Papers - Mikami, Yohei

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

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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

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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

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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

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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

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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

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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

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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

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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

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© 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

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© 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

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© 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

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© 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

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© 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

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© 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

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© 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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