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. 2016 Dec 1;64(5):982-992.
doi: 10.1016/j.molcel.2016.10.025. Epub 2016 Nov 23.

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

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Free PMC article

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

Kimberly A Krautkramer et al. Mol Cell. .
Free PMC article

Abstract

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 associated with colonization. These findings have profound implications for understanding the complex functional interactions between diet, gut microbiota, and host health.

Keywords: SCFA; epigenetic; gut microbiota; histone PTM; histone acetylation; histone methylation; histone proteomics; microbiome; short-chain fatty acid.

Figures

Figure 1
Figure 1
Gut microbiota affect host tissue epigenetic states. (A) Experimental design: 1. tissues harvested from germ-free (GF), conventionally raised (ConvR), and conventionalized (ConvD) mice. 2-3. Histones extracted, chemically derivatized and trypsinized. 4-5. Histone peptides injected onto mass spectrometer and data acquired on >60 unique histone PTM states. (B) Relative abundance of histone PTMs on H3, H3.3, and H4. Values are reported as a fold change vs. GF controls (log2). Mean % of peptide family total across all samples (right-most column). *p<0.05, **p<0.01, ***p<0.001, n=4 mice per condition.
Figure 2
Figure 2
Gut microbiota-mediated epigenetic changes are sensitive to diet. (A) Experimental design: 1. GF and ConvR mice on either chow or a HF/HS (“Westernized”) diet. 2-5. Tissues prepared and analyzed as described in Figure 1. (B) Weights of GF and ConvR mice fed a HF/HS diet at the time of sacrifice. (C) Hepatic total cholesterol, and (D) hepatic triglycerides in GF, ConvD, and ConvR mice on chow and HF/HS diets. (E) SCFA measurement in cecal contents from GF, ConvR, and ConvD animals on chow and HF/HS diet. *p<0.05, **p<0.01, error bars represent standard deviation, n = 4 mice per condition. (F-H) H4 (K5, K8, K12, and K16) acetylation in colonized liver (F), adipose tissue (G), and proximal colon (H) relative to GF controls (fold change, log2). (I-J) H3 K18 and K23 methylation and acetylation in colonized liver (I) and proximal colon (J) relative to GF controls (fold change, log2). *p<0.05, **p<0.01, ***p<0.001, error bars represent standard error from the mean, n=4 mice per condition
Figure 3
Figure 3
Hepatic genes are co-regulated in colonized mice as a function of diet or colonization status. (A) K-means clustering of differentially expressed hepatic genes (left, fold change vs. GF, log2) and KEGG pathway enrichment terms (right). (B-D) Interaction network for cluster 2 (B), cluster 4 (C), and cluster 6 (D). Only genes with at least one reported interaction are graphed. Edges indicate interaction. Node size indicates relative expression in HF/HS-fed mouse livers. Node color indicates relative expression in chow-fed mouse livers.
Figure 4
Figure 4
SCFA-supplementation mimics colonization-induced epigenetic programming. (A) Experimental design: 1. Germ-free mice supplemented with SCFAs (GF+SCFA) or colonized (ConvD) and tissues were harvested. 2-5. Histone extracts prepared as described in figure 1. (B) Hierarchical clustering of histone PTMs in colonized and GF+SCFA mouse tissues (fold change vs. GF, log2). (C-D) Pearson's correlation of ConvD and GF+SCFA mouse tissue histone PTM states in liver (C) and proximal colon (D). (E) K-means clustering of differentially expressed hepatic genes in ConvD and GF+SCFA mice. FDR cutoff for differential expression = 0.05, n = 3 mice per condition. (F) GO-term enrichment in clusters b and c. (G) Overlap of differentially expressed genes between ConvD and GF+SCFA mice.

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