The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target

Abstract

The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10-20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut-liver axis in NAFLD pathogenesis and progression.

Keywords: endotoxin; gut permeability; leaky gut; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis.

Figure 1

Mechanisms of NAFLD progression promoted by intestinal and hepatic side factors. SIBO; small intestinal bacterial overgrowth.

Figure 2

Therapeutic effects of lubiprostone on NAFLD via targeting the intestinal barrier. LUB, lubiprostone; NAFLD, nonalcoholic fatty liver disease; SIBO, small intestinal bacterial overgrowth.