Multi-omics analyses unveil gut microbiota and metabolites signatures in deoxycholic acid-associated intestinal inflammation.

OBJECTIVE: High-fat diet (HFD) is closely related to the increased incidence of inflammatory bowel disease (IBD), and excessive fecal deoxycholic acid (DCA) induced by HFD makes significant contribution to the colonic inflammation. However, the precise mechanisms remain unclear. This study aims to explore the association between DCA-induced alteration of gut microbiota as well as related metabolites and intestinal inflammation. METHODS: Wild-type C57BL/6 J mice were orally administrated with or without 0.2% DCA for 12 weeks, then the alteration of gut microbiota signature and fecal metabolites were analyzed by metagenomic sequencing and widely-targeted metabolomics, respectively. The colonic tissue injury was confirmed by histopathological analysis and pro-inflammatory cytokines production was determined by qPCR and ELISA. RESULTS: DCA administration induced gut microbiota dysbiosis and fecal metabolomic profile disturbance, accompanied with significantly increased expression of pro-inflammatory cytokines in intestine, including TNF-α, IL-6 and IL-1β, and obvious tissue damage. Specifically, α-diversity of gut microbiota was greatly reduced by excessive DCA, and abundance analysis together with linear discriminant analysis of effect size (LEfSe) identified Bacteroides and Desulfovibrio as potential biomarkers of DCA exposure. Excessive DCA significantly decreased the abundance of Eubacterium plexicaudatum, bacterium 1xD42-87 and Ruminococcus flavefaciens, which were positively correlated with the downregulation of multiple metabolites reported to possess anti-inflammatory activities, especially indoles, vitamin D3 and alpha-CEHC. Meanwhile, DCA administration dramatically increased the abundance of Parabacteroides distasonis and Bacteroide acidifacien, which were positively correlated with the upregulation of metabolites reported to have pro-inflammatory properties, including multiple bile acid metabolites such as chenodeoxycholic acid, glycochenodeoxycholic acid and lithocholic acid. Spearman correlation analysis emphasized the important effects of aforementioned microbiota and metabolites in the association between DCA and intestinal inflammation. CONCLUSION: Our study revealed that excessive DCA led to concurrent alterations of gut microbiota and metabolites, which exhibited significant correlations with intestinal inflammation, suggesting a potential indirect regulatory pathway that may involve gut microbiota. Targeting DCA-related gut microbiota or metabolites might represent a promising intervention for HFD-associated colonic inflammation.