Review Article

Emerging Role of the Gut Microbiome in the Progression of Nonalcoholic Fatty Liver Disease and Potential Therapeutic Implications

Saumya Jayakumar; Rohit Loomba

Disclosures

Aliment Pharmacol Ther. 2019;50(2):144-158. 

In This Article

Gut Microbiota and Bile Acids

BA composition is influenced by gut microbiota, and BAs are also thought to play a role in the development of NAFLD.[115] Compared with healthy controls, patients with NASH have been shown to have higher concentrations of total faecal BA, cholic acid, chenodeoxycholic acid and BA synthesis, and a higher ratio of primary BA to secondary BA.[95] BAs such as chenodeoxycholic acid bind to the farnesoid X receptor (FXR) in the intestines.[116,117] FXR is a member of the nuclear receptor superfamily and plays a key role in the absorption and transport of BA into the liver, as well as de novo hepatic lipogenesis, very low-density lipoprotein transport and TG metabolism.[96,115,118] Mice deficient in FXR demonstrated increased hepatic TG and cholesterol content,[119] whereas FXR stimulation has been seen to suppress NFκB signalling, leading to decreased hepatic inflammation.[120] Of note, findings using the high-fat diet murine model of NAFLD demonstrated that intestinal antagonism of FXR through the manipulation of gut microbiota resulted in decreased hepatic lipogenesis.[115] Stimulation of FXR has also been shown to alter carbohydrate metabolism, phospho-enolpyruvate carboxykinase gene expression and gluconeogenesis regulation.[121]

Glucose homeostasis is also governed by GLP-1, which is stimulated by G-protein coupled receptor 5 (TGR5). Because the ligands for TGR5 are gut bacteria-derived secondary BAs, the gut microbiome may play a large part in both lipid metabolism (through FXR) and glucose homeostasis (through TGR5).[96,122] Animal models of NAFLD have shown reductions in hepatic steatosis after exposure to BA derivatives that are FXR agonists;[123] in the FXR Ligand Obeticholic Acid in NASH Treatment trial, improvement of hepatic steatosis and inflammation was observed in patients with NAFLD who received obeticholic acid.[124]

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