The protective effect and mechanism of the FXR agonist obeticholic acid via targeting gut microbiota in non-alcoholic fatty liver disease

• Published in: Drug design, development and therapy development and therapy, 2019-07, Vol.13, p.2249-2270
• Main Authors: Zhang, Dan-Ying, Zhu, Lin, Liu, Hai-Ning, Tseng, Yu-Jen, Weng, Shu-Qiang, Liu, Tao-Tao, Dong, Ling, Shen, Xi-Zhong
• Format: Article
• Language: English
• Subjects: Abundance; Acids; Agonists; Animals; Antibiotics; Bacteria; Bile; bile acid; Bile acids; Bile Acids and Salts - antagonists & inhibitors; Bile Acids and Salts - biosynthesis; Biotechnology industries; Chenodeoxycholic Acid - analogs & derivatives; Chenodeoxycholic Acid - chemistry; Chenodeoxycholic Acid - pharmacology; Cholesterol; Deoxycholic acid; Diabetes; Diet; Digestive system; Drinking water; Endotoxemia; farnesoid X receptor; Fatty acids; Fatty liver; Fibrosis; Gastroenterology; gastrointestinal microbiome; Gastrointestinal Microbiome - drug effects; Gastrointestinal tract; Gene expression; High fat diet; Homeostasis; Hospitals; House mouse; Immune system; International economic relations; Intestinal microflora; Intestine; Laboratory animals; Liver; Liver diseases; Male; Medical research; metabolic diseases; Metabolism; Metabolites; Metronidazole; Mice; Mice, Inbred C57BL; Microbiomes; Microbiota; Microbiota (Symbiotic organisms); Microorganisms; Neomycin; Non-alcoholic fatty liver disease; Non-alcoholic Fatty Liver Disease - microbiology; Non-alcoholic Fatty Liver Disease - prevention & control; Obesity; Obeticholic acid; Oral administration; Original Research; Physiological aspects; Protective Agents - chemistry; Protective Agents - pharmacology; Proteins; Receptors, Cytoplasmic and Nuclear - agonists; Research methodology; RNA; rRNA 16S; Taurine; Tumor necrosis factor-TNF; Type 2 diabetes
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S207277

It is reported that various diseases such as non-alcoholic fatty liver disease (NAFLD) are associated with imbalance of microbiome. And FXR has been well investigated in liver diseases. The objective of this study was to identify the role of farnesoid X receptor agonist obeticholic acid via targeting gut microbiota in NAFLD. Male C57BL/6 mice were fed either a normal-chow diet or a high-fat diet (HFD). Obeticholic acid(30mg/(kg·d)) and/or a combination of antibiotics were administered orally by gavage to mice for 12 weeks. Gut microbiota profiles were established through 16S rRNA amplicon sequencing. The effects of obeticholic acid on liver inflammation, the gut barrier, endotoxemia, gut microbiome and composition of the bile acid were also investigated. Obeticholic acid treatment can significantly improve obesity, circulation metabolism disorders, liver inflammation and fibrosis, and intestinal barrier damage caused by HFD. Removal of normal commensal bacteria can weaken the effect of obeticholic acid. The gut microbial structure was changed, and abundance of Blautia was increased significantly after treated with obeticholic acid. After obeticholic acid treatment, the concentration of taurine-bound bile acid caused by HFD was reduced in the liver. Taken together, these data suggest that obeticholic acid has aprotective effect on NAFLD via changing the components of gut microbiota, specifically increasing the abundance of Blautia.