Wild-Derived Microbiota Protect Against Diet-Induced Obesity via an Immune-Mediated Effect on Brown Adipocytes 2305928

Abstract Introduction The prevalence of obesity and metabolic diseases increased in industrialized nations in parallel to reduced diversity of gut microbiota. We recently demonstrated that the reconstitution of conventional laboratory mice with complex microbiota from wild mice protects against diet-induced obesity. Methods To determine the mechanism for this protection, we studied energy expenditure, adipocyte transcriptome and immune response of a colony mice with complex natural microbiota (Wildlings) that was generated by rederiving C57BL/6 embryos in wild mice. Results Wildlings were protected against diet-induced obesity throughout life and irrespective of sex, diet, genetics. Wildlings had increased energy expenditure, which decreased significantly in thermoneutral conditions but remained higher than that of conventional laboratory mice on the same genetic background. Single-nuclei RNA sequencing revealed that the wild-derived microbiota induced changes in the brown adipocyte transcriptome, that indicated increased thermogenic activity. While conventional laboratory mice acquired the protective phenotype only when cohoused with Wildlings in the first two weeks of life, germ-free mice acquired it even after week-10 of age. This suggests that the timing of exposure to the natural microbiota relative to the induction of immune responses is relevant. Increased type 2 responses in brown adipose tissue did not contribute to the obesity protection phenotype, because IL-33 KO and STAT6 KO Wildlings were protected from diet-induced obesity. Rather, recruitment of bone marrow-derived monocytes was essential because CCR2 KO Wildlings showed reduced energy expenditure and no protection from diet-induced obesity. Transfer of Wildling bone marrow cells into CCR2 KO Wildling pups reconstituted the phenotype. Conclusion Collectively, these results demonstrate that wild-derived microbiota protect against diet-induced obesity via immune-mediated induction of brown adipose tissue thermogenesis. Funding Source Intramural Research Program of NIDDK, NIH Topic Categories Cytokines and Chemokines and their Receptors (CCR)