The pathophysiology of gut–liver connection

The physiological functions of the liver and the intestine are intimately connected by tightly regulated mechanisms. The liver secretes bile acids in the intestine, which are fundamental in lipid digestion but also regulate the composition of the gut microbiota. In turn, the intestine regulates the synthesis of bile acids by a feedback loop based on the FXR/FGF-19 axis, and secretes in the blood stream a number of incretins that participate in glucose and lipid metabolism, at least in part by modulating hepatic functions. Moreover, alteration of the gut permeability induced by a variety of factors (including dysbiosis) deeply influences the quantity and quality of metabolites and bacterial products that reach the liver via the portal blood and modulate hepatic molecular pathways. The dysregulation of the gut–liver axis plays therefore a crucial role in the pathogenesis of many metabolic diseases, and is actively studied in the context of nonalcoholic fatty liver disease (NAFLD). Strategies aiming at restoring intestinal permeability, modulating dysbiosis, or influencing molecular pathways involved in the regulation of the gut–liver axis have actively been investigated as potential new therapies for NAFLD. In the present chapter, the physiopathological bases of the “leaky gut hypothesis” and their relevance to the development of NAFLD will be presented in details. Moreover, current knowledge on incretins and bile acid pathway modulation in NAFLD will be discussed.