Gut Microbiome and Intestinal Permeability Are Promising Targets for Treating Nonalcoholic Fatty Liver Disease

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is a leading liver disease worldwide with a prevalence of approximately 24% among adult population. It is a spectrum of liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Obesity, insulin resistance, inflammation, disrupted gut microbiome (dysbiosis), and increased intestinal permeability (“leaky gut”) are important risk factors associated with and/or contributing to NAFLD. In the absence of specific drugs to treat NAFLD, management relies mainly on lifestyle changes (diet and exercise). Gut microbiome and intestinal permeability are becoming promising targets for the treatment of several diseases including NAFLD. Methods: A systematic search of literature was conducted using the search terms nonalcoholic fatty liver disease, obesity, insulin resistance, inflammation, gut microbiome, intestinal permeability, and targeted therapy. Results: Several clinical studies have shown the association of qualitative and quantitative changes in gut microbiome (e.g., increased Lactobacillus and Gram-negative bacteria) with NAFLD and its severity. The increased gut microbiome taxa may produce more short-chain fatty acids (SCFAs), alcohol, and lipopolysaccharides (LPS). Increased SCFAs, alcohol, and LPS (endotoxins) associated with increased intestinal permeability are implicated in the pathogenesis of NAFLD and its evolution to NASH (promotion of obesity and inflammation). Gut microbiome and intestinal permeability can be modified with diet, prebiotics, probiotics, synbiotics, and fecal microbiota transplantation. A high-fiber diet for 6 months in NAFLD subjects caused a decrease in intestinal permeability (as assessed by serum zonulin) and a reduction of liver enzymes and fatty liver. Treatment with a prebiotic (oligofructose) for 8 weeks in NASH subjects showed a significant decrease in markers of liver inflammation. Administration of probiotics (e.g., Lactobacillus, Bifidobacterium, and VSL#3) for 8 to 16 weeks in NAFLD subjects had several beneficial effects including reduction of liver enzymes and fatty liver. Clinical studies using fecal microbiota transplantation in NAFLD subjects are currently ongoing. To optimize the efficacy of therapies using prebiotics, probiotics, synbiotics, and fecal microbiota transplantation in NAFLD subjects, focus should be on the altered gut microbiome taxa responsible for high SCFAs, alcohol, and LPS production. Conclusion: NAFLD is the most common chronic liver disease. NAFLD subjects have disrupted gut microbiome associated with increased intestinal permeability. In addition to weight loss (when excess body weight is present), targeting gut microbiome and intestinal permeability with diet, prebiotics, probiotics, synbiotics, and fecal microbiota transplantation represents a promising novel approach in the treatment of NAFLD.