Gut dysbiosis in nonalcoholic fatty liver disease: pathogenesis, diagnosis, and therapeutic implications

Abstract

The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing recently and has become one of the most common clinical liver diseases. Since the pathogenesis of NAFLD has not been completely elucidated, few effective therapeutic drugs are available. As the "second genome" of human body, gut microbiota plays an important role in the digestion, absorption and metabolism of food and drugs. Gut microbiota can act as an important driver to advance the occurrence and development of NAFLD, and to accelerate its progression to cirrhosis and hepatocellular carcinoma. Growing evidence has demonstrated that gut microbiota and its metabolites directly affect intestinal morphology and immune response, resulting in the abnormal activation of inflammation and intestinal endotoxemia; gut dysbiosis also causes dysfunction of gut-liver axis via alteration of bile acid metabolism pathway. Because of its composition diversity and disease-specific expression characteristics, gut microbiota holds strong promise as novel biomarkers and therapeutic targets for NAFLD. Intervening intestinal microbiota, such as antibiotic/probiotic treatment and fecal transplantation, has been a novel strategy for preventing and treating NAFLD. In this article, we have reviewed the emerging functions and association of gut bacterial components in different stages of NAFLD progression and discussed its potential implications in NAFLD diagnosis and therapy.

Keywords: bile acid metabolism; gut dysbiosis; nonalcoholic fatty liver disease; novel treatment strategies; probiotics.

Figure 1

The roles of gut microbiota metabolites in NAFLD pathogenesis. Gut microbial metabolites, such as monosaccharides, SCFAs, BAs and TMA, not only are potently involved in energy metabolism of liver and intestinal epithelial cells, but affect directly liver lipogenesis and systemic inflammation. AMPK, adenosine monophosphate-dependent protein kinase; ChREBP, carbohydrate-responsive element-binding protein; CYP7A1, cytochrome P450 7A1; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; GPCR41/43, G protein-coupled receptor 41/43; PYY, peptide YY; SREBP-1, sterol regulatory element-binding protein 1; TGR5, takeda G protein receptor 5; TMAO, trimethylamine oxide.

Figure 2

Intestinal barrier disrupted by gut dysbiosis facilitates bacterial endotoxins to liver and exacerbates inflammatory process and fat accumulation in the pathogenesis of NAFLD. Unhealth lifestyle (e.g., high-fat, low-fiber diet) alters the microbiota colonization in gut, increases gut permeability, and produces various proinflammatory molecules, such as LPS, TMAO, SBAs, and bacterial 16sDNA. These proinflammatory molecules worsen the liver inflammation and fibrosis and potentially accelerate NAFLD progression. Treatment with FXR/TGR5 agonist, probiotics and FMT strengthens intestinal tight junction, and mediates the glucose and lipid metabolism via activation of FXR and TGR5 signaling as well as inhibition of TLR4//NF-κB and JAK1/STAT6 pathways.