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The balance between bacterial colonization and its containment in the intestine is indispensable for the symbiotic relationship between humans and their bacteria. One component to maintain homeostasis at the mucosal surfaces is immunoglobulin A (IgA), the most abundant immunoglobulin in mammals.sup.1,2. Several studies have revealed important characteristics of poly-reactive IgA.sup.3,4, which is produced naturally without commensal bacteria. Considering the dynamic changes within the gut environment, however, it remains uncertain how the commensal-reactive IgA pool is shaped and how such IgA affects the microbial community. Here we show that acetate--one of the major gut microbial metabolites--not only increases the production of IgA in the colon, but also alters the capacity of the IgA pool to bind to specific microorganisms including Enterobacterales. Induction of commensal-reactive IgA and changes in the IgA repertoire by acetate were observed in mice monocolonized with Escherichia coli, which belongs to Enterobacterales, but not with the major commensal Bacteroides thetaiotaomicron, which suggests that acetate directs selective IgA binding to certain microorganisms. Mechanistically, acetate orchestrated the interactions between epithelial and immune cells, induced microbially stimulated CD4 T cells to support T-cell-dependent IgA production and, as a consequence, altered the localization of these bacteria within the colon. Collectively, we identified a role for gut microbial metabolites in the regulation of differential IgA production to maintain mucosal homeostasis. Acetate--a major gut microbial metabolite--increases the production of IgA in the colon, alters the capacity of the IgA pool to bind to specific microorganisms and alters the localization of these bacteria within the colon., Author(s): Tadashi Takeuchi [sup.1] [sup.2] , Eiji Miyauchi [sup.1] , Takashi Kanaya [sup.1] [sup.3] , Tamotsu Kato [sup.1] [sup.3] , Yumiko Nakanishi [sup.1] [sup.3] [sup.4] , Takashi Watanabe [sup.5] , [...]

The intestine is the largest peripheral lymphoid organ in animals, including humans, and interacts with a vast array of microorganisms called the gut microbiota. Comprehending the symbiotic relationship between the gut microbiota and our immune system is essential not only for the field of immunology but also for understanding the pathogenesis of various systemic diseases, including cancer, cardiometabolic disorders, and extraintestinal autoimmune conditions. Whereas microbe-derived antigens are crucial for activating the intestinal immune system, particularly T and B cells, as environmental cues, microbes and their metabolites play a critical role in directing the differentiation of these immune cells. Microbial metabolites are regarded as messengers from the gut microbiota, since bacteria have the ability to produce unique molecules that humans cannot, and many immune cells in the intestine express receptors for these molecules. This review highlights the distinct relationships between microbial metabolites and the differentiation and function of the immune system. [ABSTRACT FROM AUTHOR]

The gut microbial metabolite butyrate is shown to induce the differentiation of colonic T regulatory cells in mice and to ameliorate the development of colitis; it also increases histone H3 acetylation at the Foxp3 promoter. Bacterial butyrate influences immune balance Several lines of evidence indicate that subsets of commensal microbes shape the gut immune system. For instance, colonization with Clostridia promotes extrathymic generation of regulatory T (T.sub.reg) cells that have a central role in the suppression of inflammatory and allergic responses. However, the molecular basis of such microbe-mediated T.sub.reg induction remains unknown. Two papers in this issue of Nature show that the colonic microbial fermentation product butyrate significantly accelerates the differentiation of colonic T.sub.reg cells and ameliorates colitis in conjunction with an increase in histone H3 acetylation at the Foxp3 promoter. This finding links butyrate to the induction of functional T.sub.reg cells in the colonic mucosa, and also provides molecular insight into the therapeutic application of butyrate. Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell.sup.1,2,3,4,5. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (T.sub.reg) cells, which have a central role in the suppression of inflammatory and allergic responses.sup.3. However, the molecular mechanisms by which commensal microbes induce colonic T.sub.reg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic T.sub.reg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of T.sub.reg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of T.sub.reg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4.sup.+CD45RB.sup.hi T cells in Rag1.sup.-/- mice. Treatment of naive T cells under the T.sub.reg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of T.sub.reg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut., Author(s): Yukihiro Furusawa [sup.1] [sup.2] , Yuuki Obata [sup.1] [sup.2] [sup.3] , Shinji Fukuda [sup.1] [sup.4] , Takaho A. Endo [sup.1] , Gaku Nakato [sup.1] , Daisuke Takahashi [sup.1] , [...]