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Gut Microbiota Composition Is Associated With the Global DNA Methylation Pattern in Obesity

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Gut Microbiota Composition Is Associated With the Global DNA Methylation Pattern in Obesity

Bruno Ramos-Molina et al. Front Genet.

Abstract

Objective: Obesity and obesity-related metabolic diseases are characterized by gut microbiota and epigenetic alterations. Recent insight has suggested the existence of a crosstalk between the gut microbiome and the epigenome. However, the possible link between alterations in gut microbiome composition and epigenetic marks in obesity has been not explored yet. The aim of this work is to establish a link between the gut microbiota and the global DNA methylation profile in a group of obese subjects and to report potential candidate genes that could be epigenetically regulated by gut microbiota in adipose tissue. Methods: Gut microbiota composition was analyzed in DNA stool samples from 45 obese subjects by 16S ribosomal RNA (rRNA) gene sequencing. Twenty patients were selected based on their Bacteroidetes-to-Firmicutes ratio (BFR): HighBFR group (BFR > 2.5, n = 10) and LowBFR group (BFR < 1.2, n = 10). Genome-wide analysis of DNA methylation pattern in both whole blood and visceral adipose tissue of these selected patients was performed with an Infinium EPIC BeadChip array-based platform. Gene expression analysis of candidate genes was done in adipose tissue by real-time quantitative PCR. Results: Genome-wide analysis of DNA methylation revealed a completely different DNA methylome pattern in both blood and adipose tissue in the low BFR group vs. the high BFR group. Two hundred fifty-eight genes were differentially methylated in both blood and adipose tissue, of which several potential candidates were selected for gene expression analysis. We found that in adipose tissue, both HDAC7 and IGF2BP2 were hypomethylated and overexpressed in the low BFR group compared with the high BFR group. β values of both genes significantly correlated with the BFR ratio and the relative abundance of Bacteroidetes and/or Firmicutes. Conclusions: In this study, we demonstrate that the DNA methylation status is associated with gut microbiota composition in obese subjects and that the expression levels of candidate genes implicated in glucose and energy homeostasis (e.g., HDAC7 and IGF2BP2) could be epigenetically regulated by gut bacterial populations in adipose tissue.

Keywords: adipose tissue; epigenetics; gut microbiota; methylation; obesity.

Figures

Figure 1
Figure 1
Categorization of study patients into the HighBFR and LowBFR groups according to dominant bacterial phyla. Box plots (range min–max) show the Bacteroidetes-to-Firmicutes ratio and the relative abundance (%) of five more predominant bacterial phyla: Bacteroidetes, Firmicutes, Proteobacteria, Acidobacteria, and Fusobacteria. Comparisons between groups were performed using t test analysis (***p < 0.0001).
Figure 2
Figure 2
Association between the gut microbiota composition and the DNA methylome in blood (A) and visceral adipose tissue (VAT) (B). The analysis of methylation data yielded a set of genes that were significant differentially methylated among subjects with a predominance of either Bacteroidetes (HighBFR) or Firmicutes (LowBFR) in the gut microbial population. Green indicates decreased and red indicates increased methylation in the LowBFR group compared with the promoter methylation in the HighBFR group. (C) Venn diagram of genes differentially methylated in both whole blood and visceral adipose tissue.
Figure 3
Figure 3
Association between the DNA methylation status of histone deacetylase 7 (HDAC7) and the gut microbiota composition in obese subjects. (A) Methylation of HDAC7 (쌠β value) in the HighBFR vs. LowBFR groups in both visceral adipose tissue and whole blood. Data (n = 10 per group) are plotted as means ± SE. Significance was tested using Mann–Whitney U test and is indicated as *p < 0.05. (B) Spearman correlations between HDAC7 methylation and the ratio Bact/Firm in both visceral adipose tissue and whole blood. (C) Spearman correlation between HDAC7 methylation and the relative abundance (%) of Firmicutes in whole blood. (D) Spearman correlation between HDAC7 methylation and the relative abundance (%) of Bacteroidetes in visceral adipose tissue.
Figure 4
Figure 4
Association between the DNA methylation status of insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) and the gut microbiota composition in obese subjects. (A) Methylation of IGF2BP2 (쌠β value) in the HighBFR vs. LowBFR groups in both visceral adipose tissue and whole blood. Data (n = 10 per group) are plotted as means ± SE. Significance was tested using Mann–Whitney U test and is indicated as *p < 0.05. (B) Spearman correlations between IGF2BP2 methylation in visceral adipose tissue and the ratio Bact/Firm or the relative abundance (%) of Bacteroidetes.

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