There is compelling evidence implicating intestinal permeability in the pathogenesis of nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain poorly understood. Here we examined the role of bile acids (BA) in western diet (WD)‐induced loss of colonic epithelial barrier (CEB) function in mice with a genetic impairment in intestinal epithelial barrier function, junctional adhesion molecule A knockout mice, F11r ^−/− . WD‐fed knockout mice developed severe NASH, which was associated with increased BA concentration in the cecum and loss of CEB function. Analysis of cecal BA composition revealed selective increases in primary unconjugated BAs in the WD‐fed mice, which correlated with increased abundance of microbial taxa linked to BA metabolism. In vitro permeability assays revealed that chenodeoxycholic acid (CDCA), which was elevated in the cecum of WD‐fed mice, increased paracellular permeability, while the BA‐binding resin sevelamer hydrochloride protected against CDCA‐induced loss of barrier function. Sequestration of intestinal BAs by in vivo delivery of sevelamer to WD‐fed knockout mice attenuated colonic mucosal inflammation and improved CEB. Sevelamer also reduced hepatic inflammation and fibrosis, and improved metabolic derangements associated with NASH. Collectively, these findings highlight a hitherto unappreciated role for BAs in WD‐induced impairment of the intestinal epithelial barrier in NASH.

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of progressive liver diseases ranging from simple steatosis to steatohepatitis and fibrosis. Globally, NAFLD is the leading cause of morbidity and mortality associated with chronic liver disease, and NAFLD patients are at a higher risk of developing cirrhosis and hepatocellular carcinoma. While there is a consensus that inflammation plays a key role in promoting NAFLD progression, the underlying mechanisms are not well understood. Recent clinical and experimental evidence suggest that increased hepatic translocation of gut microbial antigens, secondary to diet-induced impairment of the intestinal barrier may be important in driving hepatic inflammation in NAFLD. Here, we briefly review various endogenous and exogenous factors influencing the intestinal barrier and present recent advances in our understanding of cellular and molecular mechanisms underlying intestinal barrier dysfunction in NAFLD.

Integrin α₄β₇+ T cells perpetuate tissue injury in chronic inflammatory diseases, yet their role in hepatic fibrosis progression remains poorly understood. Here, we report increased accumulation of α₄β₇+ T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl₄-induced liver fibrosis was associated with enrichment of intrahepatic α₄β₇+ CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of α₄β₇ or its ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 attenuated hepatic inflammation and prevented fibrosis progression in CCl₄-treated mice. Improvement in liver fibrosis was associated with a significant decrease in the infiltration of α₄β₇+ CD4 and CD8 T cells, suggesting that α₄β₇/MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and α₄β₇+ T cells promote hepatic fibrosis progression. Analysis of hepatic α₄β₇+ and α₄β₇- CD4 T cells revealed that α₄β₇+ CD4 T cells were enriched for markers of activation and proliferation, demonstrating an effector phenotype. The findings suggest that α₄β₇+ T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of α₄β₇ or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.