A Metagenome-Wide Association Study of the Gut Microbiome and Metabolic Syndrome

Abstract

Metabolic syndrome (MetS) is a wide-ranging disorder, which includes insulin resistance, altered glucose and lipid metabolism, and increased blood pressure and visceral obesity. MetS symptoms combine to result in a significant increase in cardiovascular risk. It is therefore critical to treat MetS in the early stages of the disorder. In this study, 123 MetS patients and 304 controls were recruited to determine whether the gut microbiome plays a role in MetS development and progression. By using whole-genome shotgun sequencing, we found that the gut microbiomes of MetS patients were different from those of controls, with MetS patients possessing significantly lower gut microbiome diversity. In addition, 28 bacterial species were negatively correlated with waist circumstance, with Alistipes onderdonkii showing the strongest correlation, followed by Bacteroides thetaiotaomicron, Clostridium asparagiforme, Clostridium citroniae, Clostridium scindens, and Roseburia intestinalis. These species were also enriched in controls relative to MetS patients. In addition, pathways involved in the biosynthesis of carbohydrates, fatty acids, and lipids were enriched in the MetS group, indicating that microbial functions related to fermentation may play a role in MetS. We also found that microbiome changes in MetS patients may aggravate inflammation and contribute to MetS diseases by inhibiting the production of short-chain fatty acids (SCFAs). Taken together, these results indicate the potential utility of beneficial gut microbiota as a potential therapeutic to alleviate MetS.

Keywords: comparative genomics; gut microbiota; metabolic pathway; metabolic syndrome; metagenomics.

FIGURE 1

The gut microbiota composition of the MetS and control groups. In both the MetS and control groups, gut microbiota was dominated by four abundant phyla, namely, Bacteroidetes (50.22 and 50.15%), Firmicutes (40.40 and 39.60%), Proteobacteria (4.50 and 4.88%), and Actinobacteria (2.32 and 2.19%). There were no significant differences in the phyla of the MetS compared to the control group (p > 0.05).

FIGURE 2

Alpha diversity, beta diversity, and bacterial profiles of feces. (A,B) Alpha diversity was measured by both Shannon index and Gini index for comparisons between the MetS and control groups. The MetS subject microbiomes had significantly lower species-level alpha diversity compared to the microbiomes of the control group (p = 0.03487 and p = 0.03678). (C–F) Beta diversity between the MetS group and control group. Beta diversity was calculated based on the Hellinger distance, JSD distance, Bray distance, and Spearman distance, and no significant differences were found between the MetS and control groups.

FIGURE 3

The relative abundance of bacterial species between the MetS and control groups. We used Wilcoxon tests to analyze the relative abundance of bacterial species and found significant differences in 39 species, with 31 enriched in the control group and 8 enriched in the MetS group. p < 0.05.

FIGURE 4

Significant correlations between bacteria and clinical characteristics. We found 28 species in which the abundance was negatively correlated with WC. Three species (Alistipes onderdonkii, Bacteroides thetaiotaomicron, and Clostridium asparagiforme) were negatively correlated with WC, VFA, FBG, HbA1c, and UC.*p < 0.05, **p < 0.01.

FIGURE 5

The functional shifts of bacterial species between the MetS and control groups. We found that 64 pathways were significantly different, and 57 pathways were enriched in MetS subjects. p < 0.05. Within the 57 MetS-enriched pathways, we showed the 23 pathways that were responsible for metabolism of carbohydrates, fatty acids, lipids, amino acid, hormones, and halting cellular protein synthesis.