Intestinal epithelial β Klotho is a critical protective factor in alcohol-induced intestinal barrier dysfunction and liver injury

BACKGROUND: Intestinal barrier dysfunction is crucial in alcohol-associated liver disease (ALD). The decreased beta-Klotho (KLB) expression caused by gene variation is associated with hyperpermeability in patients with irritable bowel syndrome. Here we investigated the roles of intestinal KLB in maintaining the intestinal epithelial barrier in ALD and the underlying mechanisms. METHODS: We constructed the intestine-specific overexpression KLB mice to investigate the role of KLB on alcohol-induced intestinal barrier dysfunction and liver injury in an ALD mouse model. To investigate the molecular mechanism in vitro, Caco2 cells were cultured and infected with the KLB overexpression lentivirus, or transfected with KLB/TRPV6 siRNA, or TRPV6/FXR1 overexpression plasmid, and treated with or without ethanol. FINDINGS: The upregulation of KLB in enterocytes effectively protected mice from alcohol-induced intestinal barrier hyperpermeability, thereby ameliorating hepatic steatosis and inflammation. KLB competitively suppressed FXR1 binding to the TRPV6 mRNA, increasing TRPV6 mRNA stability and protein abundance in intestinal epithelial cells. Furthermore, KLB formed a complex with TRPV6 and tight junction (TJ) proteins, protecting against alcohol-induced TJ proteins endocytosis and degradation as well as intestinal barrier impairment. INTERPRETATION: This work suggested that KLB attenuated alcohol-induced intestinal epithelial barrier dysfunction and liver injury through FXR1/TRPV6/TJ proteins pathway. FUNDING: National Natural Science Foundation of China, Chongqing Natural Science Foundation, Talent Project of Chongqing and the Science and Technology Research Program of Chongqing Municipal Education Commission.