Current Concepts, Opportunities, and Challenges of Gut Microbiome-Based Personalized Medicine in Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NALFD) is now a leading cause of chronic liver disease worldwide, in part, as a consequence of rapidly rising levels of obesity and metabolic syndrome and is a major risk factor for cirrhosis, hepatocellular carcinoma, and liver-related mortality. From NAFLD stems a myriad of clinical challenges related to both diagnosis and management. A growing body of evidence suggests an intricate linkage between the gut microbiome and the pathogenesis of NAFLD. We highlight how our current knowledge of the gut-liver axis in NAFLD may be leveraged to develop gut microbiome-based personalized approaches for disease management, including its use as a non-invasive biomarker for diagnosis and staging, as a target for therapeutic modulation, and as a marker of drug response. We will also discuss current limitations of these microbiome-based approaches. Ultimately, a better understanding of microbiota-host interactions in NAFLD will inform the development of novel preventative strategies and precise therapeutic targets.

Keywords: biomarker; cirrhosis; fibrosis; microbiota; nonalcoholic steatohepatitis.

Figure 1.. Potential microbiome-based therapeutic interventions in nonalcoholic fatty liver disease (NAFLD).

Intestinal barrier dysfunction, in part related to leaky tight junctions, allows microbial products from gut bacteria, such as lipopolysaccharide, to enter the portal circulation and stimulate toll-like receptors (TLRs), leading to activation of the innate immune system. NAFLD is associated with perturbations in gut microbiota composition, often referred to as intestinal dysbiosis. Modulation of the gut microbiota is feasible via a diverse array of strategies including antimicrobials, prebiotics, probiotics, synbiotics, fecal microbiota transplantation (FMT), and bacteriophage therapy. Gut microbiota contribute to disease pathogenesis through metabolism of dietary substrates, xenobiotics, as well as host molecules (such as primary bile acids), resulting in the production of bioactive small molecules that enter the portal circulation and modulate microbiota-host interactions. Interventions specifically targeted to microbial metabolism may include postbiotics and small molecule inhibition and genetically engineered microbes to precisely alter the production of bacterial metabolites. Metabolites of particular interest in NAFLD pathogenesis include short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), indoles, and secondary bile acids (derived from microbial metabolism of primary bile acids). Personalized dietary approaches may modulate dietary-microbiome crosstalk, with ensuing effects on both microbiota composition and metabolic output.