○Shunya Hatai1,2 Yasutaka Motomura2,3 Kazuyo Moro1,2,4 et al.4 Lab. for Innate Immune Syst., Immunology Frontier Res. Center, The Univ. of Osaka.1 Lab. for Innate Immune Systems, RIKEN IMS.2 Lab. for Innate Immune Syst., The Univ. of Osaka. 3 Res. Inst. for Biomedical Sci., Tokyo Univ. of Sci.Cecal resection-driven gut microbiota dynamics alleviate ColitisUlcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa, characterized by persistent erosions and ulcerations. Epidemiological studies indicate that appendectomy significantly reduces the lifetime risk of UC, yet the underlying mechanisms remain elusive. Here, we uncover a novel gut microbiota-metabolite axis through which cecal resection (CR) mitigates UC pathology, even in mice inherently lacking a cecum. CR significantly reduces weight loss, colonic bleeding, and pro-inflammatory cytokine levels, while simultaneously increasing tuft cell numbers and IL-25 production, which activate group 2 innate lymphoid cells (ILC2s). Although IL-5 from ILC2s does not contribute to colitis alleviation, IL-13 enhances mucosal barrier function by promoting goblet cell hyperplasia and mucus production, thereby reinforcing epithelial integrity. Notably, the protective effects of CR were abolished by cohousing with untreated mice, highlighting the role of gut microbiota in mediating these benefits. Metagenomic analysis revealed that CR enhances gut microbiota evenness, while metabolomic profiling demonstrated that CR increases fecal levels of 11-hydroxy-eicosapentaenoic acid (11-HEPE). Most strikingly, rectal administration of 11-HEPE induces tuft cell hyperplasia, which in turn attenuates colitis. Further supporting this mechanism, tuft cell hyperplasia was observed in post-appendectomy patients, and 11-HEPE was found to drive tuft cell differentiation in human colonic organoids. Together, these findings establish a novel microbiota-metabolite-tuft cell axis linking CR to UC suppression and identify 11-HEPE and tuft cells as promising therapeutic targets for UC treatment. 42P 012
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