RIKEN IMS AnnualReport 2020
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Enormous numbers of commensal bacteria, the gut microbiota, reside in 40<Germ free>ILC2ILC2<SPF>ILC2ILC2ILC2B cellcommensal bacteriaIL-33IL-33R (ST2)Terminal differentiationIgA class switchIL-5IL-33IL-7LumenEpitheliumIL-7IL-7Rα(CD127)sIgAour intestines. Our lab has been studying the molecular mechanisms of host-gut microbiota interaction.We do not unconditionally accept those microorganisms. Instead, the in-testinal immune system senses the kinds and quantity of bacteria in the gut lumen and tries to contain them. To this end, our gut equips M cells, special-ized intestinal epithelial cells, for recognition and uptake of luminal bacteria to initiate intestinal immune responses. Our lab has been elucidated the molecular mechanisms of M-cell differentiation and function.Host-gut microbiota interactions deeply impact our physiology and pathol-ogy. We are studying this by applying an integrated omics approach, where cyclopedic analyses at different layers of organismal activities are combined, including (meta)genomics, epigenomics, (meta)transcriptomics and metabo-lomics. In the past year, we have published two papers reporting the role of the gut microbiota in autoimmune diseases. Multiple sclerosis (MS) is an autoim-mune demyelinating disease in the central nervous system. By employing mu-rine experimental autoimmune encephalomyelitis (EAE) as a model of MS, we have shown that two commensal bacteria in the small intestine act together to exacerbate EAE pathogenesis. We have also reported that Ruminococcus species in the gut can suppress the pathogenesis of autoimmune type 1 diabetes mel-litus by increasing immunosuppressive CD8+ regulatory T cells.The stomach has been almost a no man’s land in terms of immunology re-search, especially the innate lymphoid cells (ILCs). We have shown that ILC2s are dominant among ILCs, are dependent on stomach microbiota for their presence and are important for containing Helicobacter pylori infection (Figure).In addition, we are studying the impact of the gut microbiota and its me-tabolites on the gut immune system and the host metabolic activities, and also on diseases such as pediatric allergic diseases, type 2 diabetes and autoimmune diseases.Figure: Stomach ILC2s respond to commensal bacteriaIn germ-free (GF) mice (left), there are few ILC2s. Under GF conditions, IL-7 expression in the stomach tissue is hardly detectable and IL-7 receptor expression on stomach ILC2s is also lower than that under SPF condi-tions. By contrast, the expression of IL-33 in the stomach tissue is similar and that of the IL-33 receptor on the stomach ILC2s is slightly decreased in GF compared to SPF conditions. Under SPF conditions (right), stimula-tion by commensal bacteria upregulates the expression of IL-7 and IL-33 in the stomach tissue as well as that of IL-7 receptors on stomach ILC2s. This leads to an increase in the number of stomach ILC2s and their IL-5 secretion, which then promotes IgA production from plasma B cells (modified from Ohno H and Satoh-Takayama N. Exp Mol Med 52: 1377-1382 (2020)).Recent Major PublicationsMiyauchi E, Kim S-W, Suda W, Kawasumi M, Onawa S, Taguchi-Atarashi N, Morita M, Taylor TD, Hattori M, Ohno H. Gut microbes act in concert to exacerbate inflamma-tion in spinal cords. Nature 585, 102-106 (2020)Shimokawa C, Kato T, Takeuchi T, Ohshima N, Furuki T, Ohtsu Y, Suzue K, Imai T, Obi S, Olia A, Izumi T, Sakurai M, Arakawa H, Ohno H, Hisaeda H. CD8+ regulatory T cells are critical in prevention of autoimmune-mediated diabetes. Nat Commun. 11, 1922 (2020)Satoh-Takayama N, Kato T, Motomura Y, Kageyama T, Taguchi-Atarashi N, Kinoshita-Daitoku R, Kuroda E, Di Santo JP, Mimuro H, Moro K, Ohno H. Bacteria-Induced Group 2 Innate Lymphoid Cells in the Stomach Provide Immune Protection through Induction of IgA. Immu-nity 52, 635-649.e4 (2020)Invited presentationsOhno H. “Autoimmune diseases and gut microbiota” Fudan University Immunology Seminar (China/Online) December 2020Ohno H. “Gut microbiota and autoimmune diseases” The 29th Symposium on Intestinal Flora (Tokyo, Japan) November 2020Ohno H. “The role of gut microbiome in obesity and glucose intolerance” 2020 International Congress on Obesity and Metabolic Syndrome. Korean Society for the Study of Obesity (South Korea/Online) September 2020Ohno H. “Birth cohort-based analysis of pediatric atopic dermatitis and gut microbiota” Educational lecture, The 119th Annual Meeting of the Japanese Dermatological Association (Online) June 2020Ohno H. “Gut microbiota and autoimmune diseases” The 4th Chiba Probiotics Academic Seminar (Chiba, Japan) February 2020Laboratory for Intestinal EcosystemTeam Leader: Hiroshi Ohno

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