Lymphotoxin reduces commensal diversity to enable diet induced obesity (120.2)

Abstract

Abstract Commensal microbes exist in a state of symbiosis with host immunity and are essential for weight gain in diet induced obesity (DIO). Lymphotoxin α (LTα), a key molecule in mucosal defense, has been linked to obesity. We report that mice lacking LTα, LTβ, and LTβ-receptor (LTβR) resist DIO. The microbial communities of LTβR+/- mice and LTβR-/- mice differed on normal chow (NCD) and after high fat diet (HFD). The microbial community of LTβR+/- mice was less diverse after HFD, a hallmark of the “obese microbiome” in humans. On the contrary, LTβR-/- animals maintained similarly diverse communities to their NCD counterparts while on HFD. A specific microbe, Segmented Filamentous Bacteria (SFB), was cleared after HFD in LTβR+/- but not LTβR-/- mice and served as a marker of diversity loss. Transplantation of cecal contents from LTβR-/- animals conferred less weight gain than that of LTβR+/- mice to WT germ free mice, demonstrating a causal relationship between differing microbiota and weight gain. Housing LTβR-/- mice with their LTβR+/- siblings rescued weight gain, demonstrating horizontal transmissibility of the obese phenotype. HFD induced IL-23, an SFB associated cytokine, within the colon, but this induction was absent in LTβR-/- mice. Mice deficient in IL-23 (p19-/-) and the downstream cytokine IL-22 (RORγt-/-) also resisted DIO. Our data suggests that HFD induced inflammation reduces commensal diversity to enable weight gain, which may underlie the pathogenesis of obesity.