Diet-Microbiota Interactions Mediate Global Epigenetic Programming in Multiple Host Tissues

Abstract

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.

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

“…Antibiotic administration can impact transcript levels and histone modifications in IECs (Thaiss et al 2016); however, it's unclear if these changes are indirect effects caused by alterations to microbiota composition, direct effects of the antibiotic on host cells, or the effects of remaining antibiotic-resistant microbiota (Morgun et al 2015). Previous studies have shown that histone deacetylase 3 is required in IECs to maintain intestinal homeostasis in the presence of microbiota (Alenghat et al 2013) and that overall histone acetylation and methylation in the intestine is altered by microbiota colonization (Krautkramer et al 2016). However, the direct and specific effects of the microbiota on host CRRs and subsequent transcriptional responses in IECs remain unknown.…”

Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels

“…The ketone body ␤-hydroxybutyrate can also act as a histone deacetylase inhibitor that elevates tissue histone acetylation levels and alters gene expression patterns under ketogenic dietary conditions (14). Finally, it has recently been shown that short-chain fatty acids produced by gut microbiota influence host tissue histone acetylation and methylation in a diet-dependent manner (15).…”

The Western Diet–Microbiome-Host Interaction and Its Role in Metabolic Disease

“…However, recent studies in rodents have demonstrated that loss of microbiota diversity due to dietary changes can be transferred to later generations , with progressive loss of diversity [35]. Also, a Western diet could lead to a permanent loss of bacteria important to microbiome function [36], and possibly induce inheritable metabolic changes via the epigenome [37]. In sum, the environment created in the gut by ultra-processed foods could be an evolutionarily unique selection ground for microbes with behaviors that promote diverse forms of inflammation-related disease.…”