Diet-microbiota interactions mediate global epigenetic programming in multiple host tissues

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.