Summary Histone-modifying enzymes regulate transcription and are sensitive to availability of endogenous small-molecule metabolites, allowing chromatin to respond to changes in environment. The gut microbiota produces a myriad of metabolites that affect host physiology and susceptibility to disease, however the underlying molecular events remain largely unknown. Here we demonstrate that microbial colonization regulates global histone acetylation and methylation in multiple host tissues in a diet-dependent manner: consumption of a “Western-type” diet prevents many of the microbiota-dependent chromatin changes that occur in a polysaccharide rich diet. Finally, we demonstrate that supplementation of germ-free mice with short-chain fatty acids, major products of gut bacterial fermentation, is sufficient to recapitulate chromatin modification states and transcriptional responses of colonization on host epigenetic programming. These findings have profound implications for understanding the complex functional interactions between diet, gut microbiota, and host health.

SUMMARY Genetic variation drives phenotypic diversity and influences the predisposition to metabolic disease. Here, we characterize the metabolic phenotypes of eight genetically distinct inbred mouse strains in response to a 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 and identified taxa associated with these traits. Follow-up microbiota transplant experiments showed that altering the composition of the gut microbiota modifies strain-specific susceptibility to diet-induced metabolic disease. Animals harboring microbial communities with enhanced capacity for processing dietary sugars and for generating hydrophobic bile acids showed increased susceptibility to metabolic disease. Notably, differences in glucose-stimulated insulin secretion between different mouse strains were partially recapitulated via gut microbiota transfer. Our results suggest that the gut microbiome contributes to the genetic and phenotypic diversity observed among mouse strains and provide a link between the gut microbiome and insulin secretion.

Genetic variation drives phenotypic diversity and determines predisposition to cardiovascular disease. Previous work revealed a large degree of variation on atherosclerosis susceptibility among 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). Additionally, each HMDP inbred strain shows a distinct microbiota composition. Here, we assessed the contributions of the gut microbiome to the development of atherosclerosis. Cecal samples from four HMDP strains showing disparate atherosclerosis phenotypes were transplanted into groups of ApoE -/- germ-free mice. Transplanted ApoE -/- mice were maintained on a high-plant polysaccharide diet containing 0.2% cholesterol for 8 weeks and analyzed for atherosclerotic lesions, microbiome, and metabolome. We found that mice colonized with cecal microbes from two HMDP donors prone to atherosclerosis development exhibited larger lesions compared to recipient mice colonized with samples from donors that show little signs of atherosclerosis. Metabolomic analyses of plasma from transplanted mice and metagenomic analyses of cecal contents from the transplanted and 24 HMDP donor mice identified microbial functions that are associated with the severity of disease. Altogether, our work provides novel insights into how microbes contribute to the development of cardiovascular disease and suggest that host genotype may select for microbial communities that modulate progression of atherosclerosis.