Details of a Researcher - Mikami, Yohei

Papers - Mikami, Yohei

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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<sup>+</sup> 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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