The Gut Microbiota, Intestinal Permeability, Bacterial Translocation, and Nonalcoholic Fatty Liver Disease: What Comes First?

onalcoholic fatty liver disease (NAFLD) is one of the Nleading causes of chronic liver disease in the United States, and its prevalence is rising in the developed as well as in the developing world. Although tremendous headway has been made in understanding the pathogenesis of NAFLD, the role of the gut microbiota and intestinal permeability in augmenting disease progression from nonalcoholic fatty liver (NAFL), the nonprogressive form of NAFLD, to nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, remains incompletely understood. In the current issue of Cellular and Molecular Gastroenterology and Hepatology, Luther et al evaluate the association between NAFLD and increased intestinal permeability. A higher prevalence of increased intestinal permeability has been seen in patients with obesity or NAFLD, with some studies suggesting a role in the pathogenesis of NAFLD. Through a meta-analysis of five such studies, Luther et al found that almost 40% of patients with NAFLD had increased intestinal permeability. In contrast, only 6.8% of healthy controls demonstrated these changes. A subgroup analysis of NASH patients showed a stronger association with altered intestinal permeability, with nearly 50% affected, suggesting that the necroinflammatory changes seen in NASH may be more closely associated with increased gut permeability. Previous studies have tried to explain the association between intestinal permeability and NAFLD. In an experimental model of NASH, Gäbele et al were able to propagate liver injury and inflammation by inducing colitis. They hypothesized that injury to the intestinal epithelium led to increased permeability and passage of bacterial products to the portal vein, leading to enhanced liver injury. Others have shown that obesity itself may lead to altered intestinal permeability through an increase in tumor necrosis factor-a (TNFa) levels and increased intestinal inflammation. Furthermore, it has been found that the intestinal microbiome is perturbed in both obesity and NAFLD, which may lead to changes in microbial products and a resultant leaky gut. In their study, Luther et al have taken another approach to explain this association by hypothesizing that liver injury may precede the development of increased intestinal permeability. They suggest that an initial liver injury may lead to the release of inflammatory cytokines, which in turn affects the intestinal tight junctions and increases intestinal permeability passage of bacterial elements into the portal circulation propagating the preexisting liver injury. To evaluate this hypothesis, they chose a dietary model in which mice rapidly develop steatosis and inflammation