Probiotics, prebiotics, and synbiotics in nonalcoholic fatty liver disease and alcohol-associated liver disease

Abstract

The use of probiotics, prebiotics, and synbiotics has become an important therapy in numerous gastrointestinal diseases in recent years. Modifying the gut microbiota, this therapeutic approach helps to restore a healthy microbiome. Nonalcoholic fatty liver disease and alcohol-associated liver disease are among the leading causes of chronic liver disease worldwide. A disrupted intestinal barrier, microbial translocation, and an altered gut microbiome metabolism, or metabolome, are crucial in the pathogenesis of these chronic liver diseases. As pro-, pre-, and synbiotics modulate these targets, they were identified as possible new treatment options for liver disease. In this review, we highlight the current findings on clinical and mechanistic effects of this therapeutic approach in nonalcoholic fatty liver disease and alcohol-associated liver disease.

Keywords: NAFLD; alcohol-associated liver disease; gut barrier; gut microbiome; microbiota.

Graphical abstract

Figure 1.

Pro-, pre-, and synbiotics improve nonalcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) by abrogating various microbiome-related pathophysiological mechanisms. Western diet and alcohol consumption increase potentially pathogenic and decrease helpful bacteria and fungi in the intestine (dysbiosis), which increase the abundance of harmful and decrease beneficial microbial products and metabolites. Alcohol further leads to toxic levels of ethanol and its metabolite acetaldehyde in the gut and liver. Although in both NAFLD and ALD, the concentration of LPS, bile acids, and ethanol increases, SCFAs decrease. Levels of TMAO and amino acids can be variable. Dysbiosis further causes a disrupted intestinal barrier with decreased tight junctions leading to an increased translocation of microbial products and metabolites from the gut into the bloodstream. Entering the liver via the portal vein, microbial products and metabolites promote hepatic inflammation, cell injury, steatosis and fibrosis. Pro-, pre-, and synbiotics ameliorate NAFLD/NASH and ALD by shifting intestinal dysbiosis to a healthy gut microbiota, reducing gut permeability and production of endogenous toxins, as well as microbial translocation into the portal circulation. They thereby reduce the degree of hepatic inflammation, fibrosis, steatosis, and cell injury, key characteristics of NAFLD/NASH and ALD. LPS, lipopolysaccharides; NASH, nonalcoholic steatohepatitis; SCFAs, short-chain fatty acids; TMAO, trimethylamine N-oxide. Created from BioRender.com with permission.

Figure 2.

Pro-, pre-, and synbiotics improve dysbiosis, gut barrier, and microbial metabolites in nonalcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD). Pro-, pre-, and synbiotics ameliorate NAFLD/NASH and ALD by shifting intestinal dysbiosis to a healthier gut microbiota, improving the gut barrier and modulating the production of endogenous toxins and metabolites as well as their translocation into the portal circulation. Subsequently, harmful stimuli such as activation of TLR4 signaling and release of proinflammatory cytokines decrease in the liver, whereas the activation of farnesoid X receptor (FXR) and fibroblast growth factor (FGF) 15 (in mice)/19 (in humans) is modulated. This shifting of microbiome-related pathophysiological mechanisms toward a healthy state improves NAFLD/NASH and ALD. LPS, lipopolysaccharides; NASH, nonalcoholic steatohepatitis; SCFAs, short-chain fatty acids; TLR4, Toll-like receptor 4; TMAO, trimethylamine N-oxide; ZO-1, zonula occludens-1. Created from BioRender.com with permission.