Dihydromyricetin improves DSS-induced colitis in mice via modulation of fecal-bacteria-related bile acid metabolism

• Published in: Pharmacological research 2021-09, Vol.171, p.105767, Article 105767
• Main Authors: Dong, Sijing, Zhu, Min, Wang, Ke, Zhao, Xiaoye, Hu, Longlong, Jing, Wanghui, Lu, Haitao, Wang, Sicen
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Bacteria - genetics; Bacteria - metabolism; Bile acids; Bile Acids and Salts - metabolism; Caco-2 Cells; Colitis; Colitis - chemically induced; Colitis - immunology; Colitis - microbiology; Colitis - therapy; Colon - immunology; Colon - pathology; Dextran Sulfate; Dihydromyricetin; Dysbiosis - chemically induced; Dysbiosis - immunology; Dysbiosis - microbiology; Dysbiosis - therapy; Farnesoid X receptor; Fecal Microbiota Transplantation; Feces - microbiology; Flavonols - pharmacology; Flavonols - therapeutic use; G-protein-coupled bile acid receptor; Gastrointestinal Microbiome - drug effects; Gut microbiota; Humans; Interleukin-1beta - immunology; Male; Mice; Mice, Inbred C57BL; Receptors, Cytoplasmic and Nuclear - immunology; Receptors, G-Protein-Coupled - immunology; Tumor Necrosis Factor-alpha - immunology
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2021.105767

Recent studies show that the nutraceutical supplement dihydromyricetin (DHM) can alleviate IBD in murine models by downregulating the inflammatory pathways. However, the molecular mechanistic link between the therapeutic efficiency of DHM, gut microbiota, and the metabolism of microbial BAs remains elusive. In this study, we explored the improvement of DHM on the dysregulated gut microbiota of mice with dextran sulfate sodium (DSS)-induced colitis. We found that DHM could markedly improve colitis symptoms, gut barrier disruption, and colonic inflammation in DSS-treated mice. In addition, bacterial 16S rDNA sequencing assay demonstrated that DHM could alleviate gut dysbiosis in mice with colitis. Furthermore, antibiotic-mediated depletion of the gut microflora and fecal microbiome transplantation (FMT) demonstrated that the therapeutic efficiency of DHM was closely associated with gut microbiota. BA-targeted metabolomics analysis revealed that DHM restored the metabolism of microbial BAs in the gastrointestinal tract during the development of colitis. DHM significantly enriched the proportion of the beneficial Lactobacillus and Akkermansia genera, which were correlated with increased gastrointestinal levels of unconjugated BAs involving chenodeoxycholic acid and lithocholic acid, enabling the BAs to activate specific receptors, such as FXR and TGR5, and maintaining intestinal integrity. Taken together, DHM could alleviate DSS-induced colitis in mice by restoring the dysregulated gut microbiota and BA metabolism, leading to improvements in intestinal barrier function and colonic inflammation. Increased microbiota-BAs-FXR/TGR5 signaling may be the potential targets of DHM in colitis. Therefore, our findings provide novel insights into the development of novel DHM-derived drugs for the management of IBD. [Display omitted]