Host genotype and gut microbiome modulate insulin secretion and diet-induced metabolic phenotypes

Genetic variation drives phenotypic diversity and determines predisposition to metabolic disease. Host genetics also modulates the composition of the gut microbiota. However, the relative contributions of host vs. microbial genetic variation in the development of diet-induced metabolic phenotypes remain largely unknown. Here, we characterize the metabolic phenotypes of eight genetically distinct inbred mouse strains in response to a western-style high-fat/high-sucrose diet. We found significant variation in diabetes-related phenotypes and gut microbiota composition among the different mouse strains in response to the dietary challenge. Follow-up gnotobiotic mouse experiments showed that altering the composition of the gut microbiota modifies strain-specific susceptibility to diet-induced metabolic disease and insulin secretion. Animals with increased susceptibility to metabolic disease and increased insulin secretion exhibited an enhanced capacity to metabolize dietary sugars, higher levels of short-chain fatty acids and microbiota-derived bile acids (BA), and increased pancreatic gene expression of the BA-dependent regulator and activator of insulin secretion, Fxr. Our results suggest that the gut microbiome contributes to the genetic and phenotypic diversity observed among mouse strains and provide novel mechanistic insights linking microbial metabolism and insulin secretion.