Fiber-mediated nourishment of gut microbiota protects against diet-induced obesity by restoring IL-22-mediated colonic health

Dietary supplementation with fermentable fiber is thought to suppress metabolic syndrome via production of short-chain fatty acids (SCFA), which activate free fatty acid receptors including GPR43. However, herein, we demonstrate that fermentable (inulin), but not insoluble (cellulose) fiber, markedly protected mice against high-fat diet (HFD)-induced metabolic syndrome, which was not largely impaired by either inhibition of SCFA production nor genetic ablation of GPR43. Rather, we found that HFD decimates gut microbiota resulting in loss of IL-22 expression and enterocyte proliferation, leading to microbiota encroachment, low-grade inflammation (LGI) and metabolic syndrome. Enriching HFD with inulin restored microbiota loads, IL-22 production, enterocyte proliferation, and anti-microbial gene expression in a microbiota dependent manner, as assessed by antibiotic and germ-free approaches. Inulin-induced IL-22 expression, which required innate lymphoid cells, prevented microbiota encroachment and protected against LGI and metabolic syndrome. Thus, fermentable fiber protects against metabolic syndrome by nourishing microbiota to restore IL-22-mediated enterocyte function.