7 The mechanism for the maintenance of intestinal homeostasis竹田 潔1) Oguro-Igashira E, Murakami M, Mori R, et al. The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells. Proc Natl Acad Sci U S A. 2024. 121(44): e2318767121.2) Yokoi T, Murakami M, Kihara T, et al. Identification of a unique subset of tissue resident memory CD4+ T cells in Crohn's disease. Proc Natl Acad Sci USA. 2023. 120(1):e2204269120.3) Otake-Kasamoto Y, Kayama H, Kishikawa T, et al. Lysophosphatidylserines derived from microbiota in Crohn's disease elicit pathological Th1 response. J. Exp. Med. 2022. 219(7): e20211291.4) Morita N, Umemoto Eiji, Fujita S, et al. GPR31-dependent dendrite protrusion of intestinal CX3CR1+ cells by bacterial metabolites. Nature. 2019. 566(7742):110-114.5) Okumura R, Kurakawa T, Nakano T, et al. Lypd8 promotes the segregation of flagellated microbiota and colonic epithelia. Nature. 2016. 532(7597):117-121.大阪大学 免疫学フロンティア研究センター3. 腸管恒常性の維持機構The intestine is a unique tissue where microbiota exists. In a healthy condition, the activity of intestinal immunity is finely regulated to prevent inflammatory responses to microbiota. Dysregulated interaction of intestinal microbiota and intestinal immunity causes the development of inflammatory bowel disease (IBD). We found that Lypd8, which is selectively expressed on colonic epithelial cells, blocks the direct interaction of intestinal microbiota with the host cells, thereby regulating intestinal homeostasis. We also analyze how intestinal microbiota, which does not directly contact the intestinal epithelia, act on the host. Intestinal CX3CR1+ myeloid cells extend their dendrites into the lumen to uptake luminal antigens and induce adaptive immune responses. We purified luminal contents that induce dendrite extension of CX3CR1+ myeloid cells. It was found that lactate and pyruvate, which were produced in the intestinal lumen by bacteria, induce dendrite extension through Gpr31 and enhance immune responses against intestinal pathogenic bacteria. We then analyzed whether bacterial metabolites are implicated in the pathogenesis of IBD. Lysophosphatidylserine, which was increased in the intestinal lumen of Crohn’s disease patients, who had an increased number of bacteria possessing the phospholipase A gene, was found to mediate exacerbation of intestinal inflammation. Thus, bacterial metabolites mediating the host and microbiota interaction are implicated in intestinal homeostasis and intestinal inflammation.Immunology Frontier Research Center, The University of OsakaKiyoshi Takeda
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