N., Saito D., Yokoyama K., Moriya K., Tsuchiya K., Shibui S., Kawamoto A., Shimizu H., Okamoto R., Sakamoto K., Yaguchi K., Kunisaki R., Akiyama S., Hayashi R., Hasui K., Kanmura S., Bamba S., Mishima Y., Kakimoto K., Sugimoto S., Nakazawa A., Abe T., Ogata H., Hisamatsu T., Matsuoka K., Omori T., Nakase H., Wagatsuma K., Uchiyama K., Takagi T., Fujiya M., Ueno N., Sasaki M., Takashima Y., Nanjyo S., Handa O., Shiotani A., Kanai T., Mikami Y., Sujino T., Kiyohara H., Nakamura S., Miyazaki T., Ishihara S., Andoh A., Sakuraba H., Tanaka S., Oka S., Takasago K., Kobayashi K., Betto T., Otsuka K., Nagahori M., Saito E., Fukata N.

Journal of Gastroenterology 60 ( 4 ) 430 - 441 2025.04

ISSN 09441174

Background: Despite the availability of several biologics for ulcerative colitis (UC), there remains a critical need to identify first-line treatment biologics. The superiority of infliximab (IFX) over vedolizumab (VED) and ustekinumab (UST) was evaluated as initial UC treatments in patients with biologic-naïve UC. Methods: This multicenter, randomized control trial was conducted across 20 Japanese medical institutions. An independent center randomly allocated patients with UC (Mayo score ≥ 6) who had not previously used biologics to three treatment groups (IFX, VED, UST). The primary endpoint was the clinical remission (CR) rate at week 12, with other endpoints including the treatment continuation rate at week 26 and adverse events (AEs). Results: From May 2021 to June 2023, 107 cases were registered, including 104 for safety and 97 for efficacy evaluation. CR rate at week 12 was 36.4% (95%CI:20.4–54.9), 32.4% (95%CI:17.4–50.5) and 43.3% (95%CI:25.5–62.6) in IFX, VED, and UST group, respectively. Continuation rates at week 26 were 50.0%(IFX), 58.3% (VED), and 82.4% (UST). AEs related to study medication were 14.7% (IFX), 16.7% (VED), and 5.9% (UST). Predictors for CR at week 12 were thiopurine use in IFX (p = 0.04), lower baseline Mayo score (p = 0.007), and lower Patient report outcome 2 (p = 0.003) at week 2 in VED. Conclusion: Due to small sample size, it is challenging to make conclusions for main endpoints from this study while our study suggested that use of thiopurines in IFX group and lower activity at enrollment in VED group may enhance treatment efficacy. (jRCT1031200329; available at https://jrct.niph.go.jp/).

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The gut–organ axis: Clinical aspects and immune mechanisms

Fukasawa N., Tsunoda J., Sunaga S., Kiyohara H., Nakamoto N., Teratani T., Mikami Y., Kanai T.

Allergology International 74 ( 2 ) 197 - 209 2025.04

ISSN 13238930

The gut-brain axis exemplifies the bidirectional connection between the intestines and the brain, as evidenced by the impact of severe stress on gastrointestinal symptoms including abdominal pain and diarrhea, and conversely, the influence of abdominal discomfort on mood. Clinical observations support the notion of the gut–brain connection, including an increased prevalence of inflammatory bowel disease (IBD) in patients with depression and anxiety, as well as the association of changes in the gut microbiota with neurological disorders such as multiple sclerosis, Parkinson's disease, stroke and Alzheimer's disease. The gut and brain communicate via complex mechanisms involving inflammatory cytokines, immune cells, autonomic nerves, and gut microbiota, which contribute to the pathogenesis in certain gut and brain diseases. Two primary pathways mediate the bidirectional information exchange between the intestinal tract and the brain: signal transduction through bloodstream factors, such as bacterial metabolites and inflammatory cytokines, and neural pathways, such as neurotransmitters and inflammatory cytokines within the autonomic nervous system through the interaction between the nerve cells and beyond. In recent years, the basic mechanisms of the pathophysiology of the gut-brain axis have been gradually elucidated. Beyond the gut-brain interaction, emerging evidence suggests the influence of the gut extends to other organs, such as the liver and lungs, through intricate inter-organ communication pathways. An increasing number of reports on this clinical and basic cross-organ interactions underscore the potential for better understanding and novel therapeutic strategies targeting inter-organs networks. Further clarification of interactions between multiorgans premises transformative insights into cross-organ therapeutic strategies.

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Maternal circadian rhythms during pregnancy dictate metabolic plasticity in offspring

Yao N., Kinouchi K., Katoh M., Ashtiani K.C., Abdelkarim S., Morimoto H., Torimitsu T., Kozuma T., Iwahara A., Kosugi S., Komuro J., Kato K., Tonomura S., Nakamura T., Itoh A., Yamaguchi S., Yoshino J., Irie J., Hashimoto H., Yuasa S., Satoh A., Mikami Y., Uchida S., Ueki T., Nomura S., Baldi P., Hayashi K., Itoh H.

Cell Metabolism 37 ( 2 ) 395 - 412.e6 2025.02

ISSN 15504131

Tissue-level oscillation is achieved by tissue-intrinsic clocks along with network-dependent signals originating from distal organs and organismal behavior. Yet, it remains unexplored whether maternal circadian rhythms during pregnancy influence fetal rhythms and impact long-term susceptibility to dietary challenges in offspring. Here, we demonstrate that circadian disruption during pregnancy decreased placental and neonatal weight yet retained transcriptional and structural maturation. Intriguingly, diet-induced obesity was exacerbated in parallel with arrhythmic feeding behavior, hypothalamic leptin resistance, and hepatic circadian reprogramming in offspring of chronodisrupted mothers. In utero circadian desynchrony altered the phase-relationship between the mother and fetus and impacted placental efficiency. Temporal feeding restriction in offspring failed to fully prevent obesity, whereas the circadian alignment of caloric restriction with the onset of the active phase virtually ameliorated the phenotype. Thus, maternal circadian rhythms during pregnancy confer adaptive properties to metabolic functions in offspring and provide insights into the developmental origins of health and disease.

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Leucine-rich alpha-2 glycoprotein in combination with C-reactive protein for predicting endoscopic activity in Crohn’s disease: a single-centre, cross-sectional study

Takada Y., Kiyohara H., Mikami Y., Taguri M., Sakakibara R., Aoki Y., Nanki K., Kawaguchi T., Yoshimatsu Y., Sugimoto S., Sujino T., Takabayashi K., Hosoe N., Ogata H., Kato M., Iwao Y., Nakamoto N., Kanai T.

Annals of Medicine 57 ( 1 ) 2453083 2025

ISSN 07853890

Background and objective: Leucine-rich alpha-2 glycoprotein (LRG) is a novel biomarker for Crohn’s disease (CD). The utility of combination use of LRG and C-reactive protein (CRP) has not been reported. This study aimed to investigate the diagnostic performance of LRG in combination with CRP to predict endoscopic activity. Methods: A single-centre, retrospective, cross-sectional study was conducted. Patients with CD who had serum LRG concentrations measured at least once between June 2020 and May 2021 were enrolled. Clinical activity was evaluated with the Harvey–Bradshaw Index (HBI). Spearman’s rank correlation coefficient (rs) was used to analyse the correlations between the HBI, LRG concentrations and CRP concentrations. In patients undergoing ileocolonoscopy or balloon-assisted enteroscopy within 60 days before or after LRG measurement, endoscopic activity was evaluated with the simple endoscopic score for Crohn’s disease (SES-CD). The diagnostic performance of LRG and CRP for endoscopic activity was evaluated using receiver operating characteristic (ROC) analysis. Results: Four hundred and eighty-nine measurements in 343 patients were analysed. Although a strong correlation was found between LRG and CRP concentrations (rs = 0.75), the HBI did not well correlate with LRG or CRP concentrations. Endoscopic activity was analysed in 56 patients. In diagnosing endoscopically moderate to severe activity (SES-CD > 6), the area under the ROC curve of LRG was greater than that of CRP (0.74 vs. 0.63; p = .037). The optimal cut-off value estimated by Youden’s index was 15.5 µg/mL for LRG, and 0.13 mg/dL for CRP. LRG and CRP concentrations were considered positive when they were above these cut-off values, and the sensitivity and specificity for an SES-CD > 6 were 58.3% and 93.8%, respectively. Dual positivity of LRG and CRP showed the highest specificity. Conclusions: Combination use of dual positive LRG and CRP is useful for diagnosing endoscopically moderate to severe disease.

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Interleukin-17A Inhibitor-induced Pouchitis

Kiyohara H., Mikami Y., Kanai T.

Clinical Gastroenterology and Hepatology 2025

ISSN 15423565

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Clinical outcomes of patients with remitting ulcerative colitis after discontinuation of indigo naturalis

Shimada F., Yoshimatsu Y., Sujino T., Fukuda T., Aoki Y., Hayashi Y., Tojo A., Kawaguchi T., Kiyohara H., Sugimoto S., Nanki K., Mikami Y., Miyamoto K., Takabayashi K., Hosoe N., Kato M., Ogata H., Naganuma M., Kanai T.

Scientific Reports (Scientific Reports) 14 ( 1 ) 5778 2024.12

ISSN 2045-2322

Indigo naturalis is an effective treatment for ulcerative colitis. However, long-term use of indigo naturalis causes adverse events, such as pulmonary hypertension. The natural history of patients with ulcerative colitis who discontinued indigo naturalis after induction therapy is unknown. Moreover, the clinical features of patients who relapsed within 52 weeks after the discontinuation of indigo naturalis are unclear. This study aimed to assess the clinical outcomes of patients with ulcerative colitis after discontinuation of indigo naturalis and to identify potential markers responsible for relapse. This single-center retrospective study investigated the follow-up of 72 patients who achieved a clinical response 8 weeks after indigo naturalis treatment. We observed relapse in patients with ulcerative colitis after the discontinuation of indigo naturalis. We analyzed the factors predicting long-term outcomes after discontinuation of indigo naturalis. Relapse was observed in 24%, 57%, and 71% of patients at 8, 26, and 52 weeks, respectively. There were no predictive markers in patients who relapsed within 52 weeks after the discontinuation of indigo naturalis. The ulcerative colitis relapse rate after indigo naturalis discontinuation was high. Follow-up treatment is required after the discontinuation of indigo naturalis in patients with ulcerative colitis.

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Usefulness of Underwater EMR for neoplastic lesions in ulcerative colitis

Takabayashi, K; Imura, Y; Murata, S; Minezaki, D; Tojo, A; Sakurai, H; Iwata, K; Miyazaki, K; Masunaga, T; Mizutani, M; Akimioto, T; Takatori, Y; Yoshimatsu, Y; Sugimoto, S; Kiyohara, H; Kawasaki, S; Mikami, Y; Matsuura, N; Sujino, T; Nakayama, A; Yahagi, N; Kato, M; Kanai, T

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 39 331 - 331 2024.11

ISSN 0815-9319

USEFULNESS OF UNDERWATER ENDOSCOPIC MUCOSAL RESECTION FOR SPORADIC NEOPLASM IN ULCERATIVE COLITIS

Takabayashi, K; Imura, Y; Murata, S; Sato, M; Morioka, K; Sakurai, H; Okuzawa, A; Miyazaki, K; Iwata, K; Masunaga, T; Kubosawa, Y; Mizutani, M; Akimoto, T; Takatori, Y; Yoshimatsu, Y; Sugimoto, S; Kiyohara, H; Kawasaki, S; Mikami, Y; Matsuura, N; Sujino, T; Nakayama, A; Kanai, T; Kato, M

GASTROINTESTINAL ENDOSCOPY 99 ( 6 ) AB490 - AB491 2024.06

ISSN 0016-5107

USEFULNESS OF UNDERWATER ENDOSCOPIC MUCOSAL RESECTION FOR SPORADIC NEOPLASM IN ULCERATIVE COLITIS

GASTROINTESTINAL ENDOSCOPY 99 ( 6 ) AB572 - AB572 2024.06

ISSN 0016-5107

A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification

Liu C., Nagashima H., Fernando N., Bass V., Gopalakrishnan J., Signorella S., Montgomery W., Lim A.I., Harrison O., Reich L., Yao C., Sun H.W., Brooks S.R., Jiang K., Nagarajan V., Zhao Y., Jung S., Phillips R., Mikami Y., Lareau C.A., Kanno Y., Jankovic D., Aryee M.J., Pękowska A., Belkaid Y., O'Shea J., Shih H.Y.

Immunity (Immunity) 57 ( 5 ) 1005 - 1018.e7 2024.05

ISSN 10747613

Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.

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Ulcerative colitis-associated neoplasms often harbor poor prognostic histologic components with low detection by biopsy

Sakakibara, R; Sugimoto, S; Takabayashi, K; Kiyohara, H; Wakisaka, Y; Kaieda, Y; Kawaida, M; Yoshimatsu, Y; Sujino, T; Hosoe, N; Kato, M; Shimoda, M; Mikami, Y; Iwao, Y; Kanai, T

INTESTINAL RESEARCH 22 ( 4 ) 428 - 438 2024.05

ISSN 1598-9100

Background/Aims: Poorly differentiated adenocarcinoma, signet-ring cell carcinoma, and mucinous adenocarcinoma (por/sig/muc), which are considered to be histologic subtypes with a poor prognosis, occur more frequently with colitis-associated cancer than with sporadic tumors. However, their invasiveness and manifestations are unclear. This study aimed to determine the prevalence of the por/sig/muc component in ulcerative colitis-associated neoplasms (UCANs) and its association with invasiveness and to clarify its clinicohistologic and endoscopic features. Methods: This retrospective observational study included patients diagnosed with ulcerative colitis-associated high-grade dysplasia or adenocarcinoma from 1997 to 2022 who were divided according to the presence or absence of a por/sig/muc component. Results: Thirty-five patients had UCAN with a por/sig/muc component and 66 had UCAN without this component. The 5-year survival rate was significantly lower in the por/sig/muc group than in the tub group (67% vs. 96%, P=0.001), which was attributed to disease above stage III and depth to below the subserosa. Biopsy-based diagnosis before resection detected a por/sig/muc component in only 40% of lesions (14/35). Lesions with a por/sig/muc component were prevalent even in the early stages: stage 0 (4/36, 11%), I (8/20, 40%), II (7/12, 58%), III (10/14, 71%), and IV (6/8, 75%). Conclusions: This is the first investigation that shows UCANs with a por/sig/muc component tended to be deeply invasive and were often not recognized preoperatively. Endoscopists should be aware that UCAN often has a por/sig/muc component that is not always recognized on biopsy, and the optimal treatment strategy needs to be carefully considered.

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Efficacy of Dose Escalation of Oral 5-Aminosalicylic Acid for Ulcerative Colitis With a Mayo Endoscopic Subscore of 1: An Open Label Randomized Controlled Trial

Fukuda, T; Aoki, Y; Kiyohara, H; Yokoyama, A; Nakazawa, A; Yoshimatsu, Y; Sugimoto, S; Nanki, K; Mikami, Y; Fukuhara, K; Mizuno, S; Sujino, T; Mutaguchi, M; Takabayashi, K; Morohoshi, Y; Hosoda, Y; Ogata, H; Iwao, Y; Naganuma, M; Kanai, T

INFLAMMATORY BOWEL DISEASES 31 ( 3 ) 716 - 724 2024.04

ISSN 1078-0998

Background: Endoscopic healing is generally defined as Mayo endoscopic subscore (MES) ≤1 in ulcerative colitis (UC). However, patients with an MES of 1 are at higher relapse risk than those with an MES of 0. This study evaluated the therapeutic efficacy of proactive dose escalation of oral 5-aminosalicylic acid (5-ASA) in UC patients with an MES of 1. Methods: An open-label, randomized controlled trial was conducted in 5 hospitals between 2018 and 2022. Ulcerative colitis patients in clinical remission under oral 5-ASA therapy and diagnosed as having an MES of 1 were enrolled. Patients receiving maintenance therapy other than 5-ASA and immunomodulator were excluded. Patients were randomly assigned in a 1:1 ratio to receive either a dose-escalated (intervention) or constant dose (control) of 5-ASA. Concomitant immunomodulator was used as the stratification factor in the randomization. The primary end point was relapse within 1 year. The subgroup analysis was stratified for the use of immunomodulators. Results: The full analysis set included 79 patients (39 intervention and 40 control). Immunomodulators were used in 20 (25.3%) patients. Relapse was less in the intervention group (15.4%) than the control group (37.5%; P = .026). In the subgroup with concomitant immunomodulators, relapse was also less in the intervention group (10.0%) than the control group (70.0%; P = .020). In patients without immunomodulators, the difference was not significant between 2 groups (intervention, 17.2%; control, 26.7%; P = .53). Conclusions: Dose escalation of 5-ASA reduced relapse within 1 year in UC patients in clinical remission with an MES of 1.

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Video capsule endoscopy in overt and occult obscure gastrointestinal bleeding: Insights from a single-center, observational study in Japan

Tojo A., Sujino T., Hayashi Y., Kamiya K.J.L.L., Sato M., Hinako S., Yoshimatsu Y., Kinoshita S., Kiyohara H., Mikami Y., Takabayashi K., Kato M., Ogata H., Kanai T., Hosoe N.

DEN Open (DEN Open) 4 ( 1 ) e354 2024.04

ISSN 2692-4609

Objective: This study aimed to evaluate the use of video capsule endoscopy (VCE) in patients with obscure gastrointestinal bleeding (OGIB), compare cases of overt and occult OGIB, assess the rates of balloon-assisted enteroscopy (BAE) interventions and rebleeding, and identify predictive markers of positive VCE findings. Methods: Medical records of 430 patients who underwent VCE for OGIB between 2004 and 2022 were analyzed. Occult OGIB was defined as IDA or positive fecal occult blood, whereas overt OGIB was defined as clinically imperceptible bleeding. We retrospectively analyzed demographics, VCE findings based on Saurin classification (P0, P1, and P2), outcome of BAE interventions, and rebleeding rates. Results: A total of 253 patients with overt OGIB and 177 with occult OGIB were included. P1 findings were predominant in both groups, with a similar distribution. The percentage of patients receiving conservative therapy was higher in P1 than in P2 for both overt and occult OGIB. BAE was more frequently performed in P2 than in P1 VCE (83.0% vs. 35.3% in overt OGIB, 84.4% vs. 24.4% in occult OGIB). The percentage of positive findings and intervention in total BAE performed patients were comparable in P1 and P2 of overt OGIB, whereas these percentages in P2 were more than P1 of occult OGIB. Conclusion: VCE effectively identified OGIB lesions requiring intervention, particularly occult OGIB lesions, potentially reducing unnecessary BAE. Rebleeding rates varied according to the VCE findings, emphasizing the importance of follow-up in high-risk patients.

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Characteristics of flat-type ulcerative colitis-associated neoplasia on chromoendoscopic imaging with indigo carmine dye spraying

Takabayashi K., Sugimoto S., Nanki K., Yoshimatsu Y., Kiyohara H., Mikami Y., Sujino T., Kato M., Hosoe N., Shimoda M., Yahagi N., Ogata H., Iwao Y., Kanai T.

Digestive Endoscopy (Digestive Endoscopy) 36 ( 4 ) 446 - 454 2024.04

ISSN 09155635

Objectives: Despite recent advances in endoscopic equipment and diagnostic techniques, early detection of ulcerative colitis-associated neoplasia (UCAN) remains difficult because of the complex background of the inflamed mucosa of ulcerative colitis and the morphologic diversity of the lesions. We aimed to describe the main diagnostic patterns for UCAN in our cohort, including lateral extension surrounding flat lesions. Methods: Sixty-three lesions in 61 patients with flat-type dysplasia that were imaged with dye chromoendoscopy (DCE) were included in this analysis. These DCE images were analyzed to clarify the dye-chromoendoscopic imaging characteristics of flat dysplasia, and the lesions were broadly classified into dysplastic and nondysplastic mucosal patterns. Results: Dysplastic mucosal patterns were classified into two types: small round patterns with round to roundish structures, and mesh patterns with intricate mesh-like structures. Lesions with a nondysplastic mucosal pattern were divided into two major types: a ripple-like type and a gyrus-like type. Of note, 35 lesions (55.6%) had a small round pattern, and 51 lesions (80.9%) had some type of mesh pattern. About 70% of lesions with small round patterns and 49% of lesions with mesh patterns were diagnosed as high-grade dysplasia or carcinoma, while about 30% of lesions with small round patterns and 51% of lesions with mesh patterns were diagnosed as low-grade dysplasia. Conclusion: When a characteristic mucosal pattern, such as a small round or mesh pattern, is found by DCE, the possibility of UCAN should be considered.

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Gastrointestinal symptoms in COVID-19 and disease severity: a Japanese registry-based retrospective cohort study

Matsubara Y., Kiyohara H., Mikami Y., Nanki K., Namkoong H., Chubachi S., Tanaka H., Azekawa S., Sugimoto S., Yoshimatsu Y., Sujino T., Takabayashi K., Hosoe N., Sato T., Ishii M., Hasegawa N., Okada Y., Koike R., Kitagawa Y., Kimura A., Imoto S., Miyano S., Ogawa S., Fukunaga K., Kanai T.

Journal of gastroenterology (Journal of gastroenterology) 59 ( 3 ) 195 - 208 2024.03

ISSN 0944-1174

BACKGROUND: Research on whether gastrointestinal symptoms correlate with the severity of Coronavirus Disease 2019 (COVID-19) has been inconclusive. This study aimed to clarify any associations between gastrointestinal symptoms and the prognosis of COVID-19. METHODS: We collected data from the Japanese nationwide registry for COVID-19 to conduct a retrospective cohort study. Data from 3498 Japanese COVID-19 patients, diagnosed at 74 facilities between February 2020 and August 2022, were analyzed in this study. Hospitalized patients were followed up until discharge or transfer to another hospital. Outpatients were observed until the end of treatment. Associations between gastrointestinal symptoms and clinical outcomes were investigated using multivariable-adjusted logistic regression models. RESULTS: The prevalence of diarrhea, nausea/vomiting, abdominal pain, and melena were 16.6% (581/3498), 8.9% (311/3498), 3.5% (121/3498), and 0.7% (23/3498), respectively. In the univariable analysis, admission to intensive care unit (ICU) and requirement for mechanical ventilation were less common in patients with diarrhea than those without (ICU, 15.7% vs. 20.6% (p = 0.006); mechanical ventilation, 7.9% vs. 11.4% (p = 0.013)). In the multivariable-adjusted analysis, diarrhea was associated with lower likelihood of ICU admission (adjusted odds ratio (aOR), 0.70; 95% confidence interval (CI), 0.53-0.92) and mechanical ventilation (aOR, 0.61; 95% CI, 0.42-0.89). Similar results were obtained in a sensitivity analysis with another logistic regression model that adjusted for 14 possible covariates with diarrhea (ICU; aOR, 0.70; 95% CI, 0.53-0.93; mechanical ventilation; aOR 0.62; 95% CI, 0.42-0.92). CONCLUSIONS: Diarrhea was associated with better clinical outcomes in COVID-19 patients.

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Proximal and Distal Bronchioles Contribute to the Pathogenesis of Non-Cystic Fibrosis Bronchiectasis

Asakura, T; Okuda, K; Chen, G; Dang, H; Kato, T; Mikami, Y; Schworer, SA; Gilmore, RC; Radicioni, G; Hawkins, P; Cardenas, SMB; Saito, M; Cawley, AM; De la Cruz, G; Chua, M; Alexis, NE; Masugi, Y; Noone, PG; Ribeiro, CMP; Kesimer, M; Olivier, KN; Hasegawa, N; Randell, SH; O'Neal, WK; Boucher, RC

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 209 ( 4 ) 374 - 389 2024.02

ISSN 1073-449X

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Post-marketing surveillance of tofacitinib in patients with ulcerative colitis in Japan: A final report of effectiveness and safety data

Matsuoka, K; Motoya, S; Yamamoto, T; Matsuura, M; Fujii, T; Shinzaki, S; Mikami, Y; Arai, S; Oshima, J; Endo, Y; Yuasa, H; Hoshi, M; Sato, K; Hisamatsu, T

JOURNAL OF CROHNS & COLITIS 18 I1407 - I1409 2024.01

ISSN 1873-9946

Clinical features and surgical necessity rate of fistulising perianal disease in newly diagnosed patients with Crohn's disease: Interim analysis of inception cohort registry study of patients with Crohn's disease (iCREST-CD)

Takatsu, N; Yamamoto, T; Nakase, H; Shinzaki, S; Watanabe, K; Fujii, T; Okamoto, R; Matsuoka, K; Yamada, A; Kunisaki, R; Matsuura, M; Shiga, H; Bamba, S; Mikami, Y; Shimoyama, T; Motoya, S; Torisu, T; Kobayashi, T; Ohmiya, N; Saruta, M; Matsuda, K; Matsumoto, T; Maemoto, A; Yoshigoe, S; Tsuchiya, H; Nishimura, R; Murata, Y; Hisamatsu, T

JOURNAL OF CROHNS & COLITIS 18 I2104 - I2106 2024.01

ISSN 1873-9946

Microbial ligand-independent regulation of lymphopoiesis by NOD1

Iwamura C., Ohnuki H., Flomerfelt F.A., Zheng L., Carletti A., Wakashin H., Mikami Y., Brooks S.R., Kanno Y., Gress R.E., Tosato G., Nakayama T., O’Shea J.J., Sher A., Jankovic D.

Nature Immunology (Nature Immunology) 24 ( 12 ) 2080 - 2090 2023.12

ISSN 15292908

Aberrant differentiation of progenitor cells in the hematopoietic system is known to severely impact host immune responsiveness. Here we demonstrate that NOD1, a cytosolic innate sensor of bacterial peptidoglycan, also functions in murine hematopoietic cells as a major regulator of both the generation and differentiation of lymphoid progenitors as well as peripheral T lymphocyte homeostasis. We further show that NOD1 mediates these functions by facilitating STAT5 signaling downstream of hematopoietic cytokines. In steady-state, loss of NOD1 resulted in a modest but significant decrease in numbers of mature T, B and natural killer cells. During systemic protozoan infection this defect was markedly enhanced, leading to host mortality. Lack of functional NOD1 also impaired T cell-dependent anti-tumor immunity while preventing colitis. These findings reveal that, in addition to its classical role as a bacterial ligand receptor, NOD1 plays an important function in regulating adaptive immunity through interaction with a major host cytokine signaling pathway.

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Bacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis

Ichikawa M., Nakamoto N., Kredo-Russo S., Weinstock E., Weiner I.N., Khabra E., Ben-Ishai N., Inbar D., Kowalsman N., Mordoch R., Nicenboim J., Golembo M., Zak N., Jablonska J., Sberro-Livnat H., Navok S., Buchshtab N., Suzuki T., Miyamoto K., Teratani T., Fujimori S., Aoto Y., Konda M., Hayashi N., Chu P.S., Taniki N., Morikawa R., Kasuga R., Tabuchi T., Sugimoto S., Mikami Y., Shiota A., Bassan M., Kanai T.

Nature Communications (Nature Communications) 14 ( 1 ) 3261 2023.12

Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fibrosis. Although gut commensals are associated with PSC, their causative roles and therapeutic strategies remain elusive. Here we detect abundant Klebsiella pneumoniae (Kp) and Enterococcus gallinarum in fecal samples from 45 PSC patients, regardless of intestinal complications. Carriers of both pathogens exhibit high disease activity and poor clinical outcomes. Colonization of PSC-derived Kp in specific pathogen-free (SPF) hepatobiliary injury-prone mice enhances hepatic Th17 cell responses and exacerbates liver injury through bacterial translocation to mesenteric lymph nodes. We developed a lytic phage cocktail that targets PSC-derived Kp with a sustained suppressive effect in vitro. Oral administration of the phage cocktail lowers Kp levels in Kp-colonized germ-free mice and SPF mice, without off-target dysbiosis. Furthermore, we demonstrate that oral and intravenous phage administration successfully suppresses Kp levels and attenuates liver inflammation and disease severity in hepatobiliary injury-prone SPF mice. These results collectively suggest that using a lytic phage cocktail shows promise for targeting Kp in PSC.

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Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development

Ono K., Sujino T., Miyamoto K., Harada Y., Kojo S., Yoshimatsu Y., Tanemoto S., Koda Y., Zheng J., Sayama K., Koide T., Teratani T., Mikami Y., Takabayashi K., Nakamoto N., Hosoe N., London M., Ogata H., Mucida D., Taniuchi I., Kanai T.

Nature Communications (Nature Communications) 14 ( 1 ) 5152 2023.12

Intestinal intraepithelial lymphocytes (IELs) reside in the gut epithelial layer, where they help in maintaining intestinal homeostasis. Peripheral CD4+ T cells can develop into CD4+CD8αα+ IELs upon arrival at the gut epithelium via the lamina propria (LP). Although this specific differentiation of T cells is well established, the mechanisms preventing it from occurring in the LP remain unclear. Here, we show that chemokine receptor 9 (CCR9) expression is low in epithelial CD4+CD8αα+ IELs, but CCR9 deficiency results in CD4+CD8αα+ over-differentiation in both the epithelium and the LP. Single-cell RNA sequencing shows an enriched precursor cell cluster for CD4+CD8αα+ IELs in Ccr9 −/− mice. CD4+ T cells isolated from the epithelium of Ccr9 −/− mice also display increased expression of Cbfβ2, and the genomic occupancy modification of Cbfβ2 expression reveals its important function in CD4+CD8αα+ differentiation. These results implicate a link between CCR9 downregulation and Cbfb2 splicing upregulation to enhance CD4+CD8αα+ IEL differentiation.

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The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis

Miyamoto K., Sujino T., Harada Y., Ashida H., Yoshimatsu Y., Yonemoto Y., Nemoto Y., Tomura M., Melhem H., Niess J.H., Suzuki T., Suzuki T., Suzuki S., Koda Y., Okamoto R., Mikami Y., Teratani T., Tanaka K., Yoshimura A., Sato T., Kanai T.

Cell Reports (Cell Reports) 42 ( 8 ) 113005 2023.08

ISSN 2211-1247

The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4+ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1+ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.

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Association of ulcerative colitis symptom severity and proctocolectomy with multidimensional patient-reported outcomes: a cross-sectional study

Matsuoka K., Yamazaki H., Nagahori M., Kobayashi T., Omori T., Mikami Y., Fujii T., Shinzaki S., Saruta M., Matsuura M., Yamamoto T., Motoya S., Hibi T., Watanabe M., Fernandez J., Fukuhara S., Hisamatsu T.

Journal of Gastroenterology (Journal of Gastroenterology) 58 ( 8 ) 751 - 765 2023.08

ISSN 09441174

Background: The YOu and Ulcerative colitis: Registry and Social network (YOURS) is a large-scale, multicenter, patient-focused registry investigating the effects of lifestyle, psychological factors, and clinical practice patterns on patient-reported outcomes in patients with ulcerative colitis in Japan. In this initial cross-sectional baseline analysis, we comprehensively explored impacts of symptom severity or proctocolectomy on nine patient-reported outcomes. Methods: Patients receiving tertiary care at medical institutions were consecutively enrolled in the YOURS registry. The patients completed validated questionnaires on lifestyle, psychosocial factors, and disease-related symptoms. Severity of symptoms was classified with self-graded stool frequency and rectal bleeding scores (categories: remission, active disease [mild, moderate, severe]). The effects of symptom severity or proctocolectomy on nine scales for quality of life, fatigue, anxiety/depression, work productivity, and sleep were assessed by comparing standardized mean differences of the patient-reported outcome scores. Results: Of the 1971 survey responses analyzed, 1346 (68.3%) patients were in remission, 583 (29.6%) had active disease, and 42 (2.1%) had undergone proctocolectomy. A linear relationship between increasing symptom severity and worsening quality of life, fatigue, anxiety, depression, and work productivity was observed. Patients with even mild symptoms had worse scores than patients in remission. Patients who had undergone proctocolectomy also had worse scores than patients in remission. Conclusions: Ulcerative colitis was associated with reduced mood, quality of life, fatigue, and work productivity even in patients with mild symptoms, suggesting that management of active ulcerative colitis may improve patient-reported outcomes irrespective of disease severity. (UMIN Clinical Trials Registry: UMIN000031995, https://www.umin.ac.jp/ctr/index-j.htm).

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IL-15-producing splenic B cells play pathogenic roles in the development of autoimmune hepatitis

Fujimori S., Chu P.S., Teratani T., Harada Y., Suzuki T., Amiya T., Taniki N., Kasuga R., Mikami Y., Koda Y., Ichikawa M., Tabuchi T., Morikawa R., Yamataka K., Noguchi F., Tsujikawa H., Kurebayashi Y., Sakamoto M., Kanai T., Nakamoto N.

JHEP Reports (JHEP Reports) 5 ( 7 ) 100757 2023.07

Background & Aims: B-cell depletion therapy with an anti-CD20 is an effective treatment strategy for patients with refractory autoimmune hepatitis (AIH). However, the mechanisms underlying B-cell action are unclear. Methods: Herein, we used the adeno-associated virus IL-12 model, in which hepatic IL-12 expression triggers liver injuries characteristic of AIH. We also analysed the clinical samples of patients with AIH. Results: B-cell depletion using anti-CD20 or splenectomy was found to improve liver functions and decrease the cytotoxic CD8+ T-cell (cytotoxic T lymphocyte [CTL]) count in the liver. This improvement was reversed by the adoptive transfer of splenic B cells derived from AAV IL-12-treated mice to splenectomised mice as it caused the hepatic CTL count to increase. RNA-sequencing analysis identified IL-15 as a key factor in pathogenic B cells, which promotes CTL expansion and subsequent migration to the liver via the CXCL9/CXCR3 axis. Indeed, IL-15 neutralisation ameliorated hepatitis by suppressing splenic and hepatic CTLs in vivo. The close distribution of B220+ B cells and CD8+ T cells in the spleen of AIH mice suggested mutual interactions. Mechanistically, IFNγ and CD40L/CD40 signalling were indispensable for the expression of IL-15 in B cells, and in vitro co-culture experiments revealed that splenic CD40L+CD8+ T cells promoted IL-15 production in B cells, which led to CTL expansion. In patients with AIH, high serum IL-15 concentration and IL-15+ B-cell counts, positively correlating with serum alanine aminotransferase levels, support translation and potential therapeutic targeting in human AIH. Conclusions: This investigation elucidated the roles of IL-15-producing splenic B cells that occur in concert with pathogenic CD8+ T cells during the development of AIH. Impact and Implications: IL-15-producing B cells were shown to exacerbate experimental AIH via cytotoxic T lymphocyte expansion. CD40L+CD8+ T cells promoted IL-15 expression in B cells, indicating the mutual interaction of both cells. High serum IL-15 concentrations, IL-15+ B-cell counts, and CD40L+IL-15Rα+CD8+ T-cell counts were confirmed in the blood of patients with AIH.

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Safety and Effectiveness of Vedolizumab in Patients with Moderate-to-Severe Ulcerative Colitis: An Interim Analysis of a Japanese Post-Marketing Surveillance Study

Matsuoka K., Hisamatsu T., Mikami Y., Yamamoto T., Motoya S., Shinzaki S., Iwakiri R., Sugiura K., Nishimura K., Kajita M., Fernandez J.L.

Advances in Therapy (Advances in Therapy) 40 ( 6 ) 2902 - 2914 2023.06

ISSN 0741238X

Introduction: This ongoing post-marketing surveillance monitors the long-term safety and effectiveness of vedolizumab in routine clinical practice in patients with moderate-to-severe ulcerative colitis (UC) in Japan. This interim analysis assessed induction-phase data, covering the initial three doses of vedolizumab. Methods: Patients were enrolled via a web-based electronic data capture system from approximately 250 institutions. Incidence of adverse events and treatment responses were assessed by the physicians after the patient had received three doses of vedolizumab or when the drug was discontinued, whichever occurred first. Therapeutic response was defined as any treatment response, including remission or improvement of complete or partial Mayo score, and was assessed in the total and stratified patient populations according to prior tumor necrosis factor alpha (TNFα) inhibitor treatments and/or baseline partial Mayo score. Results: The total incidence of adverse drug reactions (ADRs) was 4.10% (11/268). Common ADRs were dizziness, nausea, and arthralgia, each reported in 0.75% of patients (2/268). Serious ADRs were herpes zoster oticus and UC, each reported in 0.37% of patients (1/268). Therapeutic response was reported in 84.5% (218/258) of all patients, 85.8% (127/148) of TNFα inhibitor-naïve patients, and 82.7% (91/110) of TNFα inhibitor-experienced patients. Among patients with partial Mayo score of ≥ 4 at baseline, partial Mayo score remission in patients without or with prior TNFα inhibitor treatment was 62.5% (60/96) and 45.6% (36/79), respectively. Conclusion: The results confirm a safety and effectiveness profile of vedolizumab consistent with that observed in previous trials. Clinical Trial Registration: JapicCTI-194603, NCT03824561.

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Bacteriophage therapy against pathological Klebsiella pneumoniae that determine the clinical course of primary sclerosing cholangitis

Ichikawa, M; Nakamoto, N; Kredo-Russo, S; Weinstock, E; NadavWeiner, I; Khabra, E; Ben-Ishai, N; Inbar, D; Kowalsman, N; Mordoch, R; Nicenboim, J; Golembo, M; Zak, N; Suzuki, T; Miyamoto, K; Teratani, T; Fujimori, S; Aoto, Y; Konda, M; Hayashi, N; Chu, PS; Taniki, N; Morikawa, R; Kasuga, R; Tabuchi, T; Sugimoto, S; Mikami, Y; Shiota, A; Bassan, M; Kanai, T

JOURNAL OF HEPATOLOGY 78 S409 - S409 2023.06

ISSN 0168-8278

Spatial Transcriptional Profiling of the Bronchiolectatic Lungs With Non-cystic Fibrosis Bronchiectasis (NCFB)

Asakura, T; Dang, H; Okuda, K; Chen, G; Kato, T; Mikami, Y; Gilmore, RC; Hawkins, P; Schworer, SA; Masugi, Y; Hasegawa, N; Randell, SH; O'Neal, WK; Boucher, RC

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 207 2023.05

ISSN 1073-449X

Enrichement of type I interferon signalling in the colonic ILC2 under inflammatory condition

Mikami, Y; Emi, I; Rino, I; Ichiro, M; Kanai, T

JOURNAL OF IMMUNOLOGY 210 ( 1 ) 2023.05

ISSN 0022-1767

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Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis

Takimoto Y., Chu P.s., Nakamoto N., Hagihara Y., Mikami Y., Miyamoto K., Morikawa R., Teratani T., Taniki N., Fujimori S., Suzuki T., Koda Y., Ishihara R., Ichikawa M., Honda A., Kanai T.

iScience (iScience) 26 ( 3 ) 106220 2023.03

The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b+ cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy.

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Network Approaches to Uncover Pathogenesis and Therapeutic Targets of Inflammatory Bowel Diseases.

Mikami Y, Kanai T

The Keio journal of medicine (Keio Journal of Medicine) 72 ( 2 ) 29 - 43 2023.03

ISSN 0022-9717

Inflammatory bowel diseases (IBD) are currently recognized to involve chronic intestinal inflammation in genetically susceptible individuals. Patients with IBD mainly develop gastrointestinal inflammation, but it is sometimes accompanied by extraintestinal manifestations such as arthritis, erythema nodo-sum, episcleritis, pyoderma gangrenosum, uveitis, and primary sclerosing cholangitis. These clinical aspects imply the importance of interorgan networks in IBD. In the gastrointestinal tract, immune cells are influenced by multiple local environmental factors including microbiota, dietary environment, and intercellular networks, which further alter molecular networks in immune cells. Therefore, decipher-ing networks at interorgan, intercellular, and intracellular levels should help to obtain a comprehensive understanding of IBD. This review focuses on the intestinal immune system, which governs the physiological and pathological functions of the digestive system in harmony with the other organs. (DOI: 10.2302/kjm.2022-0015-IR; Keio J Med 72 (2): 29–43, June 2023).

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Diagnosis and Clinical Features of Perianal Lesions in Newly Diagnosed Crohn's Disease: Subgroup Analysis from Inception Cohort Registry Study of Patients with Crohn's Disease (iCREST-CD).

Yamamoto T, Nakase H, Watanabe K, Shinzaki S, Takatsu N, Fujii T, Okamoto R, Matsuoka K, Yamada A, Kunisaki R, Matsuura M, Shiga H, Bamba S, Mikami Y, Shimoyama T, Motoya S, Torisu T, Kobayashi T, Ohmiya N, Saruta M, Matsuda K, Matsumoto T, Maemoto A, Murata Y, Yoshigoe S, Nagasaka S, Yajima T, Hisamatsu T, iCREST-CD Study Group

Journal of Crohn's & colitis (Journal of Crohn's and Colitis) 17 ( 8 ) 1193 - 1206 2023.03

ISSN 1873-9946

Background and Aims: Perianal lesion is a refractory phenotype of Crohn's disease [CD] with significantly diminished quality of life. We evaluated the clinical characteristics of perianal lesions in newly diagnosed CD patients and the impact of perianal lesions on the quality of life in Japanese patients with CD. Methods: Patients newly diagnosed with CD after June 2016 were included between December 2018 and June 2020 from the Inception Cohort Registry Study of Patients with CD [iCREST-CD]. Results: Perianal lesions were present in 324 [48.2%] of 672 patients with newly diagnosed CD; 71.9% [233/324] were male. The prevalence of perianal lesions was higher in patients aged <40 years vs ≥40 years, and it decreased with age. Perianal fistula [59.9%] and abscess [30.6%] were the most common perianal lesions. In multivariate analyses, male sex, age <40 years and ileocolonic disease location were significantly associated with a high prevalence of perianal lesions, whereas stricturing behaviour and alcohol intake were associated with low prevalence. Fatigue was more frequent [33.3% vs 21.6%] while work productivity and activity impairment-work time missed [36.3% vs 29.5%] and activity impairment [51.9% vs 41.1%] were numerically higher in patients with than those without perianal lesions. Conclusions: At the time of CD diagnosis, approximately half of the patients had perianal lesions; perianal abscesses and perianal fistulas were the most common. Young age, male sex, disease location and behaviour were significantly associated with the presence of perianal lesions. The presence of perianal lesion was associated with fatigue and impairment of daily activities. Clinical trials registry: University Hospital Medical Information Network Clinical Trials Registry System [UMIN-CTR, UMIN000032237].

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Risk of venous thromboembolism with a central venous catheter in hospitalized Japanese patients with inflammatory bowel disease: a propensity score-matched cohort study

Aoki Yasuhiro, Kiyohara Hiroki, Mikami Yohei, Nanki Kosaku, Kawaguchi Takaaki, Yoshimatsu Yusuke, Sugimoto Shinya, Sujino Tomohisa, Takabayashi Kaoru, Hosoe Naoki, Ogata Haruhiko, Iwao Yasushi, Kanai Takanori

INTESTINAL RESEARCH (Intestinal Research) 21 ( 3 ) 318 - 327 2023.02

ISSN 1598-9100

Background/Aims: Thromboprophylaxis is recommended for hospitalized patients with inflammatory bowel disease (IBD) in Western countries, although it is selectively administered to high-risk patients in East Asia. A central venous catheter (CVC) is commonly placed in patients with IBD. Although CVC placement is considered a risk factor for venous thromboembolism (VTE), the degree of increased risk in patients with IBD is uncertain. This study aimed to identify the risk of VTE with CVC placement in hospitalized Japanese patients with IBD without thromboprophylaxis. Methods: This retrospective cohort study included patients with ulcerative colitis or Crohn’s disease who were admitted for disease flares at Keio University Hospital between January 2016 and December 2020. Patients who already had thrombosis or were administered any antithrombotic treatment on admission were excluded. VTE development during the hospitalization was surveyed, and VTE risk associated with CVC indwelling was estimated using propensity score matching and inverse probability of treatment weighting analyses. Results: Altogether, 497 hospitalized patients with IBD (ulcerative colitis, 327; Crohn’s disease, 170) were enrolled. VTE developed in 9.30% (12/129) of catheterized patients and in 0.82% (3/368) of non-catheterized patients. The propensity score matching yielded 127 matched pairs of patients. The catheterized group demonstrated higher odds for VTE than the non-catheterized group (odds ratio, 13.15; 95% confidence interval, 1.68–102.70). A similar result was obtained in the inverse probability of treatment weighting analysis (odds ratio, 11.02; 95% confidence interval, 2.64–46.10). Conclusions: CVC placement is a major risk factor for VTE among hospitalized Japanese patients with IBD without thromboprophylaxis.

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Expert consensus on vaccination in patients with inflammatory bowel disease in Japan

Ishige T., Shimizu T., Watanabe K., Arai K., Kamei K., Kudo T., Kunisaki R., Tokuhara D., Naganuma M., Mizuochi T., Murashima A., Inoki Y., Iwata N., Iwama I., Koinuma S., Shimizu H., Jimbo K., Takaki Y., Takahashi S., Cho Y., Nambu R., Nishida D., Hagiwara S.i., Hikita N., Fujikawa H., Hosoi K., Hosomi S., Mikami Y., Miyoshi J., Yagi R., Yokoyama Y., Hisamatsu T.

Journal of Gastroenterology (Journal of Gastroenterology) 58 ( 2 ) 135 - 157 2023.02

ISSN 09441174

Immunosuppressive therapies can affect the immune response to or safety of vaccination in patients with inflammatory bowel disease (IBD). The appropriateness of vaccination should be assessed prior to the initiation of IBD treatment because patients with IBD frequently undergo continuous treatment with immunosuppressive drugs. This consensus was developed to support the decision-making process regarding appropriate vaccination for pediatric and adult patients with IBD and physicians by providing critical information according to the published literature and expert consensus about vaccine-preventable diseases (VPDs) [excluding cervical cancer and coronavirus disease 2019 (COVID-19)] in Japan. This consensus includes 19 important clinical questions (CQs) on the following 4 topics: VPDs (6 CQs), live attenuated vaccines (2 CQs), inactivated vaccines (6 CQs), and vaccination for pregnancy, childbirth, and breastfeeding (5 CQs). These topics and CQs were selected under unified consensus by the members of a committee on intractable diseases with support by a Health and Labour Sciences Research Grant. Physicians should provide necessary information on VPDs to their patients with IBD and carefully manage these patients’ IBD if various risk factors for the development or worsening of VPDs are present. This consensus will facilitate informed and shared decision-making in daily IBD clinical practice.

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Non-cystic fibrosis bronchiectasis (NCFB) is a bronchiolectatic disease characterized by MUC5B-dominated mucus hyperproduction

Asakura, T; Okuda, K; Chen, G; Kato, T; Mikami, Y; Gilmore, R; Cardenas, SMB; Chua, M; Masugi, Y; Noone, P; Ribeiro, CMP; Olivier, K; Hasegawa, N; Randell, S; O'Neal, W; Boucher, R

RESPIROLOGY 28 6 - 7 2023.02

ISSN 1323-7799

Disease activity and treatment patterns of newly diagnosed adult patients with Crohn's disease in Japan: Interim analysis of inception cohort registry study of patients with Crohn's disease (iCREST-CD)

Shinzaki, S; Matsuoka, K; Fujii, T; Okamoto, R; Yamada, A; Kunisaki, R; Matsuura, M; Watanabe, K; Shiga, H; Takatsu, N; Bamba, S; Mikami, Y; Yamamoto, T; Shimoyama, T; Motoya, S; Torisu, T; Kobayashi, T; Ohmiya, N; Saruta, M; Matsuda, K; Matsumoto, T; Nakase, H; Maemoto, A; Murata, Y; Yoshigoe, S; Tsuchiya, H; Hisamatsu, T

JOURNAL OF CROHNS & COLITIS 17 905 - 907 2023.02

ISSN 1873-9946

Dose escalation of oral 5-aminosalicylic acid for ulcerative colitis with Mayo endoscopic subscore of one improves long-term prognosis: a one-year multicentre, open-label, randomized controlled trial.

Aoki, Y; Fukuda, T; Kiyohara, H; Yokoyama, A; Nakazawa, A; Yoshimatsu, Y; Sugimoto, S; Nanki, K; Mikami, Y; Fukuhara, K; Mizuno, S; Sujino, T; Mutaguchi, M; Takabayashi, K; Morohoshi, Y; Hosoda, Y; Ogata, H; Iwao, Y; Naganuma, M; Kanai, T

JOURNAL OF CROHNS & COLITIS 17 548 - 548 2023.02

ISSN 1873-9946

Significance of 5-Aminosalicylic Acid Intolerance in the Clinical Management of Ulcerative Colitis

Mikami Y., Tsunoda J., Suzuki S., Mizushima I., Kiyohara H., Kanai T.

Digestion (Digestion) 104 ( 1 ) 58 - 65 2023.01

ISSN 00122823

Background: Two major types of 5-aminosalicylic acid (5-ASA)-containing preparations, namely, mesalazine/5-ASA and sulfasalazine (SASP), are currently used as first-line therapy for ulcerative colitis. Recent reports show that optimization of 5-ASA therapy is beneficial for both patient outcomes and healthcare costs. Although 5-ASA and SASP have good efficacy and safety profiles, clinicians occasionally encounter patients who develop 5-ASA intolerance. Summary: The most common symptoms of acute 5-ASA intolerance syndrome are exacerbation of diarrhea, fever, and abdominal pain. Patients who discontinue 5-ASA therapy because of intolerance have a higher risk of adverse clinical outcomes, such as hospital admission, colectomy, need for advanced therapies, and loss of response to anti-tumor necrosis factor (TNF) biologics. When patients develop symptoms of 5-ASA intolerance, the clinician should consider changing the type of 5-ASA preparation. Recent genome-wide association studies and meta-analyses have shown that 5-ASA allergy is associated with certain single-nucleotide polymorphisms. Although there are no modalities or biomarkers for diagnosing 5-ASA intolerance, the drug-induced lymphocyte stimulation test can be used to assist in the diagnosis of acute 5-ASA intolerance syndrome with high specificity and low sensitivity. This review presents a general overview of 5-ASA and SASP in the treatment of inflammatory bowel disease and discusses the latest insights into 5-ASA intolerance. Key Messages: 5-ASA is used as first-line therapy for ulcerative colitis. Optimization of 5-ASA may be beneficial for patient outcomes and healthcare systems. Acute 5-ASA intolerance syndrome is characterized by diarrhea, fever, and abdominal pain. Periodic renal function monitoring is recommended for patients receiving 5-ASA.

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D-amino Acids Ameliorate Experimental Colitis and Cholangitis by Inhibiting Growth of Proteobacteria: Potential Therapeutic Role in Inflammatory Bowel Disease

Umeda S., Sujino T., Miyamoto K., Yoshimatsu Y., Harada Y., Nishiyama K., Aoto Y., Adachi K., Hayashi N., Amafuji K., Moritoki N., Shibata S., Sasaki N., Mita M., Tanemoto S., Ono K., Mikami Y., Sasabe J., Takabayashi K., Hosoe N., Suzuki T., Sato T., Atarashi K., Teratani T., Ogata H., Nakamoto N., Shiomi D., Ashida H., Kanai T.

Cellular and Molecular Gastroenterology and Hepatology (Cellular and Molecular Gastroenterology and Hepatology) 16 ( 6 ) 1011 - 1031 2023.01

ISSN 2352-345X

Background & Aims: D-amino acids, the chiral counterparts of protein L-amino acids, were primarily produced and utilized by microbes, including those in the human gut. However, little was known about how orally administered or microbe-derived D-amino acids affected the gut microbial community or gut disease progression. Methods: The ratio of D- to L-amino acids was analyzed in feces and blood from patients with ulcerative colitis (UC) and healthy controls. Also, composition of microbe was analyzed from patients with UC. Mice were treated with D-amino acid in dextran sulfate sodium colitis model and liver cholangitis model. Results: The ratio of D- to L-amino acids was lower in the feces of patients with UC than that of healthy controls. Supplementation of D-amino acids ameliorated UC-related experimental colitis and liver cholangitis by inhibiting growth of Proteobacteria. Addition of D-alanine, a major building block for bacterial cell wall formation, to culture medium inhibited expression of the ftsZ gene required for cell fission in the Proteobacteria Escherichia coli and Klebsiella pneumoniae, thereby inhibiting growth. Overexpression of ftsZ restored growth of E. coli even when D-alanine was present. We found that D-alanine not only inhibited invasion of pathological K. pneumoniae into the host via pore formation in intestinal epithelial cells but also inhibited growth of E. coli and generation of antibiotic-resistant strains. Conclusions: D-amino acids might have potential for use in novel therapeutic approaches targeting Proteobacteria-associated dysbiosis and antibiotic-resistant bacterial diseases by means of their effects on the intestinal microbiota community.

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Usefulness of texture and color enhancement imaging in assessing mucosal healing in patients with ulcerative colitis

Hayashi Y., Takabayashi K., Kato M., Tojo A., Aoki Y., Hagihara Y., Yoshida K., Yoshimatsu Y., Kiyohara H., Sugimoto S., Nanki K., Mikami Y., Sujino T., Mutaguchi M., Kawaguchi T., Hosoe N., Yahagi N., Ogata H., Kanai T.

Gastrointestinal Endoscopy (Gastrointestinal Endoscopy) 97 ( 4 ) 759 - 766.e1 2023

ISSN 00165107

Background and aims: Endoscopic remission is known to be defined as a Mayo endoscopic subscore (MES) of ≤1 in patients with ulcerative colitis (UC). However, some individuals experience relapse even after showing endoscopic remission under white-light imaging (WLI), and no tool exists that can detect these individuals. The aim of this study was to clarify the usefulness of texture and color enhancement imaging (TXI) in the assessment of inflammation in patients with UC. Methods: This was a prospective, single-arm, observational study conducted at a university hospital. From January 2021 to December 2021, 146 UC patients with endoscopic remission were enrolled. Images were evaluated by WLI, TXI, and pathologic evaluation, followed by prognostic studies. The primary endpoint of the study was the cumulative relapse of UC in each TXI score. The secondary endpoints were the association between TXI and pathologic scores, predictors of relapse, and interobserver agreement between the MES and TXI scores. Results: Patients with TXI score 2 had significantly lower UC relapse-free rates than did those with TXI scores 0-1 (log-rank test, P <.01). When pathologic remission was defined as Matts grade ≤2, the rate of pathologic remission decreased significantly with higher TXI scores (P =.01). In multivariate analysis, TXI score 2 was the only risk factor for UC relapse (P <.01; hazard ratio, 4.16; 95% confidence interval, 1.72-10.04). Interobserver agreement on the TXI score was good (κ = 0.597-0.823). Conclusion: TXI can be used to identify populations with poor prognosis in MES 1, for whom treatment intensification has been controversial.

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Divergent roles for STAT4 in shaping differentiation of cytotoxic ILC1 and NK cells during gut inflammation

Scarno G., Mazej J., Laffranchi M., Censo C.D., Mattiola I., Candelotti A.M., Pietropaolo G., Stabile H., Fionda C., Peruzzi G., Brooks S.R., Tsai W.L., Mikami Y., Bernardini G., Gismondi A., Sozzani S., Di Santo J.P., Vosshenrich C.A.J., Diefenbach A., Gadina M., Santoni A., Sciumè G.

Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences of the United States of America) 120 ( 40 ) e2306761120 - 1208 2023

ISSN 00278424

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) require signal transducer and activator of transcription 4 (STAT4) to elicit rapid effector responses and protect against pathogens. By combining genetic and transcriptomic approaches, we uncovered divergent roles for STAT4 in regulating effector differentiation of these functionally related cell types. Stat4 deletion in Ncr1-expressing cells led to impaired NK cell terminal differentiation as well as to an unexpected increased generation of cytotoxic ILC1 during intestinal inflammation. Mechanistically, Stat4-deficient ILC1 exhibited upregulation of gene modules regulated by STAT5 in vivo and an aberrant effector differentiation upon in vitro stimulation with IL-2, used as a prototypical STAT5 activator. Moreover, STAT4 expression in NCR+ innate lymphocytes restrained gut inflammation in the dextran sulfate sodium-induced colitis model limiting pathogenic production of IL-13 from adaptive CD4+ T cells in the large intestine. Collectively, our data shed light on shared and distinctive mechanisms of STAT4-regulated transcriptional control in NK cells and ILC1 required for intestinal inflammatory responses.

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Single-cell transcriptomics of human gut T cells identifies cytotoxic CD4+CD8A+ T cells related to mouse CD4 cytotoxic T cells

Tanemoto S., Sujino T., Miyamoto K., Moody J., Yoshimatsu Y., Ando Y., Koya I., Harada Y., Tojo A.O., Ono K., Hayashi Y., Takabayashi K., Okabayashi K., Teratani T., Mikami Y., Nakamoto N., Hosoe N., Ogata H., Hon C.C., Shin J.W., Kanai T.

Frontiers in Immunology (Frontiers in Immunology) 13 977117 2022.10

ISSN 1664-3224

Cytotoxic CD4+ T cells (CD4-CTLs) show the presence of cytolytic granules, which include the enzymes granzyme and perforin. The cells have a pathogenic and protective role in various diseases, including cancer, viral infection, and autoimmune disease. In mice, cytotoxic CD4+ T cells express CD8αα+ and reside in the intestine (mouse CD4+CTLs; mCD4-CTLs). The population of cytotoxic CD4+ T cells in the human intestine is currently unknown. Moreover, it is unclear how cytotoxic CD4 T cells change in patients with inflammatory bowel disease (IBD). Here, we aimed to identify cytotoxic CD4+ T cells in the human intestine and analyze the characteristics of the population in patients with IBD using single-cell RNA-seq (scRNA-seq). In CD4+ T cells, granzyme and perforin expression was high in humanMAIT (hMAIT) cells and hCD4+CD8A+ T cell cluster. Both CD4 and CD8A were expressed in hTreg, hMAIT, and hCD4+CD8A+ T cell clusters. Next we performed fast gene set enrichment analysis to identify cell populations that showed homology to mCD4CTLs. The analysis identified the hCD4+CD8A+ T cell cluster (hCTL-like population; hCD4-CTL) similar to mouse CTLs. The percentage of CD4+CD8A+ T cells among the total CD4+ T cells in the inflamed intestine of the patients with Crohn’s disease was significantly reduced compared with that in the noninflamed intestine of the patients. In summary, we identified cytotoxic CD4+CD8+ T cells in the small intestine of humans. The integration of the mouse and human sc-RNA-seq data analysis highlight an approach to identify human cell populations related to mouse cell populations, which may help determine the functional properties of several human cell populations in mice.

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Enrichment of type I interferon signaling in colonic group 2 innate lymphoid cells in experimental colitis

Irie E., Ishihara R., Mizushima I., Hatai S., Hagihara Y., Takada Y., Tsunoda J., Iwata K., Matsubara Y., Yoshimatsu Y., Kiyohara H., Taniki N., Sujino T., Takabayashi K., Hosoe N., Ogata H., Teratani T., Nakamoto N., Mikami Y., Kanai T.

Frontiers in Immunology (Frontiers in Immunology) 13 982827 2022.10

ISSN 1664-3224

Group 2 innate lymphoid cells (ILC2s) serve as frontline defenses against parasites. However, excluding helminth infections, it is poorly understood how ILC2s function in intestinal inflammation, including inflammatory bowel disease. Here, we analyzed the global gene expression of ILC2s in healthy and colitic conditions and revealed that type I interferon (T1IFN)-stimulated genes were up-regulated in ILC2s in dextran sodium sulfate (DSS)-induced colitis. The enhancement of T1IFN signaling in ILC2s in DSS-induced colitis was correlated with the downregulation of cytokine production by ILC2s, such as interleukin-5. Blocking T1IFN signaling during colitis resulted in exaggeration of colitis in both wild-type and Rag2-deficient mice. The exacerbation of colitis induced by neutralization of T1IFN signaling was accompanied by reduction of amphiregulin (AREG) in ILC2s and was partially rescued by exogenous AREG treatment. Collectively, these findings show the potential roles of T1IFN in ILC2s that contribute to colitis manifestation.

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Severe graft-versus-host disease-like enterocolitis accompanied with cytomegalovirus-reactivation in drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms

Takamiyagi S., Iriki H., Asahina Y., Furuichi Y., Funakoshi T., Ichikawa M., Mikami Y., Okita H., Sakiyama T., Inazumi T., Amagai M., Takahashi H.

Journal of Dermatology (Journal of Dermatology) 49 ( 8 ) 796 - 799 2022.08

ISSN 03852407

Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug adverse reaction with skin eruption and visceral organ involvement. The characteristic clinical features of DIHS/DRESS are reactivation of human herpesviruses (HHV) and the development of autoimmune diseases, but their pathogenesis and associations are not yet understood. Here, we report a 66-year-old man who presented with fever, generalized erythema, diffuse lymphadenopathy, and diarrhea after 3 weeks of treatment with zonisamide. Reactivation of HHV-6 and cytomegalovirus (CMV) was detected during the clinical course. The patient was diagnosed with DIHS/DRESS and treated with systemic prednisolone, i.v. immunoglobulin therapy, and ganciclovir. However, severe enterocolitis persisted for 6 months. A series of examinations revealed features of both CMV enterocolitis, as indicated by identification of a few CMV-positive cells on immunohistochemical analysis, and graft-versus-host disease (GVHD)-like enterocolitis indicated by orange-peel appearance on endoscopic examination and histopathological loss of goblet cells. Intractable enterocolitis continued and the patient finally died of pneumonia. An autoimmune predisposition in DIHS/DRESS patients in combination with CMV reactivation was considered to trigger the severe enterocolitis of this case that showed GVHD-like features of the gastrointestinal tract. GVHD-like organ damage is a pathological condition rarely observed in DIHS/DRESS but should be recognized as one of the most severe complications of the disease.

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Neuroimmune crosstalk in the gut and liver

Teratani Toshiaki, Mikami Yohei, Kanai Takanori

INTERNATIONAL IMMUNOLOGY (International immunology) 34 ( 9 ) 475 - 484 2022.07

ISSN 0953-8178

It has long been assumed that the nervous system exerts distinct effects on immune functions, given the large number of immune disorders that are affected by mental stress. In fact, many different immune cells have been shown to possess a wide variety of neurotransmitter receptors and receive signals from various neurotransmitters, including acetylcholine and noradrenaline. Compared with the findings on local neuroimmune interactions, limited experimental techniques have so far failed to capture a comprehensive overview of neuroimmune interactions between distant organs and the autonomic nervous system in vivo, and the molecular mechanisms underlying local immune regulation of the nervous system have long remained unclear. However, the recent rapid progress in genetic recombination, microscopy and single-cell analysis has deepened our understanding of the anatomical and physiological functions of peripheral nerves at each organ to which they belong. Furthermore, the development of optogenetic and chemogenetic methods has enabled the artificial modulation of specific neuronal activities, and there has been remarkable progress in elucidation of the interaction between nerves and immune cells in vivo, particularly in barrier organs such as the gastrointestinal tract, respiratory tract and skin. This review focuses on the immunoregulatory mechanisms governed by the autonomic nervous system and outlines the latest findings in the regulation of enteric and hepatic immunity by the nervous system.

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Efficacy of Calcineurin Inhibitors for Induction of Remission in Intestinal Behçet's Disease

Kawaguchi T., Fukata M., Omori T., Kiyohara H., Sugimoto S., Nanki K., Sujino T., Mikami Y., Kanai T.

Crohn's and Colitis 360 (Crohn's and Colitis 360) 4 ( 3 ) otac017 2022.07

Background: The efficacy of calcineurin inhibitors (CNIs) for induction of remission in intestinal Behçet's disease (intestinal BD) has not been explored. Methods: A multicenter retrospective case series study of patients with active intestinal BD treated with CNIs (cyclosporin and tacrolimus) was conducted. Results: Of 16 patients, 12 (75%) showed a clinical response and 5 (31.3%) achieved clinical remission after 2 weeks of CNI treatment. Similar efficacy of CNIs was observed even in 7 patients refractory to antitumor necrosis factor-alpha therapies. Endoscopic improvement was observed in 11 of 12 patients. Conclusions: CNIs may be promising treatment options for refractory intestinal BD.

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Heterogeneity of ILC2s in the Intestine; Homeostasis and Pathology

Sunaga S., Tsunoda J., Teratani T., Mikami Y., Kanai T.

Frontiers in Immunology (Frontiers in Immunology) 13 867351 2022.05

ISSN 1664-3224

Group 2 innate lymphoid cells (ILC2s) were identified in 2010 as a novel lymphocyte subset lacking antigen receptors, such as T-cell or B-cell receptors. ILC2s induce local immune responses characterized by producing type 2 cytokines and play essential roles for maintaining tissue homeostasis. ILC2s are distributed across various organs, including the intestine where immune cells are continuously exposed to external antigens. Followed by luminal antigen stimulation, intestinal epithelial cells produce alarmins, such as IL-25, IL-33, and thymic stromal lymphopoietin, and activate ILC2s to expand and produce cytokines. In the context of parasite infection, the tuft cell lining in the epithelium has been revealed as a dominant source of intestinal IL-25 and possesses the capability to regulate ILC2 homeostasis. Neuronal systems also regulate ILC2s through neuropeptides and neurotransmitters, and interact with ILC2s bidirectionally, a process termed “neuro-immune crosstalk”. Activated ILC2s produce type 2 cytokines, which contribute to epithelial barrier function, clearance of luminal antigens and tissue repair, while ILC2s are also involved in chronic inflammation and tissue fibrosis. Recent studies have shed light on the contribution of ILC2s to inflammatory bowel diseases, mainly comprising ulcerative colitis and Crohn’s disease, as defined by chronic immune activation and inflammation. Modern single-cell analysis techniques provide a tissue-specific picture of ILC2s and their roles in regulating homeostasis in each organ. Particularly, single-cell analysis helps our understanding of the uniqueness and commonness of ILC2s across tissues and opens the novel research area of ILC2 heterogeneity. ILC2s are classified into different phenotypes depending on tissue and phase of inflammation, mainly inflammatory and natural ILC2 cells. ILC2s can also switch phenotype to ILC1- or ILC3-like subsets. Hence, recent studies have revealed the heterogeneity and plasticity of ILC2, which indicate dynamicity of inflammation and the immune system. In this review, we describe the regulatory mechanisms, function, and pathological roles of ILC2s in the intestine.

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Aryl hydrocarbon receptor signals in epithelial cells govern the recruitment and location of Helios+ Tregs in the gut

Yoshimatsu Y., Sujino T., Miyamoto K., Harada Y., Tanemoto S., Ono K., Umeda S., Yoshida K., Teratani T., Suzuki T., Mikami Y., Nakamoto N., Sasaki N., Takabayashi K., Hosoe N., Ogata H., Sawada K., Imamura T., Yoshimura A., Kanai T.

Cell Reports (Cell Reports) 39 ( 6 ) 110773 2022.05

ISSN 2211-1247

CD4+Foxp3+ regulatory T cells (Tregs) are essential for homeostasis in the colon, but the mechanism by which local environmental cues determine the localization of colonic Tregs is unclear. Here, we administer indigo naturalis (IN), a nontoxic phytochemical aryl hydrocarbon receptor (AhR) agonist used for treating patients with ulcerative colitis (UC) in Asia, and we show that IN increases Helios+ Tregs and MHC class II+ epithelial cells (ECs) in the colon. Interactions between Tregs and MHC class II+ ECs occur mainly near the crypt bottom in the steady state, whereas Tregs dramatically increase and shift toward the crypt top following IN treatment. Moreover, the number of CD25+ T cells is increased near the surface of ECs in IN-treated UC patients compared with that in patients treated with other therapies. We also highlight additional AhR-signaling mechanisms in intestinal ECs that determine the accumulation and localization of Helios+ Tregs in the colon.

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Intracellular metabolic adaptation of intraepithelial CD4+CD8αα+ T lymphocytes

Harada Y., Sujino T., Miyamoto K., Nomura E., Yoshimatsu Y., Tanemoto S., Umeda S., Ono K., Mikami Y., Nakamoto N., Takabayashi K., Hosoe N., Ogata H., Ikenoue T., Hirao A., Kubota Y., Kanai T.

iScience (iScience) 25 ( 4 ) 104021 2022.04

Intestinal intraepithelial lymphocytes (IELs), the first line of defense against microbial and dietary antigens, are classified as natural or induced based on their origin and receptor expression. Induced CD4+CD8αα+TCRβ+ T cells (double positive, DPIELs) originated from CD4+CD8α−TCRβ+ T cells (single positive, SPIELs) increase with aging. However, the metabolic requirements and the metabolic-related genes in IEL development remain unclear. We determined that the intraepithelial compartment is hypoxic in the presence of microbes and DPIELs increased more than natural IELs in this location. Moreover, DPIELs consumed less oxygen and glucose and exhibited unique alterations in mitochondria. Using inhibitors and genetically modified mice, we revealed that DPIELs adapt to their surrounding oxygen-deprived environment in peripheral tissues by modulating specific genes, including hypoxia-inducible factor, mammalian target of rapamycin complexes (mTORC), phosphorylated ribosomal protein S6 (pS6), and other glycolytic factors. Our findings provide valuable insight into the metabolic properties of IELs.

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Effectiveness and Durability of Ustekinumab Therapy With or Without Immunomodulators for Ulcerative Colitis Patients in Japan

Aoki Y., Sujino T., Kawaguchi T., Sugimoto S., Shimada F., Yoshimatsu Y., Kiyohara H., Nanki K., Mikami Y., Takabayashi K., Hosoe N., Ogata H., Iwao Y., Kanai T.

Crohn's and Colitis 360 (Crohn's and Colitis 360) 4 ( 2 ) otac010 2022.04

Background and Aims: The effectiveness and durability of ustekinumab therapy with or without thiopurine immunomodulators (IMs) for ulcerative colitis (UC) in real-world Asian, Japanese patients have not yet been elucidated. Methods: To evaluate the additive effects of IMs on ustekinumab, a retrospective cohort study of UC patients receiving ustekinumab with or without thiopurine IMs, azathioprine or 6-mercaptopurine, was conducted from March 2020 to August 2021. The primary endpoint was clinical remission or response rate at week 8. The secondary endpoints were clinical remission or response rates at weeks 24 and 52, the durability of each treatment, and adverse events. Results: Of the 50 patients with UC treated with ustekinumab, 42 were enrolled. Sixteen patients were treated with a combination of ustekinumab and an IM. The clinical response rates of all patients at weeks 8, 24, and 52 were 53.7%, 63.3%, and 42.9%, respectively. There was no significant difference in the clinical responses or remission rates between the combination therapy and monotherapy groups at weeks 8, 24, and 52. (50.0% vs. 56.0%, P =. 757; 70.0% vs. 60.0%, P =. 702; and 42.9% vs. 42.9%, P = 1.00, respectively). A Kaplan-Meier analysis showed no difference in IM use on the durability of ustekinumab treatment (log-rank test; P =. 955). Conclusions: The response rate for Japanese UC patients is similar to previous reports based on American and European UC patients. There was no significant difference between the ustekinumab monotherapy group and the ustekinumab and IM combination group in the real world.

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Organ and brain crosstalk: The liver-brain axis in gastrointestinal, liver, and pancreatic diseases

Matsubara Y., Kiyohara H., Teratani T., Mikami Y., Kanai T.

Neuropharmacology (Neuropharmacology) 205 108915 2022.03

ISSN 00283908

The liver is the largest organ in the human body and is responsible for the metabolism and storage of the three principal nutrients: carbohydrates, fats, and proteins. In addition, the liver contributes to the breakdown and excretion of alcohol, medicinal agents, and toxic substances and the production and secretion of bile. In addition to its role as a metabolic centre, the liver has recently attracted attention for its function in the liver-brain axis, which interacts closely with the central nervous system via the autonomic nervous system, including the vagus nerve. The liver-brain axis influences the control of eating behaviour in the central nervous system through stimuli from the liver. Conversely, neural signals from the central nervous system influence glucose, lipid, and protein metabolism in the liver. The liver also receives a constant influx of nutrients and hormones from the intestinal tract and compounds of bacterial origin via the portal system. As a result, the intestinal tract and liver are involved in various immunological interactions. A good example is the co-occurrence of primary sclerosing cholangitis and ulcerative colitis. These heterogeneous roles of the liver-brain axis are mediated via the vagus nerve in an asymmetrical manner. In this review, we provide an overview of these interactions, mainly with the liver but also with the brain and gut.

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Characteristics of adult patients newly diagnosed with Crohn’s disease: interim analysis of the nation-wide inception cohort registry study of patients with Crohn’s disease in Japan (iCREST-CD)

Matsuoka K., Fujii T., Okamoto R., Yamada A., Kunisaki R., Matsuura M., Watanabe K., Shiga H., Takatsu N., Bamba S., Mikami Y., Yamamoto T., Shimoyama T., Motoya S., Torisu T., Kobayashi T., Ohmiya N., Saruta M., Matsuda K., Matsumoto T., Nakase H., Maemoto A., Shinzaki S., Murata Y., Yoshigoe S., Sasaki A., Yajima T., Hisamatsu T.

Journal of Gastroenterology (Journal of Gastroenterology) 57 ( 11 ) 867 - 878 2022

ISSN 09441174

Background: The Inception Cohort Registry Study of Patients with Crohn’s Disease aimed to clarify clinical characteristics and disease course of newly diagnosed Crohn’s disease patients in Japan throughout a 4-year period. Results from an interim analysis of the largest nation-wide registry study that covers approximately 1% of Crohn’s disease patient population in Japan are reported. Methods: This prospective, observational registry study was conducted at 19 tertiary centers in Japan. Patients newly diagnosed with Crohn’s disease after June 2016 (age ≥ 16 years at informed consent) were enrolled between December 17, 2018 and June 30, 2020. Patient demographics, diagnostic procedures and categories, disease location and lesion behavior (Montreal classification) at the time of diagnosis were recorded. Results: Of 673 patients enrolled, 672 (99.9%) were analyzed (458: men, 214: women), male-to-female ratio: 2.1, median age at diagnosis 25 (range 13–86) years; peak age of disease diagnosis: 20–24 years. Most common disease location was L3 (ileocolonic; 60.1%). Non-stricturing, non-penetrating (B1) disease was most common behavior (62.8%); 48.9% reported perianal lesions. Notably, age-wise analysis revealed disease phenotypes varied between patients aged < 40 and ≥ 40 years in terms of male-to-female ratio (2.5/1.3)/disease location (L3: 66.3%/37.0%)/disease behavior (B1: 66.4%/50.0%)/perianal lesion: (55.7%/20.5%) at Crohn’s disease diagnosis, respectively. Conclusions: Interim analysis of this nation-wide Inception Cohort Registry Study of Patients with Crohn’s Disease revealed the demographics and disease characteristics of newly diagnosed Crohn’s disease patients in Japan and demonstrated that disease phenotype varied between patients aged < 40 and ≥ 40 years, serving as important information for management of individual patients.

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Mapping the human genetic architecture of COVID-19

Niemi M.E.K., Karjalainen J., Liao R.G., Neale B.M., Daly M., Ganna A., Pathak G.A., Andrews S.J., Kanai M., Veerapen K., Fernandez-Cadenas I., Schulte E.C., Striano P., Marttila M., Minica C., Marouli E., Karim M.A., Wendt F.R., Savage J., Sloofman L., Butler-Laporte G., Kim H.N., Kanoni S., Okada Y., Byun J., Han Y., Uddin M.J., Smith G.D., Willer C.J., Buxbaum J.D., Mehtonen J., Finucane H., Cordioli M., Martin A.R., Zhou W., Pasaniuc B., Julienne H., Aschard H., Shi H., Yengo L., Polimanti R., Ghoussaini M., Schwartzentruber J., Dunham I., Chwialkowska K., Francescatto M., Trankiem A., Balaconis M.K., Davis L., Lee S., Priest J., Renieri A., Sankaran V.G., van Heel D., Deelen P., Brent Richards J., Nakanishi T., Biesecker L., Eric Kerchberger V., Kenneth Baillie J., Mari F., Bernasconi A., Ceri S., Canakoglu A., Wolford B., Faucon A., Dutta A.K., Schurmann C., Harry E., Birney E., Nguyen H., Nasir J., Kaunisto M., Solomonson M., Dueker N., Vadgama N., Limou S., Rahmouni S., Mbarek H., Darwish D., Uddin M.M., Albertos R., Pérez-Tur J., Li R., Folkersen L., Moltke I., Koelling N., Teumer A., Kousathanas A., Utrilla A., Verdugo R.A., Zárate R., Medina-Gómez C., Gómez-Cabrero D., Carnero-Montoro E., Cadilla C.L., Moreno-Estrada A., Garmendia A., Moya L., Sedaghati-Khayat B.

Nature (Nature) 600 ( 7889 ) 472 - 477 2021.12

ISSN 00280836

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

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CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells

Koda Y., Teratani T., Chu P.S., Hagihara Y., Mikami Y., Harada Y., Tsujikawa H., Miyamoto K., Suzuki T., Taniki N., Sujino T., Sakamoto M., Kanai T., Nakamoto N.

Nature Communications (Nature Communications) 12 ( 1 ) 4474 2021.12

ISSN 2041-1723

Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8+ tissue-resident memory CD8+ T (CD8+ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69+CD103−CD8+ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8+ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8+ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69+CD8+ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8+ Trm in fibrosis resolution.

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Pathogenesis and management of gastrointestinal inflammation and fibrosis: from inflammatory bowel diseases to endoscopic surgery

Iwata K., Mikami Y., Kato M., Yahagi N., Kanai T.

Inflammation and Regeneration (Inflammation and Regeneration) 41 ( 1 ) 21 2021.12

ISSN 1880-9693

Gastrointestinal fibrosis is a state of accumulated biological entropy caused by a dysregulated tissue repair response. Acute or chronic inflammation in the gastrointestinal tract, including inflammatory bowel disease, particularly Crohn’s disease, induces fibrosis and strictures, which often require surgical or endoscopic intervention. Recent technical advances in endoscopic surgical techniques raise the possibility of gastrointestinal stricture after an extended resection. Compared to recent progress in controlling inflammation, our understanding of the pathogenesis of gastrointestinal fibrosis is limited, which requires the development of prevention and treatment strategies. Here, we focus on gastrointestinal fibrosis in Crohn’s disease and post-endoscopic submucosal dissection (ESD) stricture, and we review the relevant literature.

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Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell-mediated inflammation in the skin

Takahashi H., Nomura H., Iriki H., Kubo A., Isami K., Mikami Y., Mukai M., Sasaki T., Yamagami J., Kudoh J., Ito H., Kamata A., Kurebayashi Y., Yoshida H., Yoshimura A., Sun H. W., Suematsu M., O'Shea J. J., Kanno Y., Amagai M.

SCIENCE IMMUNOLOGY 6 ( 64 ) eabb6444 2021.10

ISSN 2470-9468

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MicroRNA-directed pathway discovery elucidates an miR-221/222–mediated regulatory circuit in class switch recombination

Wigton E.J., Mikami Y., McMonigle R.J., Castellanos C.A., Wade-Vallance A.K., Zhou S.K., Kageyama R., Litterman A., Roy S., Kitamura D., Dykhuizen E.C., Allen C.D.C., Hu H., O’Shea J.J., Ansel K.M.

Journal of Experimental Medicine (Journal of Experimental Medicine) 218 ( 11 ) 2021.09

ISSN 00221007

MicroRNAs (miRNAs, miRs) regulate cell fate decisions by post-transcriptionally tuning networks of mRNA targets. We used miRNA-directed pathway discovery to reveal a regulatory circuit that influences Ig class switch recombination (CSR). We developed a system to deplete mature, activated B cells of miRNAs, and performed a rescue screen that identified the miR-221/222 family as a positive regulator of CSR. Endogenous miR-221/222 regulated B cell CSR to IgE and IgG1 in vitro, and miR-221/222–deficient mice exhibited defective IgE production in allergic airway challenge and polyclonal B cell activation models in vivo. We combined comparative Ago2-HITS-CLIP and gene expression analyses to identify mRNAs bound and regulated by miR-221/222 in primary B cells. Interrogation of these putative direct targets uncovered functionally relevant downstream genes. Genetic depletion or pharmacological inhibition of Foxp1 and Arid1a confirmed their roles as key modulators of CSR to IgE and IgG1.

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Epithelium Replacement Contributes to Field Expansion of Squamous Epithelium and Ulcerative Colitis-Associated Neoplasia.

Sugimoto S, Iwao Y, Shimoda M, Takabayashi K, Sato T, Kanai T, Keio IBD Collaborators Contributors., Mutaguchi M, Nanki K, Okabayashi K, Kawaida M, Aoki Y, Yoshimatsu Y, Kiyohara H, Kawaguchi T, Mikami Y, Fukuhara K, Sujino T, Hosoe N, Ogata H, Yahagi N

Gastroenterology 2021.09

ISSN 0016-5085

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Hepatic Adenosine Triphosphate Reduction Through the Short-Chain Fatty Acids–Peroxisome Proliferator-Activated Receptor γ–Uncoupling Protein 2 Axis Alleviates Immune-Mediated Acute Hepatitis in Inulin-Supplemented Mice

Yamaguchi A., Teratani T., Chu P.s., Suzuki T., Taniki N., Mikami Y., Shiba S., Morikawa R., Amiya T., Aoki R., Kanai T., Nakamoto N.

Hepatology Communications (Hepatology Communications) 5 ( 9 ) 1555 - 1570 2021.09

How liver tolerance is disrupted in immune-mediated liver injury is currently unclear. There is also insufficient information available regarding susceptibility, precipitation, escalation, and perpetuation of autoimmune hepatitis. To explore how dietary fiber influences hepatic damage, we applied the concanavalin A (ConA)-induced acute immune-mediated liver injury model in mice fed a diet supplemented with 6.8% inulin, a water-soluble fermentable fiber. Twelve hours after ConA administration, inulin-supplemented diet-fed mice demonstrated significantly alleviated hepatic damage histologically and serologically, with down-regulation of hepatic interferon-γ and tumor necrosis factor and reduced myeloperoxidase (MPO)-producing neutrophil infiltration. Preconditioning with an inulin-supplemented diet for 2 weeks significantly reduced hepatic adenosine triphosphate (ATP) content; suramin, a purinergic P2 receptor antagonist, abolished the protective effect. Of note, the portal plasma derived from mice fed the inulin-supplemented diet significantly alleviated ConA-induced immune-mediated liver injury. Mechanistically, increased portal short-chain fatty acid (SCFA) levels, such as those of acetate and butyrate, by inulin supplementation leads to up-regulation of hepatic γ-type peroxisome proliferator-activated receptor (Pparg) and uncoupling protein 2 (Ucp2), which uncouples mitochondrial ATP synthesis downstream of PPARγ. Pparg down-regulating small interfering RNA cancelled the protective effect of inulin supplementation against MPO-producing neutrophil infiltration and the subsequent immune-mediated liver injury, suggesting that the SCFA–PPARγ–UCP2 axis plays a key role in the protective effect by inulin supplementation. Moreover, significant changes in the gut microbiota, including increased operational taxonomic units in genera Akkermansia and Allobaculum, also characterized the protective effect of the inulin-supplemented diet. Conclusion: There is a possible unraveled etiopathophysiological link between the maintenance of liver tolerance and dietary fiber. The SCFA–PPARγ–UCP2 axis may provide therapeutic targets for immune-mediated liver injury in the future.

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Circadian rhythms in the tissue-specificity from metabolism to immunity: insights from omics studies

Kinouchi K., Mikami Y., Kanai T., Itoh H.

Molecular Aspects of Medicine (Molecular Aspects of Medicine) 80 100984 2021.08

ISSN 00982997

Creatures on earth have the capacity to preserve homeostasis in response to changing environments. The circadian clock enables organisms to adapt to daily predictable rhythms in surrounding conditions. In mammals, circadian clocks constitute hierarchical network, where the central pacemaker in hypothalamic suprachiasmatic nucleus (SCN) serves as a time-keeping machinery and governs peripheral clocks in every other organ through descending neural and humoral factors. The central clock in SCN is reset by light, whilst peripheral clocks are entrained by feeding-fasting rhythms, emphasizing the point that temporal patterns of nutrient availability specifies peripheral clock functions. Indeed, emerging evidence revealed various types of diets or timing of food intake reprogram circadian rhythms in a tissue specific manner. This advancement in understanding of mechanisms underlying tissue specific responsiveness of circadian oscillators to nutrients at the genomic and epigenomic levels is largely owing to employment of state-of-the-art technologies. Specifically, high-throughput transcriptome, proteome, and metabolome have provided insights into how genes, proteins, and metabolites behave over circadian cycles in a given tissue under a certain dietary condition in an unbiased fashion. Additionally, combinations with specialized types of sequencing such as nascent-seq and ribosomal profiling allow us to dissect how circadian rhythms are generated or obliterated at each step of gene regulation. Importantly, chromatin immunoprecipitation followed by deep sequencing methods provide chromatin landscape in terms of regulatory mechanisms of circadian gene expression. In this review, we outline recent discoveries on temporal genomic and epigenomic regulation of circadian rhythms, discussing entrainment of the circadian rhythms by feeding as a fundamental new comprehension of metabolism and immune response, and as a potential therapeutic strategy of metabolic and inflammatory diseases.

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Vagus nerve-mediated intestinal immune regulation: therapeutic implications for inflammatory bowel diseases.

Mikami Y, Tsunoda J, Kiyohara H, Taniki N, Teratani T, Kanai T

International immunology (International Immunology) 34 ( 2 ) 97 - 106 2021.07

ISSN 0953-8178

The pathophysiology of inflammatory bowel diseases (IBDs) involves immunological, genetic and environmental factors. Through its ability to sense environmental stimuli, the autonomic nervous system plays a key role in the development and persistence of IBDs. The vagus nerve (VN), which contains sensory and motor neurons, travels throughout the body to innervate the gut and other visceral organs in the thoracic and abdominopelvic cavities. Recent studies show that the VN has anti-inflammatory effects via the release of acetylcholine, in what is known as the cholinergic anti-inflammatory pathway (CAIP). In the gut immune system, the CAIP is proposed to be activated directly by signals from the gut and indirectly by signals from the liver, which receives gut-derived bioactive substances via the portal vein and senses the status of the gut. The gut-brain axis and liver-brain-gut reflex arc regulate a wide variety of peripheral immune cells to maintain homeostasis in the gut. Therefore, targeting the neural reflex by methods such as VN stimulation is now under investigation for suppressing intestinal inflammation associated with IBDs. In this review, we describe the role of the VN in the regulation of intestinal immunity, and we discuss novel therapeutic approaches for IBDs that target neuroimmune interactions.

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Clinical characteristics of newly diagnosed adult patients with Crohn's disease in Japan: Interim analysis of Inception cohort registry study of patients with Crohn's disease (iCREST-CD)

Matsuoka K., Fijii T., Okamoto R., Yamada A., Kunisaki R., Matsuura M., Watanabe K., Shiga H., Takatsu N., Bamba S., Mikami Y., Yamamoto T., Shimoyama T., Motoya S., Torisu T., Kobayashi T., Ohmiya N., Saruta M., Matsuda K., Matsumoto T., Nakase H., Maemoto A., Shinzaki S., Murata Y., Yoshigoe S., Sasaki A., Yajima T., Hisamatsu T.

JOURNAL OF CROHNS & COLITIS 15 S246 - S247 2021.05

ISSN 1873-9946

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MicroRNA-221 and -222 modulate intestinal inflammatory Th17 cell response as negative feedback regulators downstream of interleukin-23

Mikami Y., Philips R.L., Sciumè G., Petermann F., Meylan F., Nagashima H., Yao C., Davis F.P., Brooks S.R., Sun H.W., Takahashi H., Poholek A.C., Shih H.Y., Afzali B., Muljo S.A., Hafner M., Kanno Y., O'Shea J.J.

Immunity (Immunity) 54 ( 3 ) 514 - 525.e6 2021.03

ISSN 10747613

MicroRNAs are important regulators of immune responses. Here, we show miR-221 and miR-222 modulate the intestinal Th17 cell response. Expression of miR-221 and miR-222 was induced by proinflammatory cytokines and repressed by the cytokine TGF-β. Molecular targets of miR-221 and miR-222 included Maf and Il23r, and loss of miR-221 and miR-222 expression shifted the transcriptomic spectrum of intestinal Th17 cells to a proinflammatory signature. Although the loss of miR-221 and miR-222 was tolerated for maintaining intestinal Th17 cell homeostasis in healthy mice, Th17 cells lacking miR-221 and miR-222 expanded more efficiently in response to IL-23. Both global and T cell-specific deletion of miR-221 and miR-222 rendered mice prone to mucosal barrier damage. Collectively, these findings demonstrate that miR-221 and miR-222 are an integral part of intestinal Th17 cell response that are induced after IL-23 stimulation to constrain the magnitude of proinflammatory response.

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Bacteriotherapy for inflammatory bowel disease.

Yoshimatsu Y, Mikami Y, Kanai T

Inflammation and regeneration (Inflammation and Regeneration) 41 ( 1 ) 3 2021.01

ISSN 1880-9693

The number of patients with inflammatory bowel disease is rapidly increasing in developed countries. The main cause of this increase is thought not to be genetic, but secondary to rapidly modernized environmental change. Changes in the environment have been detrimental to enteric probiotics useful for fermentation, inducing an increase in pathobionts that survive by means other than fermentation. This dysregulated microbiota composition, the so-called dysbiosis, is believed to have increased the incidence of inflammatory bowel disease. Bacteriotherapy, a treatment that prophylactically and therapeutically corrects the composition of disturbed intestinal microbiota, is a promising recent development. In fact, fecal microbiome transplantation for recurrent Clostridioides difficile infection in 2013 was a significant contribution for bacteriotherapy. In this paper, we comprehensively review bacteriotherapy in an easy-to-understand format.

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Granzyme A and CD160 expression delineates ILC1 with graded functions in the mouse liver

Di Censo C., Marotel M., Mattiola I., Müller L., Scarno G., Pietropaolo G., Peruzzi G., Laffranchi M., Mazej J., Hasim M.S., Asif S., Russo E., Tomaipitinca L., Stabile H., Lee S.H., Vian L., Gadina M., Gismondi A., Shih H.Y., Mikami Y., Capuano C., Bernardini G., Bonelli M., Sozzani S., Diefenbach A., Ardolino M., Santoni A., Sciumè G.

European Journal of Immunology (European Journal of Immunology) 51 ( 11 ) 200 - 200 2021

ISSN 00142980

Type 1 innate lymphoid cells (ILC1) are tissue-resident lymphocytes that provide early protection against bacterial and viral infections. Discrete transcriptional states of ILC1 have been identified in homeostatic and pathological contexts. However, whether these states delineate ILC1 with different functional properties is not completely understood. Here, we show that liver ILC1 are heterogeneous for the expression of distinct effector molecules and surface receptors, including granzyme A (GzmA) and CD160, in mice. ILC1 expressing high levels of GzmA are enriched in the liver of adult mice, and represent the main hepatic ILC1 population at birth. However, the heterogeneity of GzmA and CD160 expression in hepatic ILC1 begins perinatally and increases with age. GzmA+ ILC1 differ from NK cells for the limited homeostatic requirements of JAK/STAT signals and the transcription factor Nfil3. Moreover, by employing Rorc(γt)-fate map (fm) reporter mice, we established that ILC3-ILC1 plasticity contributes to delineate the heterogeneity of liver ILC1, with RORγt-fm+ cells skewed toward a GzmA–CD160+ phenotype. Finally, we showed that ILC1 defined by the expression of GzmA and CD160 are characterized by graded cytotoxic potential and ability to produce IFN-γ. In conclusion, our findings help deconvoluting ILC1 heterogeneity and provide evidence for functional diversification of liver ILC1.

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Predictors of necessity for endoscopic balloon dilatation in patients with Crohn’s disease-related small bowel stenosis

Hayashi Y., Takabayashi K., Hosoe N., Kiyohara H., Kinoshita S., Nanki K., Fukuhara K., Mikami Y., Sujino T., Mutaguchi M., Kawaguchi T., Kato M., Ogata H., Kanai T.

Annals of Medicine (Annals of Medicine) 53 ( 1 ) 2025 - 2033 2021

ISSN 07853890

Background and Aim: In patients with Crohn’s disease (CD) and small bowel stenosis, endoscopic balloon dilation (EBD) is considered to be useful in improving stenotic symptoms and avoiding surgery. However, it carries risks such as bleeding and perforation. The aim of this study was to identify the indications for endoscopic intervention in patients with CD and small bowel stenosis. Methods: From November 2007 to March 2020, 143 CD patients with small bowel stenosis were enrolled in this study. We identified the factors associated with not requiring endoscopic intervention during long-term follow-up of these patients. Results: Forty of the 143 patients had abdominal symptoms of stenosis and had undergone EBD, whereas the remaining 103 were asymptomatic and had not undergone endoscopic intervention. During long-term follow-up, 95 of those 103 patients never required endoscopic or surgical intervention. Multivariate logistic regression analysis revealed that not consuming an elemental diet (OR 3.18, 95% CI 1.48–6.82; p <.01) and ileocecal valve (ICV) stenosis (OR 0.30, 95% CI 0.11–0.83; p =.02) were independently associated with not requiring EBD. The cumulative emergency hospitalisation-free rate also tended to be higher in patients not consuming an elemental diet or with ICV stenosis. Conclusions: Two factors, namely not consuming an elemental diet and ICV stenosis, predict a long-term intervention-free prognosis in CD patients with small bowel stenosis.Key messages When an endoscopically impassable small bowel stenosis is found in a CD patient, long-term follow-up without endoscopic intervention may be possible if the patient is asymptomatic, is not using an elemental diet, and the stenosis is ICV.

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Environmental arginine controls multinuclear giant cell metabolism and formation

Brunner J.S., Vulliard L., Hofmann M., Kieler M., Lercher A., Vogel A., Russier M., Brüggenthies J.B., Kerndl M., Saferding V., Niederreiter B., Junza A., Frauenstein A., Scholtysek C., Mikami Y., Klavins K., Krönke G., Bergthaler A., O’Shea J.J., Weichhart T., Meissner F., Smolen J.S., Cheng P., Yanes O., Menche J., Murray P.J., Sharif O., Blüml S., Schabbauer G.

Nature Communications (Nature Communications) 11 ( 1 ) 431 2020.12

ISSN 2041-1723

© 2020, The Author(s). Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. MGC generation is energy intensive to enforce membrane fusion and cytoplasmic expansion. Using receptor activator of nuclear factor kappa-Β ligand (RANKL) induced osteoclastogenesis to model MGC formation, here we report RANKL cellular programming requires extracellular arginine. Systemic arginine restriction improves outcome in multiple murine arthritis models and its removal induces preosteoclast metabolic quiescence, associated with impaired tricarboxylic acid (TCA) cycle function and metabolite induction. Effects of arginine deprivation on osteoclastogenesis are independent of mTORC1 activity or global transcriptional and translational inhibition. Arginine scarcity also dampens generation of IL-4 induced MGCs. Strikingly, in extracellular arginine absence, both cell types display flexibility as their formation can be restored with select arginine precursors. These data establish how environmental amino acids control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodelling.

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Rapid Enhancer Remodeling and Transcription Factor Repurposing Enable High Magnitude Gene Induction upon Acute Activation of NK Cells

Sciumè G., Mikami Y., Jankovic D., Nagashima H., Villarino A.V., Morrison T., Yao C., Signorella S., Sun H.W., Brooks S.R., Fang D., Sartorelli V., Nakayamada S., Hirahara K., Zitti B., Davis F.P., Kanno Y., O'Shea J.J., Shih H.Y.

Immunity (Immunity) 53 ( 4 ) 745 - 758.e4 2020.10

ISSN 10747613

© 2020 Innate immune responses rely on rapid and precise gene regulation mediated by accessibility of regulatory regions to transcription factors (TFs). In natural killer (NK) cells and other innate lymphoid cells, competent enhancers are primed during lineage acquisition, and formation of de novo enhancers characterizes the acquisition of innate memory in activated NK cells and macrophages. Here, we investigated how primed and de novo enhancers coordinate to facilitate high-magnitude gene induction during acute activation. Epigenomic and transcriptomic analyses of regions near highly induced genes (HIGs) in NK cells both in vitro and in a model of Toxoplasma gondii infection revealed de novo chromatin accessibility and enhancer remodeling controlled by signal-regulated TFs STATs. Acute NK cell activation redeployed the lineage-determining TF T-bet to de novo enhancers, independent of DNA-sequence-specific motif recognition. Thus, acute stimulation reshapes enhancer function through the combinatorial usage and repurposing of both lineage-determining and signal-regulated TFs to ensure an effective response.

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Efficacy of novel ultrathin single-balloon enteroscopy for Crohn's disease: A propensity score-matched study

Takabayashi K., Hosoe N., Kato M., Hayashi Y., Miyanaga R., Nanki K., Fukuhara K., Mikami Y., Mizuno S., Sujino T., Mutaguchi M., Naganuma M., Yahagi N., Ogata H., Kanai T.

Gut and Liver (Gut and Liver) 14 ( 5 ) 619 - 625 2020.09

ISSN 19762283

© 2020 Editorial Office of Gut and Liver. All rights reserved. Background/Aims: The evaluation of small bowel lesions of Crohn's disease (CD) using balloon-assisted enteroscopy (BAE) is crucial because mucosal healing is associated with a good prognosis. However, BAE procedures are invasive, requiring sedation or analgesia to reduce the patient's pain. This study evaluated the clinical usefulness of a novel ultrathin single-balloon enteroscopy (SBE) procedure for CD. Methods: This single-center retrospective study included 102 CD patients who underwent trans-anal SBE between January 2012 and May 2018. Of these patients, 82 underwent enteroscopy using conventional SBE, while 20 underwent ultrathin SBE. Patients were analyzed using propensity score matching, with 20 patients per group. The median duration of the examination, terminal ileum intubation rate, median cecum intubation time, median insertion depth, adverse events, and sedated dose in each group were compared. Results: Before propensity score matching, the conventional SBE group had a larger number of surgical history patients than the ultrathin SBE group (p=0.05). After matching, the two groups did not significantly differ clinically. There were no significant differences in the mean duration of the examination, cecum intubation time, or terminal ileal intubation rate between ultrathin SBE and conventional SBE. The mean insertion depth of ultrathin SBE tended to be deeper than that of conventional SBE (p=0.09). The use of ultrathin SBE also reduced the sedative dose during needed for enteroscopy compared with conventional SBE (p=0.005). Conclusions: Novel ultrathin SBE may be less painful for CD patients than conventional SBE.

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Plasmacytoid dendrtic cells protect against acute liver injury via IL-35

Koda Yuzo, Nakamoto Nobuhiro, Chu Po-Sung, Yoshida Aya, Mikami Yohei, Teratani Toshiaki, Kanai Takanori

JOURNAL OF HEPATOLOGY 73 S565 - S566 2020.08

ISSN 0168-8278

Clinical and endoscopic characteristics of pyogenic granuloma in the small intestine: A case series with literature review

Hayashi Y., Dr N.H., Takabayashi K., Limpias Kamiya K.J.L., Mutaguchi M., Miyanaga R., Hirata K., Fukuhara S., Mikami Y., Sujino T., Masugi Y., Naganuma M., Ogata H., Kanai T.

Internal Medicine (Internal Medicine) 59 ( 4 ) 501 - 505 2020.02

ISSN 09182918

© 2020 Japanese Society of Internal Medicine. All rights reserved. Pyogenic granuloma (PG) generally appears in the skin or oral cavity, but rarely occurs in the small intestine, where it can cause bleeding. To date, only 35 cases of small intestinal PG have been reported in the English literature. We retrospectively collected information from the clinical records of seven cases of small intestinal PG that were managed in our hospital and summarized the characteristics. Further information on the clinical characteristics was obtained from the literature. Capsule endoscopy, useful for identifying the source of hemorrhage in obscure gastrointestinal bleeding, can detect PGs. Treatment can often be accomplished with endoscopic mucosal resection.

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5-Aminosalicylic acid intolerance is associated with a risk of adverse clinical outcomes and dysbiosis in patients with ulcerative colitis

Mizuno S., Ono K., Mikami Y., Naganuma M., Fukuda T., Minami K., Masaoka T., Terada S., Yoshida T., Saigusa K., Hirahara N., Miyata H., Suda W., Hattori M., Kanai T.

Intestinal Research (Intestinal Research) 18 ( 1 ) 69 - 78 2020.01

ISSN 15989100

© 2020. Korean Association for the Study of Intestinal Diseases. Background/Aims: 5-Aminosalicylic acid (ASA) causes intolerance reactions in some patients. This study was performed to examine the prognosis of patients with ulcerative colitis (UC) and 5-ASA intolerance, and to evaluate the potential interaction between 5-ASA intolerance and the intestinal microbiota. Methods: We performed a retrospective cohort study of patients with UC who visited participating hospitals. The primary endpoint was to compare the incidence of hospitalization within 12 months between the 5-ASA intolerance group and the 5-ASA tolerance group. The secondary endpoint was to compare the risk of adverse clinical outcomes after the start of biologics between the 2 groups. We also assessed the correlation between 5-ASA intolerance and microbial change in an independently recruited cohort of patients with UC. Results: Of 793 patients, 59 (7.4%) were assigned to the 5-ASA intolerance group and 734 (92.5%) were assigned to the 5-ASA tolerance group. The admission rate and incidence of corticosteroid use were significantly higher in the intolerance than tolerance group (P<0.001). In 108 patients undergoing treatment with anti-tumor necrosis factor biologics, 5-ASA intolerance increased the incidence of additional induction therapy after starting biologics (P<0.001). The 5-ASA intolerance group had a greater abundance of bacteria in the genera Faecalibacterium, Streptococcus, and Clostridium than the 5-ASA tolerance group (P<0.05). Conclusions: In patients with UC, 5-ASA intolerance is associated with a risk of adverse clinical outcomes and dysbiosis. Bacterial therapeutic optimization of 5-ASA administration may be important for improving the prognosis of patients with UC.

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Complete endoscopic remission is not only associated with higher mucosal concentrations of 5-aminosalicylic acid but also with N-acetyl-5-aminosalicylic acid in patients with ulcerative colitis

Fukuda T., Naganuma M., Takabayashi K., Hagihara Y., Tanemoto S., Nomura E., Yoshimatsu Y., Sugimoto S., Nanki K., Mizuno S., Mikami Y., Fukuhara K., Suzino T., Mutaguchi M., Inoue N., Ogata H., Iwao Y., Kanai T.

JOURNAL OF CROHNS & COLITIS 14 S522 - S523 2020.01

ISSN 1873-9946

Mucosal concentrations of N-acetyl-5-aminosalicylic acid related to endoscopic activity in ulcerative colitis patients with mesalamine

Fukuda T., Naganuma M., Takabayashi K., Hagihara Y., Tanemoto S., Nomura E., Yoshimatsu Y., Sugimoto S., Nanki K., Mizuno S., Mikami Y., Fukuhara K., Sujino T., Mutaguchi M., Inoue N., Ogata H., Iwao Y., Abe T., Kanai T.

Journal of Gastroenterology and Hepatology (Australia) (Journal of Gastroenterology and Hepatology (Australia)) 35 ( 11 ) 1878 - 1885 2020

ISSN 08159319

© 2020 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd Background and Aim: 5-Aminosalicylic acid (5-ASA) is a fundamental treatment for mild-to-moderate ulcerative colitis (UC). 5-ASA is taken up into the colonic mucosa and metabolized to N-acetyl-5-ASA (Ac-5-ASA). Few studies have assessed whether mucosal 5-ASA and Ac-5-ASA concentrations are associated with endoscopic remission. This study aimed to investigate differences in 5-ASA and Ac-5-ASA concentrations according to endoscopic activity. Methods: This single-center, prospective, cross-sectional study was conducted between March 2018 and February 2019. UC patients who were administered with 5-ASA medication for at least 8 weeks before sigmoidoscopy were enrolled. Mucosal 5-ASA and Ac-5-ASA concentrations were measured using liquid chromatography with tandem mass spectrometry. The primary endpoint was defined as the difference in mucosal concentrations of 5-ASA and Ac-5-ASA, according to the Mayo endoscopic subscore (MES). Results: Mucosal concentrations were analyzed in 50 patients. In the sigmoid colon, the median 5-ASA concentration in patients with MES of 0 (17.3 ng/mg) was significantly higher than MES ≥ 1 (6.4 ng/mg) (P = 0.019). The median 5-ASA concentrations in patients with Ulcerative Colitis Endoscopic Index of Severity ≤ 1 (16.4 ng/mg) were also significantly higher than in patients with Ulcerative Colitis Endoscopic Index of Severity ≥ 2 (4.63 ng/mg) (P = 0.047). In the sigmoid colon, the concentration of Ac-5-ASA was higher in patients with MES of 0 (21.2 ng/mg) than in patients with MES ≥ 1 (5.81 ng/mg) (P = 0.022). Conclusions: The present study showed that mucosal Ac-5-ASA concentrations, as well as 5-ASA concentrations, are higher in UC patients with endoscopic remission. Ac-5-ASA may be useful for a biomarker of 5-ASA efficacy.

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The liver–brain–gut neural arc maintains the T<inf>reg</inf> cell niche in the gut

Teratani T., Mikami Y., Nakamoto N., Suzuki T., Harada Y., Okabayashi K., Hagihara Y., Taniki N., Kohno K., Sibata S., Miyamoto K., Ishigame H., Chu P.S., Sujino T., Suda W., Hattori M., Matsui M., Okada T., Okano H., Inoue M., Yada T., Kitagawa Y., Yoshimura A., Tanida M., Tsuda M., Iwasaki Y., Kanai T.

Nature (Nature) 585 ( 7826 ) 591 - 596 2020

ISSN 00280836

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. The gut–brain axis, a reciprocal interaction between the central nervous system (CNS) and peripheral intestinal functions, is conceptually feasible from recent clinical and experimental evidence showing mutual interactions between the CNS and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel diseases (IBDs) and CNS disorders1–4. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including induction and maintenance of peripheral regulatory T cells (pTreg cells) and what environmental cues prompt the host to protect host from development of IBDs. Here, we report a novel liver-brain-gut neural arc that ensures proper differentiation and maintenance of pTreg cells in the gut. The hepatic vagal sensory afferents were responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level significantly impaired colonic pTreg cells, which was attributed to impairment of aldehyde dehydrogenase (ALDH) expression and retinoic acid (RA) synthesis by intestinal antigen-presenting cells (APCs). Muscarinic Ach receptor (mAChR) activation directly induced ALDH gene expression both in human and mouse colonic APCs, whereas genetic ablation of mAChRs abolished APC excitement in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in colitis models reduced the colonic pTreg pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver–brain–gut reflex arc tunes the number of pTreg cells and maintains the gut homeostasis. Intervening in this autonomic feedback feed-forward system could help develop new therapeutic strategies to treat or prevent immunological disorders of the gut.

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Significance of endoscopic deep small bowel evaluation using balloon-assisted enteroscopy for Crohn’s disease in clinical remission

Takabayashi K., Hosoe N., Kato M., Hayashi Y., Nanki K., Fukuhara K., Mikami Y., Mizuno S., Sujino T., Mutaguchi M., Naganuma M., Yahagi N., Ogata H., Kanai T.

Journal of Gastroenterology (Journal of Gastroenterology) 56 ( 1 ) 25 - 33 2020

ISSN 09441174

© 2020, Japanese Society of Gastroenterology. Background: Small bowel lesions of Crohn’s disease (CD) are known to be associated with a poor prognosis; however, endoscopic healing leads to favorable patients’ outcome. The aim of this study was to clarify the clinical impact of assessing deep small bowel lesions (DSB) using balloon-assisted enteroscopy (BAE) on CD patients in clinical remission. Methods: From January 2012 to July 2018, a total of 100 CD patients in clinical remission were enrolled to undergo trans-anal enteroscopy using single-balloon enteroscope. Endoscopic evaluations at the terminal ileum (TI) were performed using a partial Simple Endoscopic Score for CD (pSES-CD). Endoscopic evaluations at the DSB used a modified partial SES-CD (mpSES-CD). We evaluated the factors associated with relapse, and the correlation of endoscopic score between the TI and DSB. For this study, relapse was defined as hospitalization within a year from enteroscopy. Results: 30 patients (30.0%) relapsed within a year from enteroscopy. Multivariate logistic regression analysis revealed that the Harvey–Bradshaw Index (OR 1.77, 95% CI 1.18–2.65; p = 0.003) and an mpSES-CD at DSB (OR 3.10, 95% CI 1.86–5.15; p = 0.001) were independent predictors for relapse, whereas a SES-CD at the TI did not exhibit independence. There was a significant correlation trend between the relapse rate and greater than 5 points of an mpSES-CD at DSB; however, there was no correlation between the relapse rate and pSES-CD at the TI. Conclusion: Even when Crohn's disease is in remission, it is important to evaluate DSB using BAE to assess endoscopic mucosal healing.

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Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation

Nagashima H., Mahlakõiv T., Shih H., Davis F., Meylan F., Huang Y., Harrison O., Yao C., Mikami Y., Urban J., Caron K., Belkaid Y., Kanno Y., Artis D., O'Shea J.

Immunity (Immunity) 51 ( 4 ) 682 - 695.e6 2019.10

ISSN 10747613

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Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35

Koda Y., Nakamoto N., Chu P., Ugamura A., Mikami Y., Teratani T., Tsujikawa H., Shiba S., Taniki N., Sujino T., Miyamoto K., Suzuki T., Yamaguchi A., Morikawa R., Sato K., Sakamoto M., Yoshimoto T., Kanai T.

Journal of Clinical Investigation (Journal of Clinical Investigation) 129 ( 8 ) 3201 - 3213 2019.08

ISSN 00219738

© 2019, American Society for Clinical Investigation. Acute liver failure (ALF) is a life-threatening condition, and liver transplantation is the only therapeutic option. Although immune dysregulation is central to its pathogenesis, the precise mechanism remains unclear. Here, we show that the number of peripheral and hepatic plasmacytoid DCs (pDCs) decrease during acute liver injury in both humans and mice. Selective depletion of pDCs in Siglechdtr/+ mice exacerbated concanavalin A–induced acute liver injury. In contrast, adoptively transferred BM-derived pDCs preferentially accumulated in the inflamed liver and protected against liver injury. This protective effect was independent of TLR7 and TLR9 signaling, since a similar effect occurred following transfer of MyD88-deficient pDCs. Alternatively, we found an unexpected immunosuppressive role of pDCs in an IL-35–dependent manner. Both Il12a and Ebi3, heterodimeric components of IL-35, were highly expressed in transferred pDCs and CD4+CD25+ Tregs. However, the protective effect of pDC transfer was completely lost in mice depleted of Tregs by anti-CD25 antibody. Moreover, pDCs derived from IL-35–deficient mice had less of a protective effect both in vivo and in vitro even in the presence of Tregs. These results highlight a unique aspect of pDCs in association with Tregs, serving as a guide for immunotherapeutic options in ALF.

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CLINICAL UTILITY OF BALLOON ASSISTED ENTEROSCOPY TO EVALUATE DEEP SMALL BOWEL LESIONS OF CROHN'S DISEASE

Takabayashi Kaoru, Hosoe Naoki, Kato Motohiko, Hayashi Yukie, Miyanaga Ryoichi, Sugimoto Shinya, Nanki Kosaku, Kimura Kayoko, Mikami Yohei, Mizuno Shinta, Mutaguchi Makoto, Sujino Tomohisa, Naganuma Makoto, Ogata Haruhiko, Kanai Takanori

GASTROINTESTINAL ENDOSCOPY 89 ( 6 ) AB363 - AB363 2019.06

ISSN 0016-5107

Retinoic Acid Receptor Alpha Represses a Th9 Transcriptional and Epigenomic Program to Reduce Allergic Pathology

Schwartz D., Farley T., Richoz N., Yao C., Shih H., Petermann F., Zhang Y., Sun H., Hayes E., Mikami Y., Jiang K., Davis F., Kanno Y., Milner J., Siegel R., Laurence A., Meylan F., O'Shea J.

Immunity (Immunity) 50 ( 1 ) 106 - 120.e10 2019.01

ISSN 10747613

© 2018 CD4+ T helper (Th) differentiation is regulated by diverse inputs, including the vitamin A metabolite retinoic acid (RA). RA acts through its receptor RARα to repress transcription of inflammatory cytokines, but is also essential for Th-mediated immunity, indicating complex effects of RA on Th specification and the outcome of the immune response. We examined the impact of RA on the genome-wide transcriptional response during Th differentiation to multiple subsets. RA effects were subset-selective and were most significant in Th9 cells. RA globally antagonized Th9-promoting transcription factors and inhibited Th9 differentiation. RA directly targeted the extended Il9 locus and broadly modified the Th9 epigenome through RARα. RA-RARα activity limited murine Th9-associated pulmonary inflammation, and human allergic inflammation was associated with reduced expression of RA target genes. Thus, repression of the Th9 program is a major function of RA-RARα signaling in Th differentiation, arguing for a role for RA in interleukin 9 (IL-9) related diseases.

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Toll-Like Receptor 7 Agonist–Induced Dermatitis Causes Severe Dextran Sulfate Sodium Colitis by Altering the Gut Microbiome and Immune Cells

Kiyohara H., Sujino T., Teratani T., Miyamoto K., Arai M., Nomura E., Harada Y., Aoki R., Koda Y., Mikami Y., Mizuno S., Naganuma M., Hisamatsu T., Kanai T.

Cellular and Molecular Gastroenterology and Hepatology (Cellular and Molecular Gastroenterology and Hepatology) 7 ( 1 ) 135 - 156 2019

ISSN 2352-345X

© 2018 The Authors Background & Aims: Psoriasis and inflammatory bowel disease (IBD) are both chronic inflammatory diseases occurring in the skin and gut, respectively. It is well established that psoriasis and IBD have high concordance rates, and similar changes in immune cells and microbiome composition have been reported in both conditions. To study this connection, we used a combination murine model of psoriatic dermatitis and colitis in which mice were treated topically with the Toll-like receptor 7 agonist imiquimod (IMQ) and fed dextran sulfate sodium (DSS). Methods: We applied IMQ topically to B6 mice (IMQ mice) and subsequently fed them 2% DSS in their drinking water. Disease activity and immune cell phenotypes were analyzed, and the microbial composition of fecal samples was investigated using 16S ribosomal RNA sequencing. We transplanted feces from IMQ mice to germ-free IQI/Jic (IQI) mice and fed them DSS to assess the effect of the gut microbiome on disease. Results: We first confirmed that IMQ mice showed accelerated DSS colitis. IMQ mice had decreased numbers of IgD + and IgM + B cells and increased numbers of non–cytokine-producing macrophages in the gut. Moreover, the gut microbiomes of IMQ mice were perturbed, with significant reductions of Lactobacillus johnsonii and Lactobacillus reuteri populations. Germ-free mice transplanted with feces from IMQ mice, but not with feces from untreated mice, also developed exacerbated DSS colitis. Conclusions: These results suggest that skin inflammation may contribute to pathogenic conditions in the gut via immunologic and microbiological changes. Our finding of a novel potential skin–gut interaction provides new insights into the coincidence of psoriasis and IBD.

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Epigenetic regulation of T helper cells and intestinal pathogenicity

Hagihara Y., Yoshimatsu Y., Mikami Y., Takada Y., Mizuno S., Kanai T.

Seminars in Immunopathology (Seminars in Immunopathology) 41 ( 3 ) 379 - 399 2019

ISSN 18632297

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Inflammatory bowel diseases (IBDs) are characterized by relapsing and remitting chronic intestinal inflammation. Previous studies have demonstrated the contributions of genetic background, environmental factors (food, microbiota, use of antibiotics), and host immunity in the development of IBDs. More than 200 genes have been shown to influence IBD susceptibility, most of which are involved in immunity. The vertebrate immune system comprises a complex network of innate and adaptive immune cells that protect the host from infection and cancer. Dysregulation of the mutualistic relationship between the immune system and the gut environment results in IBD. Considering the fundamental role of epigenetic regulation in immune cells, epigenetic mechanisms, particularly in T helper (Th) cells, may play a major role in the complex regulation of mucosal immunity. Epigenetic regulation and dysregulation of Th cells are involved in the maintenance of intestinal homeostasis and its breakdown in IBD.

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Development of an Indigo Naturalis Suppository for Topical Induction Therapy in Patients with Ulcerative Colitis

Yoshimatsu Y., Naganuma M., Sugimoto S., Tanemoto S., Umeda S., Fukuda T., Nomura E., Yoshida K., Ono K., Mutaguchi M., Nanki K., Mizuno S., Mikami Y., Fukuhara K., Sujino T., Takabayashi K., Ogata H., Iwao Y., Kanai T.

Digestion (Digestion) 101 ( 4 ) 492 - 498 2019

ISSN 00122823

© 2019 S. Karger AG, Basel. All rights reserved. Background: Indigo naturalis (IN) consists of ligands for the aryl hydrocarbon receptor and exhibits anti-inflammatory effects. Previously, we demonstrated that an 8-week treatment with oral IN is effective in inducing a clinical response in patients with ulcerative colitis (UC). Some UC patients with proctitis are refractory to topical mesalamine or corticosteroids and therefore require an alternative topical treatment. Objectives: We aimed to prospectively evaluate the safety and efficacy of IN suppositories in UC patients. Method: We performed an open-label, single-center, prospective pilot study from February 2018 to October 2018. A total of 10 patients with active UC, who had moderate to severe inflammation from the rectum to the sigmoid colon, were enrolled. The patients received a daily dose of 50 mg IN suppository for 4 weeks. The primary endpoint was safety at week 4. Results: Although 1 patient experienced anal pain, no serious adverse events were observed. At week 4, the rates of clinical remission and mucosal healing were 30 and 40%, respectively. Mayo rectal bleeding subscores significantly improved after treatment (1.80 ± 0.13 vs. 0.90 ± 0.28; p = 0.009). Approximately 80% of the patients with a baseline Mayo endoscopic subscore in the rectum (r-MES) of 2 achieved mucosal healing, but those with a baseline r-MES of 3 did not. Conclusions: We found that 4 weeks of IN suppository can be tolerated by UC patients, but its efficacy was limited by the severity of the disease. Further investigation will be needed in order to confirm the optimum dose of IN suppository for patients with UC.

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Human Intestinal Organoids Maintain Self-Renewal Capacity and Cellular Diversity in Niche-Inspired Culture Condition

Fujii M., Matano M., Toshimitsu K., Takano A., Mikami Y., Nishikori S., Sugimoto S., Sato T.

Cell Stem Cell (Cell Stem Cell) 23 ( 6 ) 787 - 793.e6 2018.12

ISSN 19345909

© 2018 Elsevier Inc. Cellular diversity that shapes tissue architecture and function is governed by multiple niche signals. Nonetheless, maintaining cellular diversity in human intestinal organoids has been challenging. Based on niche ligands present in the natural stem cell milieu, we establish a refined organoid culture condition for intestinal epithelia that allows human intestinal organoids to concurrently undergo multi-differentiation and self-renewal. High-throughput screening reveals that the combination of insulin-like growth factor 1 (IGF-1) and fibroblast growth factor 2 (FGF-2) enhances the clonogenic capacity and CRISPR-genome engineering efficiency of human intestinal stem cells. The combination equally enables long-term culture of a range of intestinal organoids, including rat small intestinal organoids. Droplet-based single-cell RNA sequencing further illustrates the conservation of the native cellular diversity in human small intestinal organoids cultured with the refined condition. The modified culture protocol outperforms the conventional method and offers a viable strategy for modeling human intestinal tissues and diseases in an in vivo relevant context. Sato and colleagues develop a modified culture condition for human intestinal organoids that improves the culture efficiency and maintains their long-term multi-differentiation capacity. scRNA-seq of human small intestinal crypts and organoids demonstrates that in vivo cellular diversity can be preserved in organoids cultured with the refined condition.

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Non-classical monocytes as mediators of tissue destruction in arthritis

Puchner, A., Saferding, V., Bonelli, M., Mikami, Y., Hofmann, M., Brunner, J. S., Caldera, M., Goncalves-Alves, E., Binder, N. B., Fischer, A., Simader, E., Steiner, C. W., Leiss, H., Hayer, S., Niederreiter, B., Karonitsch, T., Koenders, M. I., Podesser, B. K., O'Shea, J. J., Menche, J., Smolen, J. S., Redlich, K. and Bluml, S.

Ann Rheum Dis (Annals of the rheumatic diseases) 77 ( 10 ) 1490 - 1497 2018.10

ISSN 0003-4967

OBJECTIVES: Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from precursor cells of the myeloid lineage. The role of the two monocyte subsets, classical monocytes (expressing CD115, Ly6C and CCR2) and non-classical monocytes (which are CD115 positive, but low in Ly6C and CCR2), in serving as precursors for OC in arthritis is still elusive. METHODS: We investigated CCR2(-/-) mice, which lack circulating classical monocytes, crossed into hTNFtg mice for the extent of joint damage. We analysed monocyte subsets in hTNFtg and K/BxN serum transfer arthritis by flow cytometry. We sorted monocyte subsets and analysed their potential to differentiate into OC and their transcriptional response in response to RANKL by RNA sequencing. With these data, we performed a gene ontology enrichment analysis and gene set enrichment analysis. RESULTS: We show that in hTNFtg arthritis local bone erosion and OC generation are even enhanced in the absence of CCR2. We further show the numbers of non-classical monocytes in blood are elevated and are significantly correlated with histological signs of joint destruction. Sorted non-classical monocytes display an increased capacity to differentiate into OCs. This is associated with an increased expression of signal transduction components of RANK, most importantly TRAF6, leading to an increased responsiveness to RANKL. CONCLUSION: Therefore, non-classical monocytes are pivotal cells in arthritis tissue damage and a possible target for therapeutically intervention for the prevention of inflammatory joint damage.

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Innate lymphoid cells in organ fibrosis

Mikami, Y., Takada, Y., Hagihara, Y. and Kanai, T.

Cytokine Growth Factor Rev 42 27 - 36 2018.08

ISSN 1359-6101

Innate lymphoid cells (ILCs) are a recently identified family of lymphoid effector cells. ILCs are mainly clustered into 3 groups based on their unique cytokine profiles and transcription factors typically attributed to the subsets of T helper cells. ILCs have a critical role in the mucosal immune response through promptly responding to pathogens and producing large amount of effector cytokines of type 1, 2, or 3 responses. In addition to the role of early immune responses against infections, ILCs, particularly group 2 ILCs (ILC2), have recently gained attention for modulating remodeling and fibrosis especially in the mucosal tissues. Herein, we overview the current knowledge in this area, highlighting roles of ILCs on fibrosis in the mucosal tissues, especially focusing on the gut and lung. We also discuss some new directions for future research by extrapolating from knowledge derived from studies on Th cells.

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NCR(+) ILC3 maintain larger STAT4 reservoir via T-BET to regulate type 1 features upon IL-23 stimulation in mice

Mikami, Y., Scarno, G., Zitti, B., Shih, H. Y., Kanno, Y., Santoni, A., O'Shea, J. J. and Sciume, G.

Eur J Immunol (European Journal of Immunology) 48 ( 7 ) 1174 - 1180 2018.07

ISSN 0014-2980

Innate lymphoid cells (ILCs) producing IL-22 and/or IL-17, designated as ILC3, comprise a heterogeneous subset of cells involved in regulation of gut barrier homeostasis and inflammation. Exogenous environmental cues in conjunction with regulated expression of endogenous factors are key determinants of plasticity of ILC3 toward the type 1 fate. Herein, by using mouse models and transcriptomic approaches, we defined at the molecular level, initial events driving ILC3 expressing natural cytotoxicity receptors (NCR(+) ILC3) to acquire type 1 features. We observed that NCR(+) ILC3 exhibited high basal expression of the signal-dependent transcription factor STAT4 due to T-BET, leading to predisposed potential for the type 1 response. We found that the prototypical inducer of type 3 response, IL-23, played a predominant role over IL-12 by accessing STAT4 and preferentially inducing its phosphorylation in ILC3 expressing T-BET. The early effector program driven by IL-23 was characterized by the expression of IL-22, followed by a production of IFN-gamma, which relies on STAT4, T-BET and required chromatin remodeling of the Ifng locus. Altogether, our findings shed light on a feed-forward mechanism involving STAT4 and T-BET that modulates the outcome of IL-23 signaling in ILC3.

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Intestinal barrier regulates immune responses in the liver via IL-10-producing macrophages

Taniki, N., Nakamoto, N., Chu, P. S., Mikami, Y., Amiya, T., Teratani, T., Suzuki, T., Tsukimi, T., Fukuda, S., Yamaguchi, A., Shiba, S., Miyake, R., Katayama, T., Ebinuma, H. and Kanai, T.

JCI Insight (JCI insight) 3 ( 12 ) 2018.06

ISSN 2379-3708

The gut-liver axis is of clinical importance as a potential therapeutic target in a wide range of liver diseases; however, the mechanisms underlying interactions between microbial products and immune responses in the liver remain unknown. In this study, we demonstrated that IL-10-producing macrophages contribute to immune tolerance in the inflamed liver under intestinal barrier disruption in a murine tandem model of dextran sulfate sodium (DSS) colitis and concanavalin A (Con A) hepatitis. Intestinal barrier disruption protected mice from subsequent liver injury, and the severity of colitis directly affected susceptibility to such injury. The protective effect of DSS-Con A was canceled in gut-sterilized mice, suggesting that gut microbiota play a substantial role in this process. Altered gut microbiota and their metabolites, along with a disrupted intestinal barrier, directly gave rise to immunological permissiveness in the inflamed liver. We identified 1-methylnicotinamide (1-MNA) as a candidate metabolite capable of suppressing liver injury with the potential to induce IL-10-producing macrophages. Consistently, expression of nicotinamide N-methyltransferase, which converts nicotinamide to 1-MNA, was upregulated in the liver of DSS-Con A mice, and this effect was abrogated by gut sterilization. Collectively, our results provide a mechanistic insight into the regulation of immunological balance in the liver via the gut-liver axis.

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Cholesterol 25-hydroxylase expressing CD4(+) T cell regulates skin inflammation

Takahashi H., Nomura H., Iriki H., Kubo A., Mukai M., Sasaki T., Mikami Y., O'Shea J., Amagai M.

JOURNAL OF INVESTIGATIVE DERMATOLOGY 138 ( 5 ) S3 - S3 2018.05

ISSN 0022-202X

GoldiRunx and Remembering Cytotoxic Memory

Mikami, Y. and Kanno, Y.

Immunity 48 ( 4 ) 614 - 615 2018.04

ISSN 1074-7613

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Commensal Lactobacillus Controls Immune Tolerance during Acute Liver Injury in Mice

Nakamoto, N., Amiya, T., Aoki, R., Taniki, N., Koda, Y., Miyamoto, K., Teratani, T., Suzuki, T., Chiba, S., Chu, P. S., Hayashi, A., Yamaguchi, A., Shiba, S., Miyake, R., Katayama, T., Suda, W., Mikami, Y., Kamada, N., Ebinuma, H., Saito, H., Hattori, M. and Kanai, T.

Cell Rep 21 ( 5 ) 1215 - 1226 2017.10

Gut-derived microbial antigens trigger the innate immune system during acute liver injury. During recovery, regulatory immunity plays a role in suppressing inflammation; however, the precise mechanism underlying this process remains obscure. Here, we find that recruitment of immune-regulatory classical dendritic cells (cDCs) is crucial for liver tolerance in concanavalin A-induced acute liver injury. Acute liver injury resulted in enrichment of commensal Lactobacillus in the gut. Notably, Lactobacillus activated IL-22 production by gut innate lymphoid cells and raised systemic IL-22 levels. Gut-derived IL-22 enhanced mucosal barrier function and promoted the recruitment of regulatory cDCs to the liver. These cDCs produced IL-10 and TGF-beta through TLR9 activation, preventing further liver inflammation. Collectively, our results indicate that beneficial gut microbes influence tolerogenic immune responses in the liver. Therefore, modulation of the gut microbiota might be a potential option to regulate liver tolerance.

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Intestinal Dysbiosis and Biotin Deprivation Induce Alopecia through Overgrowth of Lactobacillus murinus in Mice

Hayashi, A., Mikami, Y., Miyamoto, K., Kamada, N., Sato, T., Mizuno, S., Naganuma, M., Teratani, T., Aoki, R., Fukuda, S., Suda, W., Hattori, M., Amagai, M., Ohyama, M. and Kanai, T.

Cell Rep 20 ( 7 ) 1513 - 1524 2017.08

Metabolism by the gut microbiota affects host physiology beyond the gastrointestinal tract. Here, we find that antibiotic-induced dysbiosis, in particular, overgrowth of Lactobacillus murinus (L. murinus), impaired gut metabolic function and led to the development of alopecia. While deprivation of dietary biotin per se did not affect skin physiology, its simultaneous treatment with vancomycin resulted in hair loss in specific pathogen-free (SPF) mice. Vancomycin treatment induced the accumulation of L. murinus in the gut, which consumes residual biotin and depletes available biotin in the gut. Consistently, L. murinus induced alopecia when monocolonized in germ-free mice fed a biotin-deficient diet. Supplementation of biotin can reverse established alopecia symptoms in the SPF condition, indicating that L. murinus plays a central role in the induction of hair loss via a biotin-dependent manner. Collectively, our results indicate that luminal metabolic alterations associated with gut dysbiosis and dietary modifications can compromise skin physiology.

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The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells

Iwata, S., Mikami, Y., Sun, H. W., Brooks, S. R., Jankovic, D., Hirahara, K., Onodera, A., Shih, H. Y., Kawabe, T., Jiang, K., Nakayama, T., Sher, A., O'Shea, J. J., Davis, F. P. and Kanno, Y.

Immunity 46 ( 6 ) 983 - 991.e4 2017.06

ISSN 1074-7613

Host defense requires the specification of CD4(+) helper T (Th) cells into distinct fates, including Th1 cells that preferentially produce interferon-gamma (IFN-gamma). IFN-gamma, a member of a large family of anti-pathogenic and anti-tumor IFNs, induces T-bet, a lineage-defining transcription factor for Th1 cells, which in turn supports IFN-gamma production in a feed-forward manner. Herein, we show that a cell-intrinsic role of T-bet influences how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-gamma aberrantly induced a type I IFN transcriptomic program. T-bet preferentially repressed genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response did not evoke an aberrant amplification of type I IFN signaling circuitry, otherwise triggered by its own product. Thus, in addition to promoting Th1 effector commitment, T-bet acts as a repressor in differentiated Th1 cells to prevent abberant autocrine type I IFN and downstream signaling.

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Epigenomic Views of Innate Lymphoid Cells

Sciume, G., Shih, H. Y., Mikami, Y. and O'Shea, J. J.

Front Immunol 8 1579 2017

ISSN 1664-3224

The discovery of innate lymphoid cells (ILCs) with selective production of cytokines typically attributed to subsets of T helper cells forces immunologists to reassess the mechanisms by which selective effector functions arise. The parallelism between ILCs and T cells extends beyond these two cell types and comprises other innate-like T lymphocytes. Beyond the recognition of specialized effector functionalities in diverse lymphocytes, features typical of T cells, such as plasticity and memory, are also relevant for innate lymphocytes. Herein, we review what we have learned in terms of the molecular mechanisms underlying these shared functions, focusing on insights provided by next generation sequencing technologies. We review data on the role of lineage-defining- and signal-dependent transcription factors (TFs). ILC regulomes emerge developmentally whereas the much of the open chromatin regions of T cells are generated acutely, in an activation-dependent manner. And yet, these regions of open chromatin in T cells and ILCs have remarkable overlaps, suggesting that though accessibility is acquired by distinct modes, the end result is that convergent signaling pathways may be involved. Although much is left to be learned, substantial progress has been made in understanding how TFs and epigenomic status contribute to ILC biology in terms of differentiation, specification, and plasticity.

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A Single Species of Clostridium Subcluster XIVa Decreased in Ulcerative Colitis Patients

Takeshita, K., Mizuno, S., Mikami, Y., Sujino, T., Saigusa, K., Matsuoka, K., Naganuma, M., Sato, T., Takada, T., Tsuji, H., Kushiro, A., Nomoto, K. and Kanai, T.

Inflamm Bowel Dis 22 ( 12 ) 2802 - 2810 2016.12

ISSN 1078-0998

BACKGROUND: Imbalance of the intestinal microbiota is associated with gastrointestinal disease and autoimmune disease and metabolic syndrome. Analysis of the intestinal microbiota has recently progressed, and the association with inflammatory bowel disease has been reported at the species level. Such findings suggest that the recovery of homeostasis in the intestinal microbiota could cure inflammatory bowel disease. We aimed to search new probiotic candidates for inflammatory bowel disease through translational research by analysis of ulcerative colitis (UC) patients' intestinal microbiota and clarify the effects of them on inflammation. Here, we focused on Fusicatenibacter saccharivorans, which belongs to Clostridium subcluster XIVa and was successfully isolated and cultured in 2013. We analyzed the association of F. saccharivorans to UC patients' activity and inflammation for the first time. METHODS: Feces from UC patients and healthy controls were analyzed by 16S ribosomal RNA gene sequences. F. saccharivorans was administered to murine colitis model. Colitic lamina propria mononuclear cells from UC patients and mice were stimulated with F. saccharivorans. RESULTS: The whole fecal bacteria in active UC patients were less than that in quiescent UC patients. Furthermore, F. saccharivorans was decreased in active UC patients and increased in quiescent. The administration of F. saccharivorans improved murine colitis. F. saccharivorans induced interleukin 10 production by lamina propria mononuclear cells from not only colitis model mice but also UC patients. CONCLUSIONS: F. saccharivorans decreased in correlation to UC activity and suppresses intestinal inflammation. These results suggest that F. saccharivorans could lead to a novel UC treatment.

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Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality

Shih, H. Y., Sciume, G., Mikami, Y., Guo, L., Sun, H. W., Brooks, S. R., Urban, J. F., Jr., Davis, F. P., Kanno, Y. and O'Shea, J. J.

Cell 165 ( 5 ) 1120 - 1133 2016.05

ISSN 0092-8674

Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis and mirror adaptive CD4(+) T helper (Th) cell subtypes in both usage of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cell counterparts, we measured genome-wide chromatin accessibility. We find that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions is acquired in a stepwise manner during development and changes little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurs in naive CD4(+) T cells during Th cell differentiation using a type-2-infection model. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways.

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A breakthrough in probiotics: Clostridium butyricum regulates gut homeostasis and anti-inflammatory response in inflammatory bowel disease

Kanai, T., Mikami, Y. and Hayashi, A.

J Gastroenterol 50 ( 9 ) 928 - 39 2015.09

ISSN 0944-1174

Intestinal immune homeostasis is regulated by gut microbiota, including beneficial and pathogenic microorganisms. Imbalance in gut bacterial constituents provokes host proinflammatory responses causing diseases such as inflammatory bowel disease (IBD). The development of next-generation sequencing technology allows the identification of microbiota alterations in IBD. Several studies have shown reduced diversity in the gut microbiota of patients with IBD. Advances in gnotobiotic technology have made possible analysis of the role of specific bacterial strains in immune cells in the intestine. Using these techniques, we have shown that Clostridium butyricum as a probiotic induces interleukin-10-producing macrophages in inflamed mucosa via the Toll-like receptor 2/myeloid differentiation primary response gene 88 pathway to prevent acute experimental colitis. In this review, we focus on the new approaches for the role of specific bacterial strains in immunological responses, as well as the potential of bacterial therapy for IBD treatments.

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Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity

Hirahara, K., Onodera, A., Villarino, A. V., Bonelli, M., Sciume, G., Laurence, A., Sun, H. W., Brooks, S. R., Vahedi, G., Shih, H. Y., Gutierrez-Cruz, G., Iwata, S., Suzuki, R., Mikami, Y., Okamoto, Y., Nakayama, T., Holland, S. M., Hunter, C. A., Kanno, Y. and O'Shea, J. J.

Immunity 42 ( 5 ) 877 - 89 2015.05

ISSN 1074-7613

Interleukin-6 (IL-6) and IL-27 signal through a shared receptor subunit and employ the same downstream STAT transcription proteins, but yet are ascribed unique and overlapping functions. To evaluate the specificity and redundancy for these cytokines, we quantified their global transcriptomic changes and determined the relative contributions of STAT1 and STAT3 using genetic models and chromatin immunoprecipitation-sequencing (ChIP-seq) approaches. We found an extensive overlap of the transcriptomes induced by IL-6 and IL-27 and few examples in which the cytokines acted in opposition. Using STAT-deficient cells and T cells from patients with gain-of-function STAT1 mutations, we demonstrated that STAT3 is responsible for the overall transcriptional output driven by both cytokines, whereas STAT1 is the principal driver of specificity. STAT1 cannot compensate in the absence of STAT3 and, in fact, much of STAT1 binding to chromatin is STAT3 dependent. Thus, STAT1 shapes the specific cytokine signature superimposed upon STAT3's action.

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Classical Th1 cells obtain colitogenicity by co-existence of RORgammat-expressing T cells in experimental colitis

Saigusa, K., Hisamatsu, T., Handa, T., Sujino, T., Mikami, Y., Hayashi, A., Mizuno, S., Takeshita, K., Sato, T., Matsuoka, K. and Kanai, T.

Inflamm Bowel Dis 20 ( 10 ) 1820 - 7 2014.10

ISSN 1078-0998

BACKGROUND: Both Th1 and Th17 cell types are involved in the pathogenesis of chronic intestinal inflammation. We recently demonstrated that retinoid-related orphan receptor gamma t (RORgammat)-expressing Th17 cells are progenitor cells for alternative Th1 cells, which have the potential to induce colitis. However, the involvement of classical Th1 (cTh1) cells generated directly from naive T cells without RORgammat expression in the pathogenesis of colitis remains poorly understood. METHODS: We performed a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of splenic CD4CD45RB(high) T cells obtained from wild-type, RORgammat(gfp/gfp), or RORgammat(gfp/gfp) mice into RAG-2(-/-) mice. RESULTS: RAG-2(-/-) mice receiving transfer of in vitro-manipulated RORgammat(gfp/gfp) Th1 cells developed colitis. RAG-2(-/-) mice co-transferred with splenic CD4CD45RB(high) T cells obtained from wild-type mice and RORgammat(gfp/gfp) mice developed colitis with a significant increase in RORgammat cTh1 cell numbers when compared with noncolitic mice transferred with splenic CD4CD45RB(high) T cells obtained from RORgammat(gfp/gfp) mice. Furthermore, RAG-2(-/-) mice transferred with in vivo-manipulated RORgammat(gfp/gfp) cTh1 cells developed colitis with a significant increase in RORgammat(gfp/gfp) cTh1 cell numbers. CONCLUSIONS: These findings indicate that both alternative Th1 cells and cTh1 cells have the potential to be colitogenic in an adaptive transfer model. The development of cTh1 cells was dependent on the co-existence of RORgammat-expressing T cells, suggesting a critical role for the interactions of these cell types in the development of chronic intestinal inflammation.

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Cross-talk between RORgammat+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease

Mizuno, S., Mikami, Y., Kamada, N., Handa, T., Hayashi, A., Sato, T., Matsuoka, K., Matano, M., Ohta, Y., Sugita, A., Koganei, K., Sahara, R., Takazoe, M., Hisamatsu, T. and Kanai, T.

Inflamm Bowel Dis 20 ( 8 ) 1426 - 34 2014.08

ISSN 1078-0998

BACKGROUND: Interleukin (IL)-22-producing RORgammat innate lymphoid cells (ILCs) play a pivotal role in intestinal immunity. Recent reports demonstrated that ILCs contribute to mucosal protection and intestinal inflammation in mice. In humans, numbers of RORgammat ILCs are significantly increased in the intestine of patients with Crohn's disease (CD), suggesting that ILCs may be associated with intestinal inflammation in CD. However, the mechanism by which ILCs are regulated in the intestine of patients with CD is poorly understood. This study aimed to determine the activation mechanism of intestinal ILCs in patients with CD. METHODS: CD45 lineage marker ILCs were isolated from intestinal lamina propria of patients with CD. ILCs were then subdivided into 4 distinct populations based on the expression of CD56 and CD127. Purified ILC subsets were cocultured with intestinal CD14 macrophages, and IL-22 production was evaluated. RESULTS: CD127CD56 and CD127CD56 ILC, but not CD127CD56 or CD127CD56 ILC, subsets expressed RORgammat and produced IL-22. IL-22 production by these ILC subsets was enhanced when ILCs were cocultured with intestinal macrophages. IL-23 or cell-to-cell contact was required for macrophage-mediated activation of ILCs. IL-22 production by ILCs was perturbed in inflamed mucosa compared with noninflamed mucosa. IL-22 induced the expression of Reg1alpha and Claudin-1 in human intestinal epithelial organoids. CONCLUSIONS: RORgammat ILCs might enhance mucosal barrier function through the upregulation of Reg1alpha through production of IL-22. Although CD14 macrophages augment intestinal inflammation in patients with CD, macrophages also promote a negative feedback pathway through the activation of IL-22 production by RORgammat ILCs.

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Risk and management of intra-abdominal abscess in Crohn's disease treated with infliximab

Yoneno, K., Hisamatsu, T., Matsuoka, K., Okamoto, S., Takayama, T., Ichikawa, R., Sujino, T., Miyoshi, J., Takabayashi, K., Mikami, Y., Mizuno, S., Wada, Y., Yajima, T., Naganuma, M., Inoue, N., Iwao, Y., Ogata, H., Hasegawa, H., Kitagawa, Y., Hibi, T. and Kanai, T.

Digestion 89 ( 3 ) 201 - 8 2014

ISSN 0012-2823

BACKGROUND AND AIMS: Infliximab (IFX) is a monoclonal antibody used to treat patients with Crohn's disease (CD). Intra-abdominal abscess formation is a major complication of CD with negative effects on patient prognosis. We have analyzed risk factors for abscess formation in CD patients treated with IFX. METHODS: CD patients who received IFX between January 2000 and April 2011 at Keio University Hospital were analyzed retrospectively. Risk factors for abscess formation were assessed by univariate and multivariate logistic regression analyses. RESULTS: Intra-abdominal abscess was seen in 15 of 258 patients. Univariate analyses showed serum C-reactive protein (CRP) concentration at 14 weeks after initiation of IFX (p = 0.021), serum albumin concentration at week 0 (p = 0.022) and week 14 (p = 0.004), the presence of anal lesions (p = 0.036), progression of intestine deformation (p = 0.015) and early loss of response to IFX (p < 0.0001) to be risk factors. Multivariate analysis showed that CRP concentration at 14 weeks [odds ratio (OR) 1.361] and loss of IFX response within 6 months (OR 5.361) were independent risk factors. CONCLUSIONS: Abscess formation should be suspected in patients with symptoms of CD recurrence during IFX therapy. Uncontrolled CRP concentration and early loss of response to IFX are risk factors.

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Helper T cell plasticity: impact of extrinsic and intrinsic signals on transcriptomes and epigenomes

Bonelli, M., Shih, H. Y., Hirahara, K., Singelton, K., Laurence, A., Poholek, A., Hand, T., Mikami, Y., Vahedi, G., Kanno, Y. and O'Shea, J. J.

Curr Top Microbiol Immunol 381 279 - 326 2014

ISSN 0070-217X

CD4(+) helper T cells are crucial for autoimmune and infectious diseases; however, the recognition of the many, diverse fates available continues unabated. Precisely what controls specification of helper T cells and preserves phenotypic commitment is currently intensively investigated. In this review, we will discuss the major factors that impact helper T cell fate choice, ranging from cytokines and the microbiome to metabolic control and epigenetic regulation. We will also discuss the technological advances along with the attendant challenges presented by "big data," which allow the understanding of these processes on comprehensive scales.

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Macrophages and dendritic cells emerge in the liver during intestinal inflammation and predispose the liver to inflammation

Mikami, Y., Mizuno, S., Nakamoto, N., Hayashi, A., Sujino, T., Sato, T., Kamada, N., Matsuoka, K., Hisamatsu, T., Ebinuma, H., Hibi, T., Yoshimura, A. and Kanai, T.

PLoS One 9 ( 1 ) e84619 2014

ISSN 1932-6203

The liver is a physiological site of immune tolerance, the breakdown of which induces immunity. Liver antigen-presenting cells may be involved in both immune tolerance and activation. Although inflammatory diseases of the liver are frequently associated with inflammatory bowel diseases, the underlying immunological mechanisms remain to be elucidated. Here we report two murine models of inflammatory bowel disease: RAG-2(-/-) mice adoptively transferred with CD4(+)CD45RB(high) T cells; and IL-10(-/-) mice, accompanied by the infiltration of mononuclear cells in the liver. Notably, CD11b(-)CD11c(low)PDCA-1(+) plasmacytoid dendritic cells (DCs) abundantly residing in the liver of normal wild-type mice disappeared in colitic CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) mice and IL-10(-/-) mice in parallel with the emergence of macrophages (Mphis) and conventional DCs (cDCs). Furthermore, liver Mphi/cDCs emerging during intestinal inflammation not only promote the proliferation of naive CD4(+) T cells, but also instruct them to differentiate into IFN-gamma-producing Th1 cells in vitro. The emergence of pathological Mphi/cDCs in the liver also occurred in a model of acute dextran sulfate sodium (DSS)-induced colitis under specific pathogen-free conditions, but was canceled in germ-free conditions. Last, the Mphi/cDCs that emerged in acute DSS colitis significantly exacerbated Fas-mediated hepatitis. Collectively, intestinal inflammation skews the composition of antigen-presenting cells in the liver through signaling from commensal bacteria and predisposes the liver to inflammation.

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C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice

Chu, P. S., Nakamoto, N., Ebinuma, H., Usui, S., Saeki, K., Matsumoto, A., Mikami, Y., Sugiyama, K., Tomita, K., Kanai, T., Saito, H. and Hibi, T.

Hepatology 58 ( 1 ) 337 - 50 2013.07

ISSN 0270-9139

UNLABELLED: Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. C-C motif chemokine receptor (CCR) 9(+) macrophages are crucial in the pathogenesis of acute liver inflammation, but the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed that tumor necrosis factor alpha (TNF-alpha)-producing CCR9(+) macrophages accumulated during the initiation of carbon tetrachloride (CCl4 )-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9(+) macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl4 or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9(-/-) mice compared with wild-type (WT) mice, assessed by alpha-smooth muscle actin (alpha-SMA) immunostain, Sirius red staining, and messenger RNA (mRNA) expression levels of alpha-SMA, collagen 1alpha1, transforming growth factor (TGF)-beta1, and tissue inhibitor of metalloproteinase (TIMP)-1. Accumulated CD11b(+) macrophages in CCl4 -treated WT mice showed marked increases in TNF, NO synthase-2, and TGF-beta1 mRNA expression compared with CCR9(-/-) mice, implying proinflammatory and profibrogenic properties. Hepatic CD11b(+) macrophages from CCl4 -treated WT mice (i.e., CCR9(+) macrophages), but not CD8(+) T lymphocytes or non-CD11b(+) cells, significantly activated HSCs in vitro compared with those from CCR9(-/-) mice. TNF-alpha or TGF-beta1 antagonism attenuated CCR9(+) macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro. CONCLUSION: Accumulated CD11b(+) macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis.

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A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice

Hayashi, A., Sato, T., Kamada, N., Mikami, Y., Matsuoka, K., Hisamatsu, T., Hibi, T., Roers, A., Yagita, H., Ohteki, T., Yoshimura, A. and Kanai, T.

Cell Host Microbe 13 ( 6 ) 711 - 22 2013.06

ISSN 1931-3128

Imbalance in gut bacterial composition provokes host proinflammatory responses causing diseases such as colitis. Colonization with a mixture of Clostridium species from clusters IV and XIVa was shown to suppress colitis through the induction of IL-10-producing regulatory T (Treg) cells. We demonstrate that a distinct Clostridium strain from cluster I, Clostridium butyricum (CB), prevents acute experimental colitis in mice through induction of IL-10, an anti-inflammatory cytokine. However, while CB treatment had no effect on IL-10 production by T cells, IL-10-producing F4/80(+)CD11b(+)CD11c(int) macrophages accumulated in the inflamed mucosa after CB treatment. CB directly triggered IL-10 production by intestinal macrophages in inflamed mucosa via the TLR2/MyD88 pathway. The colitis-preventing effect of CB was negated in macrophage-specific IL-10-deficient mice, suggesting that induction of IL-10 by intestinal macrophages is crucial for the probiotic action of CB. Collectively, CB promotes IL-10 production by intestinal macrophages in inflamed mucosa, thereby preventing experimental colitis in mice.

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CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion

Nakamura, Y., Kanai, T., Saeki, K., Takabe, M., Irie, J., Miyoshi, J., Mikami, Y., Teratani, T., Suzuki, T., Miyata, N., Hisamatsu, T., Nakamoto, N., Yamagishi, Y., Higuchi, H., Ebinuma, H., Hozawa, S., Saito, H., Itoh, H. and Hibi, T.

Am J Physiol Gastrointest Liver Physiol 304 ( 8 ) G700 - 7 2013.04

ISSN 0193-1857

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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Immune aspects of the pathogenesis of inflammatory bowel disease

Hisamatsu, T., Kanai, T., Mikami, Y., Yoneno, K., Matsuoka, K. and Hibi, T.

Pharmacol Ther 137 ( 3 ) 283 - 97 2013.03

ISSN 0163-7258

Although the precise etiologies of inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) remain obscure, several reports have indicated that dysfunction of the mucosal immune system plays an important role in its pathogenesis. Recent progress with genome-wide association studies has identified many IBD susceptibility genes. In individuals with genetic risk, abnormal interactions between the host immune system and gut flora, and dysregulation of cellular responses such as autophagy and ER stress, induce an abnormal host immune response in the gut resulting in intestinal inflammation. Research progress animal models in IBD, and in human IBD, has identified several key molecules in IBD pathogenesis such as TNFalpha and adhesion molecules, and molecular targeting therapies based on these molecules have been developed. Here, we review immunological aspects in IBD pathogenesis and the development of immunoregulatory therapy.

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Long-term prognosis of patients with ulcerative colitis treated with cytapheresis therapy

Takayama, T., Kanai, T., Matsuoka, K., Okamoto, S., Sujino, T., Mikami, Y., Hisamatsu, T., Yajima, T., Iwao, Y., Ogata, H. and Hibi, T.

J Crohns Colitis 7 ( 2 ) e49 - 54 2013.03

ISSN 1873-9946

BACKGROUND: Although accumulating studies in Japan show that cytapheresis (CAP) therapy is safe and effective for the induction of remission of moderate or severe ulcerative colitis (UC), the long-term prognosis of UC patients treated with CAP is unknown. The aim of this study was to determine the long-term prognosis of UC patients treated with CAP. METHODS: Ninety patients treated previously with CAP and followed for more than 3 years were evaluated. The rates of operation, readmission, and use or dose-up of corticosteroid were analyzed as long-term prognosis. RESULTS: Following the first course of CAP treatment, 64% of patients showed clinical improvement (> 4-point decrease in the clinical activity index (CAI)), and 49% of patients achieved clinical remission (CAI </= 4). Longer disease duration and lower age at the first CAP treatment correlated significantly with the therapeutic effects of CAP (p = 0.003 and 0.035, respectively). The rates of operation and readmission were significantly lower in patients who showed previous clinical effects of CAP than in those who did not respond to CAP. The rates of operation and readmission were also significantly lower in patients whose treatment was combined with immunomodulators after the initiation of CAP than in patients who did not use immunomodulators. Importantly, the second course of CAP was also effective in most of the patients who showed a clinical response to the first CAP. CONCLUSIONS: Patients who achieve remission after the first CAP therapy may have a good long-term prognosis and a good response to a second CAP therapy even after relapse.

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Dendritic cells administered intrarectally penetrate the intestinal barrier to break intestinal tolerance via Th2-medeiated colitis in mice

Handa, T., Kanai, T., Sato, T., Mikami, Y., Sujino, T., Hayashi, A., Mizuno, S., Matsumoto, A., Hisamatsu, T. and Hibi, T.

Immunol Lett 150 ( 1-2 ) 123 - 9 2013.02

ISSN 0165-2478

Intestinal lamina propria dendritic cells (LPDCs) in mice are known to extend dendrites between the intestinal epithelia and the luminal side when processing luminal antigens. We conducted intrarectal cell transfer experiments of bone marrow-derived dendritic cells (BMDCs) in mice to assess dendritic cell penetration of the intestine. Intrarectally administered GFP(+) BMDCs localized in the colonic LP within 3h and the spleen within 12h after administration. 72h after administration, recipient C57BL/6 mice showed acute diarrhea, and administration of BMDCs (once weekly for 3 weeks) induced intestinal inflammation with increased numbers of recipient macrophages and CD4(+) T cells exhibiting a Th2-mediated immune response. These results demonstrate that DCs actively communicate across the intestinal barrier, and highlight a potential technique for controlling colonic immune tolerance.

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IL-22-producing RORgammat-dependent innate lymphoid cells play a novel protective role in murine acute hepatitis

Matsumoto, A., Kanai, T., Mikami, Y., Chu, P. S., Nakamoto, N., Ebinuma, H., Saito, H., Sato, T., Yagita, H. and Hibi, T.

PLoS One 8 ( 4 ) e62853 2013

ISSN 1932-6203

Retinoid-related orphan receptor (ROR) gammat is known to be related to the development and function of various immunological compartments in the liver, such as Th17 cells, natural killer T (NKT) cells, and innate lymphoid cells (ILCs). We evaluated the roles of RORgammat-expressing cells in mouse acute hepatitis model using RORgammat deficient (RORgammat(-/-)) mice and RAG-2 and RORgammat double deficient (RAG-2(-/-) x RORgammat(-/-)) mice. Acute hepatitis was induced in mice by injection with carbon tetrachloride (CCl4), to investigate the regulation of liver inflammation by RORgammat-expressing cells. We detected RORC expression in three compartments, CD4(+) T cells, NKT cells, and lineage marker-negative SCA-1(+)Thy1(high) ILCs, of the liver of wild type (WT) mice. CCl4-treated RORgammat(-/-) mice developed liver damage in spite of lack of RORgammat-dependent cells, but with reduced infiltration of macrophages compared with WT mice. In this regard, ILCs were significantly decreased in RAG-2(-/-) x RORgammat(-/-) mice that lacked T and NKT cells. Surprisingly, RAG-2(-/-) x RORgammat(-/-) mice developed significantly severer CCl4-induced hepatitis compared with RAG-2(-/-) mice, in accordance with the fact that hepatic ILCs failed to produce IL-22. Lastly, anti-Thy1 monoclonal antibody (mAb), but not anti-NK1.1 mAb or anti-asialo GM1 Ab administration exacerbated liver damage in RAG-2(-/-) mice with the depletion of liver ILCs. Collectively, hepatic RORgammat-dependent ILCs play a part of protective roles in hepatic immune response in mice.

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MyD88-dependent interleukin-10 production from regulatory CD11b(+)Gr-1(high) cells suppresses development of acute cerulein pancreatitis in mice

Koike, Y., Kanai, T., Saeki, K., Nakamura, Y., Nakano, M., Mikami, Y., Yamagishi, Y., Nakamoto, N., Ebinuma, H. and Hibi, T.

Immunol Lett 148 ( 2 ) 172 - 7 2012.12

ISSN 0165-2478

We explored the role of the MyD88 signaling pathway. This pathway mediates the recognition of pathogen-associated molecular patterns and damage-associated molecular patterns via Toll-like receptors (TLRs) and/or IL-1/IL-18 via each cytokine receptor in a murine model of acute pancreatitis induced by cerulein administration. Our analysis revealed that: various TLRs and MyD88 molecules were constitutively expressed in the pancreas of cerulein-treated and untreated wild-type (WT) mice. MyD88(-)/(-) mice administered cerulein developed severe pancreatitis as compared with MyD88(+)/(+) WT mice. The number of IL-10-expressing CD11b(+)Gr-1(high) cells in cerulein-administered MyD88(-)/(-) mice was significantly decreased. This was in accordance with a reciprocal increase in the infiltration of CD4(+) T cells as compared with that in control MyD88(+)/(+) mice. WT mice pretreated with antibiotics and administered cerulein developed milder pancreatitis as compared with control cerulein-administered mice without antibiotic treatment. The MyD88 signaling pathway contributes to the induction of regulatory IL-10-producing macrophages/myeloid-derived suppressor cells, possibly in response to non-bacterial components in the damaged pancreas. These results provide a new concept for therapeutic strategies against acute pancreatitis.

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Anticoagulation therapy dramatically improved severe sigmoiditis with findings resembling inflammatory bowel disease, which was caused by mesenteric venous thrombosis

Mikami, Y., Kanai, T., Iwasaki, E., Naganuma, M., Yamagishi, Y., Shimoda, M., Matsuoka, K., Hisamatsu, T., Iwao, Y., Ogata, H., Nakatsuka, S., Mukai, M. and Hibi, T.

Clin J Gastroenterol 5 ( 6 ) 377 - 82 2012.12

ISSN 1865-7257

Mesenteric venous thrombosis is an insidious disease, with a high mortality rate typically attributed to the long delay in diagnosis. Rapid diagnosis and treatment are important. Here, we present a patient with idiopathic inferior mesenteric venous (IMV) thrombosis. A 65-year-old man presented with constant abdominal pain associated with fever and bloody diarrhea. He was diagnosed with severe ulcerative colitis and was treated with mesalazine and prednisolone. The prednisolone was tapered because of liver dysfunction, and he received total parenteral nutrition for a month. His abdominal pain and bloody diarrhea worsened, and he lost 5 kg of weight. He was then transferred to our institute. Computed tomography showed thickening of the left colon. Colonoscopy showed diffuse colitis with multiple ulcers, large edematous folds, congested mucosa, and stenosis of the sigmoid colon, with sparing of the rectum, raising the possibility of IMV thrombosis. Angiography confirmed IMV thrombosis. Anticoagulation therapy was initiated with intravenous heparin followed by oral warfarin. His abdominal pain and diarrhea resolved, and he was discharged from hospital. Six months later, he remained asymptomatic with normal colonoscopic findings.

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Dysregulated balance of retinoid-related orphan receptor gammat-dependent innate lymphoid cells is involved in the pathogenesis of chronic DSS-induced colitis

Kimura, K., Kanai, T., Hayashi, A., Mikami, Y., Sujino, T., Mizuno, S., Handa, T., Matsuoka, K., Hisamatsu, T., Sato, T. and Hibi, T.

Biochem Biophys Res Commun 427 ( 4 ) 694 - 700 2012.11

ISSN 0006-291X

Retinoid-related orphan receptor (ROR) gammat-expressing and IL-22-producing NKp46(+) innate lymphoid (ILC22) cells reside in the lamina propria of the intestine in mice, suggesting that ILC22 cells contribute to host defense during intestinal damage in models of colitis in mice. Nevertheless, another set of pathological interferon (IFN)-gamma and/or IL-17A-producing innate lymphoid cells (ILC1 and ICL17) may participate in the pathogenesis in different models of colitis. We here showed that RORgammat(+)IL-22(+) ILC22 cells were localized in Thy-1(high)SCA-1(high) and/or Thy-1(high)SCA-1(low) subpopulations of the intestine in normal and dextran sodium sulfate (DSS)-induced colitic RORgammat-sufficient Rag-2(-/-) mice. RORgammat-deficient Rag-2(-/-) mice developed more severe DSS-induced colitis accompanied with lower expression of REG3beta and REG3gamma in the colon, but with a lower ratio and absolute number of IFN-gamma-producing ILC1 cells as compared to control RORgammat-sufficient Rag-2(-/-) mice. Collectively, not only the presence of ILC22 cells but also the balance of protective and pathogenic ILCs may be involved in the prevention of colitis.

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T-helper 17 and interleukin-17-producing lymphoid tissue inducer-like cells make different contributions to colitis in mice

Ono, Y., Kanai, T., Sujino, T., Nemoto, Y., Kanai, Y., Mikami, Y., Hayashi, A., Matsumoto, A., Takaishi, H., Ogata, H., Matsuoka, K., Hisamatsu, T., Watanabe, M. and Hibi, T.

Gastroenterology 143 ( 5 ) 1288 - 1297 2012.11

ISSN 0016-5085

BACKGROUND & AIMS: T helper (Th) 17 cells that express the retinoid-related orphan receptor (ROR) gammat contribute to the development of colitis in mice, yet are found in normal and inflamed intestine. We investigated their development and functions in intestines of mice. METHODS: We analyzed intestinal Th17 cells in healthy and inflamed intestinal tissues of mice. We analyzed expression of lymphotoxin (LT)alpha by Th17 cells and lymphoid tissue inducer-like cells. RESULTS: LTalpha(-/-) and RORgammat(-/-) mice had significantly lower percentages of naturally occurring Th17 cells in the small intestine than wild-type mice. Numbers of CD3(-)CD4(+/-)interleukin-7Ralpha(+)c-kit(+)CCR6(+)NKp46(-) lymphoid tissue inducer-like cells that produce interleukin-17A were increased in LTalpha(-/-) and LTalpha(-/-) x recombination activating gene (RAG)-2(-/-) mice, compared with wild-type mice, but were absent from RORgammat(-/-) mice. Parabiosis of wild-type and LTalpha(-/-) mice and bone marrow transplant experiments revealed that LTalpha-dependent gut-associated lymphoid tissue structures are required for generation of naturally occurring Th17 cells. However, when wild-type or LTalpha(-/-) CD4(+)CD45RB(high) T cells were transferred to RAG-2(-/-) or LTalpha(-/-)xRAG-2(-/-) mice, all groups, irrespective of the presence or absence of LTalpha on the donor or recipient cells, developed colitis and generated Th1, Th17, and Th17/Th1 cells. RAG-2(-/-) mice that received a second round of transplantation, with colitogenic but not naturally occurring Th17 cells, developed intestinal inflammation. The presence of naturally occurring Th17 cells in the colons of mice inhibited development of colitis after transfer of CD4(+)CD45RB(high) T cells and increased the numbers of Foxp3(+) cells derived from CD4(+)CD45RB(high) T cells. CONCLUSIONS: Gut-associated lymphoid tissue structures are required to generate naturally occurring Th17 cells that have regulatory activities in normal intestines of mice, but not for colitogenic Th17 and Th17/Th1 cells during inflammation.

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IgA plasma cells express the negative regulatory co-stimulatory molecule programmed cell death 1 ligand and have a potential tolerogenic role in the intestine

Doi, T., Kanai, T., Mikami, Y., Sujino, T., Jun, L., Ono, Y., Hayashi, A. and Hibi, T.

Biochem Biophys Res Commun 425 ( 4 ) 918 - 23 2012.09

ISSN 0006-291X

To maintain immune homeostasis in the intestine, the intestinal immune system has evolved several tolerogenic mechanisms toward intestinal microflora and food antigens. Although programmed cell death-1 (PD-1) protein has been implicated in immunological tolerance in the intestine and gut-associated lymphoid tissues (GALTs), distribution of its ligands PD-L1 and PD-L2 in the small intestine lamina propria (LP) are unknown. We investigated PD-L1 expression in intestinal LP and found that IgA plasma cells (PCs) were major PD-L1 expressing cells. PD-L1 expression levels on IgA PCs were higher than that on IgG PCs in peripheral lymphoid tissues. IgA PCs expressed antigen-presenting molecule MHC class II and co-stimulatory molecules CD80, CD86, and PD-L2. IgA PCs isolated from intestinal LP exhibited antigen presentation activity, and in the presence of TGF-beta induced FoxP3(+) regulatory T cells, but not IFN-gamma(+) Th1 cells, from naive T cells. Thus, IgA PCs in the intestine may be involved in an immune regulatory role in the intestinal immune system.

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CCR9+ macrophages are required for eradication of peritoneal bacterial infections and prevention of polymicrobial sepsis

Mizukami, T., Kanai, T., Mikami, Y., Hayashi, A., Doi, T., Handa, T., Matsumoto, A., Jun, L., Matsuoka, K., Sato, T., Hisamatsu, T. and Hibi, T.

Immunol Lett 147 ( 1-2 ) 75 - 9 2012.09

ISSN 0165-2478

Sepsis is a systemic inflammatory response to infection associated with multiple organ dysfunction syndrome and a high mortality rate. In septic shock induced by severe peritonitis, early response of peritoneal macrophages against infected microbes is vital in preventing the spread of infection. We found that the mucosal homing receptor CCR9, is induced in peritoneal macrophages in response to inflammatory stimulation. We used a cecal ligation and puncture (CLP) model of sepsis to determine the role of CCR9 with respect to peritoneal macrophages, and controlling peritoneal infection and systemic inflammation. CCR9(-/-) mice showed aggravated septic shock with higher mortality rates compared with wild-type (WT) mice. Six hours after CLP, CCR9(-/-) mice demonstrated a greater inflammatory response. This was associated with higher production of inflammatory cytokines, such as IL-6, TNF and IP-10 in peritoneal lavage compared with WT mice. Although the numbers of peritoneal bacteria were elevated in CCR9(-/-) mice subjected to CLP compared with WT mice, this was normalized in CCR9(-/-) mice subjected to CLP through the adoptive transfer of WT peritoneal macrophages. We conclude that CCR9 is required for recruitment of peritoneal macrophages in the steady state to control systemic sepsis during early phases of peritoneal infection.

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CCR9+ plasmacytoid dendritic cells in the small intestine suppress development of intestinal inflammation in mice

Mizuno, S., Kanai, T., Mikami, Y., Sujino, T., Ono, Y., Hayashi, A., Handa, T., Matsumoto, A., Nakamoto, N., Matsuoka, K., Hisamatsu, T., Takaishi, H. and Hibi, T.

Immunol Lett 146 ( 1-2 ) 64 - 9 2012.08

ISSN 0165-2478

Almost all mice lacking specific molecules associated with regulatory T cells or barrier function develop intestinal inflammation in the colon, but not in the small intestine (SI). Therefore, intestinal homeostasis of the SI may be tightly controlled by other mechanisms. To determine the role of CCR9(+) plasmacytoid dendritic cells (pDCs) in intestinal homeostasis of the SI we transferred CD4(+)CD45RB(high) T cells into ccr9(-/-)xrag-2(-/-) mice. We showed that CCL25, a counterpart chemokine for CCR9, is constitutively expressed in the SI but not the colon and spleen of rag-2(-/-) or ccr9(-/-)xrag-2(-/-) mice before or after transfer of CD4(+)CD45RB(high) T cells. The ccr9(-/-)xrag-2(-/-) mice did not develop spontaneous intestinal inflammation in the SI and colon. Mice of both genotype where CD4(+)CD45RB(high) T cells were transferred developed colitis. However, the ccr9(-/-)xrag-2(-/-) mice also developed ileitis with marked infiltration of Th1 cells. These results suggest that CCR9(+) pDCs are possibly small, regulatory, antigen-presenting cells of the intestine that suppress intestinal inflammation.

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RORgammat-dependent IL-17A-producing cells in the pathogenesis of intestinal inflammation

Kanai, T., Mikami, Y., Sujino, T., Hisamatsu, T. and Hibi, T.

Mucosal Immunol 5 ( 3 ) 240 - 7 2012.05

ISSN 1933-0219

The hypothesis of helper T (T(h))1/T(h)2 cytokine balance proposed by Mosmann and Coffman is often invoked to explain the development of inflammatory diseases, including inflammatory bowel diseases (IBD). Recently, however, a newly identified class of T(h) cells-T(h)17 cells, which produce T(h)17 family cytokines-has been recognized as an essential subpopulation in the development of almost all kinds of human and animal inflammatory diseases, rather than T(h)1 and T(h)2 cells. A representative T(h)17 family cytokine, interleukin (IL)-17A, is produced by not only T(h)17 cells, but also by other types of cells, such as T-cell receptor gammadelta T cells, natural killer (NK) T cells, NK cells, myeloid cells, and innate lymphoid cells, which may also be critically involved in the initiation and persistence of IBD. Here we review recent advances in the study of such IL-17A-producing cells in the pathogenesis of IBD.

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CCR9+ macrophages are required for acute liver inflammation in mouse models of hepatitis

Nakamoto, N., Ebinuma, H., Kanai, T., Chu, P. S., Ono, Y., Mikami, Y., Ojiro, K., Lipp, M., Love, P. E., Saito, H. and Hibi, T.

Gastroenterology 142 ( 2 ) 366 - 76 2012.02

ISSN 0016-5085

BACKGROUND & AIMS: Antigen-presenting cells (APCs) are involved in the induction of liver inflammation. We investigated the roles of specific APCs in the pathogenesis of acute liver injury in mice. METHODS: We used concanavalin A (con A) or carbon tetrachloride to induce acute liver inflammation in mice and studied the roles of macrophages that express CCR9. RESULTS: After injection of con A, we detected CCR9(+)CD11b(+)CD11c(-) macrophages that express tumor necrosis factor (TNF)-alpha in livers of mice, whereas CCR9(+)Siglec-H(+)CD11b(-)CD11c(low) plasmacytoid DCs (pDCs), which are abundant in normal livers, disappeared. The CCR9(+) macrophages were also detected in the livers of RAG-2(-/-) mice, which lack lymphocytes and natural killer T cells, after injection of con A. Under inflammatory conditions, CCR9(+) macrophages induced naive CD4(+) T cells to become interferon gamma-producing Th1 cells in vivo and in vitro. CCR9(-/-) mice injected with con A did not develop hepatitis unless they also received CCR9(+) macrophages from mice that received con A; more CCR9(+) macrophages accumulated in their inflamed livers than CCR9(+) pDCs, CCR9(-) pDCs, or CCR9(-) macrophages isolated from mice that had received injections of con A. Levels of CCL25 messenger RNA increased in livers after injection of con A; neutralizing antibodies against CCL25 reduced the induction of hepatitis by con A by blocking the migration of CCR9(+) macrophages and their production of TNF-alpha. Peripheral blood samples from patients with acute hepatitis had greater numbers of TNF-alpha-producing CCR9(+)CD14(+)CD16(high) monocytes than controls. CONCLUSIONS: CCR9(+) macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.

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Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells

Sujino, T., Kanai, T., Ono, Y., Mikami, Y., Hayashi, A., Doi, T., Matsuoka, K., Hisamatsu, T., Takaishi, H., Ogata, H., Yoshimura, A., Littman, D. R. and Hibi, T.

Gastroenterology 141 ( 3 ) 1014 - 23 2011.09

ISSN 0016-5085

BACKGROUND & AIMS: Although T-helper (Th) 17 and Th1 cells are involved in pathogenesis of intestinal inflammation, their developmental pathways and sufficiency to promote disease are not known; nor are the roles of CD4(+)CD25(+) regulatory T (T(R)) cells in their development. METHODS: We performed adoptive transfer experiments to investigate the induction and suppression of colitis using naive CD4(+)CD45RB(high) T cells and/or CD4(+)CD25(+) T(R) cells that were obtained from retinoid-related orphan receptor gamma t (RORgammat) gfp/(+) or Ly5.1/Ly5.2 congenic mice. RESULTS: We observed 3 types of colitogenic CD4(+) Th1 cells (interleukin [IL]-17A(-)interferon [IFN]-gamma(+)): RORgammat(-) classical Th1 cells that differentiated directly from naive T cells; RORgammat(+) Th1-like cells; and RORgammat(-) alternative Th1 cells that were terminally differentiated from RORgammat(+) cells via Th17 (IL-17A(+)IFN-gamma(-)), Th17/Th1 (IL-17A(+)IFN-gamma(+)), or Th1-like (IL-17A(-)IFN-gamma(+)) cells. In this pathway, CD4(+)CD25(+) T(R) cells suppress the development of not only classical Th1 cells, but also alternative Th1 cells at the transition of Th17/Th1 into alternative Th1 cells, resulting in accumulation of Th17 and Th17/Th1 cells in mice in which the development of colitis was suppressed. Furthermore, T(R) cells regulated the established balance of Th17 and Th1 cells under colitic conditions to yield a high ratio of Th17 and Th17/Th1 cells to Th1 cells in noncolitic conditions. CONCLUSIONS: Th17 and Th17/Th1 cells become colitogenic alternative Th1 cells via Th17, Th17/Th1, and Th1-like cells, independently of classical Th1 cells. T(R) cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells.

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MyD88-dependent pathway accelerates the liver damage of Concanavalin A-induced hepatitis

Ojiro, K., Ebinuma, H., Nakamoto, N., Wakabayashi, K., Mikami, Y., Ono, Y., Po-Sung, C., Usui, S., Umeda, R., Takaishi, H., Yamagishi, Y., Saito, H., Kanai, T. and Hibi, T.

Biochem Biophys Res Commun 399 ( 4 ) 744 - 9 2010.09

ISSN 0006-291X

We have explored the pathological role of the MyD88 signaling pathway via Toll-like receptors (TLRs) that mediate the recognition of pathogen-associated molecular patterns (PAMPs) in a murine model of autoimmune hepatitis induced by administering Concanavalin A (ConA). We first found that various TLRs and MyD88 molecules were expressed in liver of Con A-treated and untreated wild-type (WT) mice including liver macrophages. Flowcytometric analysis revealed that liver CD11b(+)CD11c(-) and CD11b(+)CD11c(+) antigen-presenting cells express TLR2, although NK and NKT cells did not. When WT and MyD88(-/-) mice were intravenously administered with Con A, the severity of hepatitis was significantly lower in Con A-injected MyD88(-/-) mice than in WT mice in terms of the histopathology, the levels of serum transaminase and pro-inflammatory cytokines (TNF-alpha, IFN-gamma, and IL-6), and upregulation of CD80/CD86 and TNF-alpha on/in liver macrophages. The results provide evidence of a possible contribution of the TLRs-MyD88 signaling pathway in activating TLR-expressing liver macrophages in the autoimmune hepatitis model, and thus indicate that the strategy of blockade of pathological pathogens via the intestinal lumen may be feasible for the treatment of the disease.

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Competition between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis

Mikami, Y., Kanai, T., Sujino, T., Ono, Y., Hayashi, A., Okazawa, A., Kamada, N., Matsuoka, K., Hisamatsu, T., Okamoto, S., Takaishi, H., Inoue, N., Ogata, H. and Hibi, T.

Eur J Immunol 40 ( 9 ) 2409 - 22 2010.09

ISSN 0014-2980

Th17 cells and Th1 cells coordinate to play a critical role in the formation of inflammatory bowel diseases. To examine how Th17 and Th1 cells are regulated at inflammatory sites, we used Th1-dominant CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) and Th1/Th17-mixed IL-10(-/-) mice. Interestingly, not only did colitic RAG-2(-/-) mice that were parabiosed with WT mice show significant amelioration of colitis, but amelioration of disease was also observed in those parabiosed with colitic IL-10(-/-) mice. To assess the interference between Th1 and Th17 colitogenic T cells, we co-transferred colitogenic CD4(+) T cells from the lamina propria (LP) of CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) mice and IL-10(-/-) mice into RAG-2(-/-) mice. Surprisingly, the co-transferred RAG-2(-/-) mice showed a vast cellular infiltration of LP CD4(+) T cells similar to that seen in RAG-2(-/-) mice re-transferred with the cells from colitic RAG-2(-/-) mice alone, but the co-transferred RAG-2(-/-) mice did not have the wasting symptoms, which are also absent in RAG-2(-/-) mice transferred with cells from colitic IL-10(-/-) mice alone. Furthermore, the percentages of Th1 and Th17 cells originating from IL-10(-/-) mice and those of Th1 cells originating from colitic RAG-2(-/-) mice were all significantly decreased in the co-transferred mice as compared with the singly-transferred paired RAG-2(-/-) mice, suggesting that Th1 and Th17 cells are in competition, and that their orchestration results in a merged clinical phenotype of the two types of murine colitis.

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Monocyte chemoattractant protein-1 contributes to gut homeostasis and intestinal inflammation by composition of IL-10-producing regulatory macrophage subset

Takada, Y., Hisamatsu, T., Kamada, N., Kitazume, M. T., Honda, H., Oshima, Y., Saito, R., Takayama, T., Kobayashi, T., Chinen, H., Mikami, Y., Kanai, T., Okamoto, S. and Hibi, T.

J Immunol 184 ( 5 ) 2671 - 6 2010.03

ISSN 0022-1767

Lamina propria macrophages (LPMs) spontaneously produce large amounts of anti-inflammatory IL-10 and play a central role in regulation of immune responses against commensal bacteria. MCP-1 is a chemokine that plays an important role in recruitment of monocytes and macrophages to inflamed tissues. We demonstrated that, in addition to IL-10, LPMs produced large amounts of MCP-1, even in a steady state. MCP-1 deficiency caused impaired IL-10 production by LPMs and led to exacerbation of dextran sulfate sodium-induced acute colitis. As an explanation of this impaired IL-10 production by LPMs, we found that LPMs could be separated into two subsets with distinct side-scattered properties, namely LPM1 (CD11b(+)F4/80(+)CD11c(-)SSC(hi)) and LPM2 (CD11b(+)F4/80(+)CD11c(-)SSC(lo)). Unlike LPM1, the LPM2 subset migrated in response to MCP-1 and produced a larger amount of IL-10 in response to commensal bacteria. LPMs isolated from MCP-1-deficient mice produced less IL-10 as a consequence of the lack of the MCP-1-dependent LPM2 population. This imbalanced composition in LPM population may be involved in the susceptibility to DSS-induced colitis in MCP-1-deficient mice. Our results suggest that endogenous MCP-1 contributes to the composition of resident LPM subsets in the intestine. Moreover, MCP-1-dependent LPM2 subset may play an important role in maintenance of gut homeostasis in the steady state, and in the termination of excess inflammatory responses in the intestine, by producing IL-10.

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Critical role of class IA PI3K for c-Rel expression in B lymphocytes

Matsuda, S., Mikami, Y., Ohtani, M., Fujiwara, M., Hirata, Y., Minowa, A., Terauchi, Y., Kadowaki, T. and Koyasu, S.

Blood 113 ( 5 ) 1037 - 44 2009.01

ISSN 0006-4971

The fact that the Xid mutation of Btk impairs the ability of pleckstrin homology domain of Btk to bind phosphatidylinositol-(3,4,5)-trisphosphate, a product of class IA phosphoinositide-3 kinases (PI3Ks), has been considered strong evidence for the hypothesis that Btk functions downstream of PI3Ks. We demonstrate here that the Xid mutation renders the Btk protein unstable. Furthermore, class IA PI3K- and Btk-deficient mice show different phenotypes in B-cell development, collectively indicating that PI3Ks and Btk differentially function in BCR signal transduction. Nevertheless, both PI3K and Btk are required for the activation of NF-kappaB, a critical transcription factor family for B-cell development and function. We demonstrate that PI3Ks maintain the expression of NF-kappaB proteins, whereas Btk is known to be essential for IkappaB degradation and the translocation of NF-kappaB to the nucleus. The loss of PI3K activity results in marked reduction of c-Rel and to a lesser extent RelA expression. The lentivirus-mediated introduction of c-Rel corrects both developmental and proliferative defects in response to BCR stimulation in class IA PI3K-deficient B cells. These results show that the PI3K-mediated control of c-Rel expression is essential for B-cell functions.

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