Dietary fiber and microbiota-derived bile acids regulate type 2 immune response and metabolic homeostasis 3598

Abstract Description Diet alters both the composition and metabolic output of the intestinal microbiota, which has a major impact on the nature of immune responses. However, most microbiota-derived metabolites, their regulation by diet, and their immunoregulatory effects remain unknown. Employing untargeted metabolomics in mice, we show that an inulin fiber diet induces a significant shift in the levels of various microbial metabolites, notably elevated levels of bile acids. This metabolomic shift is associated with type 2 cytokine responses in several mucosal and visceral sites, characterized by elevated IL-33 in stromal cells, IL-5 production by group 2 innate lymphoid cells, and tissue eosinophilia. This eosinophilia is microbiota-dependent and can be reproduced by the administration of specific bile acids. Deletion of microbial metabolic genes or host bile acid receptors abolishes the eosinophilia. The fiber-induced eosinophils have distinct tissue-specific roles. In the mucosa, they promote defense against helminth infection but exacerbate disease outcomes during intestinal damage and inflammation. On the other hand, the fiber-induced eosinophils in visceral adipose tissues promote browning of white adipocytes and reduce tissue adiposity. Together, our studies identify novel molecular and cellular targets of diet- and microbiota-mediated immunoregulation with implications for the development of emerging precision nutrition and therapeutics for infection, inflammation, and metabolic health. Funding Sources NIH/K99AI173660, AI172027, DK132244; Crohn’s & Colitis Foundation Topic Categories Mucosal and Regional Immunology (MUC)