**7.10 With or without 'the intestinal microbiome and enterohepatic circulation'**

While the causal links between the microbiota and NAFLD have not been fully elucidated, disruption in intestinal permeability [159] and bacterial-derived ligands (e.g., LPS) and metabolites (e.g., secondary bile acids, short chain fatty acids) are putative mediators of this association.

It was elucidated recently that the presence of bacterial strain (*Klebsiella pneumoniae*), which produces high levels of endogenous alcohol was associated with NAFLD in a human cohort [160]. Bile acids are synthesised and secreted by hepatocytes and are involved in the absorption of dietary lipids. They are transported back to the liver by enterohepatic circulation and act on the nuclear farnesoid X receptor (FXR), which is also expressed on hepatocytes, thereby affecting glucose [161] and lipid metabolism. Further, the release of FGF after ileal FXR activation is a feedback mechanism that reduces bile acid synthesis, hepatic steatosis and IR [162]. Through their antimicrobial effects, bile acids also modulate the relationship between gut microbiota and chronic liver disease [163] and improve glucose metabolism by activation of G-protein coupled bile acid receptor (GPBAR1) in enterocytes. Therefore, targeting these mechanisms, for example, with an FXR agonist, is an attractive strategy for NAFLD therapy [164]. Gut-derived hormones, such as GLP-1, play a crucial role in controlling nutrient intake, absorption and metabolism and are attractive targets for metabolic disease in general, as well as in the liver [96].
