Fig. 4

Gut dysbiosis and bile acid metabolism in non-alcoholic fatty liver disease (NAFLD). a. Hepatocytes produce primary bile acids via the classic and alternative pathways. The classic pathway starts with cholesterol 7α-hydroxylase (CYP7A1) and the action of sterol 12α-hydroxylase (CYP8B1), which produces cholic acid (CA) or chenodeoxycholic acid (CDCA) through sterol 27 hydroxylase (CYP27A1) [227, 228]. The alternative pathway is initiated by CYP27A1 and produces CDCA through the action of oxysterol 7α-hydroxylase (CYP7B1) [229]. After a meal, the release of cholecystokinin from the pancreas causes bile stored in the gallbladder to be released into the duodenum. Then, ~ 95% of the bile acids involved in the hepatic intestinal circulation are reabsorbed by enterocytes via the apical sodium-dependent bile salt transporter (ASBT) [230] and excreted into the portal vein via organic solute transporter-α and -β (OSTα and OSTβ) [231, 232]. Finally, ~ 5% of bile acids are transported into the systemic circulation from hepatocytes via multidrug resistance-associated protein 3 (MRP3), MRP4, OSTα and OSTβ. b. Two kinds of farnesoid X receptor (FXR)-dependent pathways have been proposed for the feedback regulation of bile acid synthesis. Activation of hepatic FXR in the liver increases the expression of the small heterodimer partner (SHP), which inhibits CYP7A1 and CYP8B1 expression [233, 234]. In addition, FXR plays a key role in regulating metabolism in the liver by suppressing de novo lipogenesis (DNL), promoting β-oxidation and producing very-low-density lipoprotein (VLDL) [235,236,237]. In addition, activation of FXR in the intestine stimulates the production of FGF15/19, which inhibits CYP7A1 and activates the DNL pathway [238]. Another vital receptor for bile acids is Takeda G protein-coupled receptor 5 (TGR5), which promotes the production of glucagon-like peptide-1 (GLP-1) through increased cyclic adenosine monophosphate (cAMP) [239, 240]. c. In healthy conditions, the production of butyrate aids in the consumption of oxygen to maintain anaerobic conditions through β-oxidation and decreases the production of nitrate, which is available for specific pathogens via conjunction with peroxisome proliferator activated receptor gamma (PPARγ). Short-chain fatty acids (SCFAs), another beneficial product derived from nondigestible carbohydrates [241], help to maintain metabolic homeostasis through the secretion of GLP-1 and Yin-Yang 1 (YY1) [110, 242]. However, under pathogenic conditions, decreased butyrate and SCFA levels disturb metabolic homeostasis