The functional role and translational potential of gut microbiota and microbial metabolites in liver diseases

Chronic liver diseases associated with metabolic disorders and inflammation are one of the most common diseases in the developed world, and their incidence is rapidly rising. Non-alcoholic fatty liver disease (NAFLD) afflicts a third of the general population in the Western world and heightens the risk of severe conditions including steatohepatitis (NASH), cirrhosis, and even NAFLD-associated hepatocellular carcinoma (HCC). HCC incidence has also seen an upward spiral, especially for non-viral associated HCC. In parallel with changes in lifestyle and diet in the West, there have been huge changes in gut microbiota—the vast reserve of microorganisms residing in our gut. Gut microbiota could modulate liver via the gut–liver axis, whereby gut microbial metabolites or toxins are transported to the liver via the portal vein. It is now becoming clear that a healthy gut microbiota is important to maintain liver homeostasis, whereas gut dysbiosis plays a central role in the pathogenesis of chronic liver diseases. How we could harness the power of gut microbiota for treatment of liver diseases has also attracted great interest. To address this important subject, in this issue of JGH, we have gathered several review articles that summarized the latest research in understanding of the functional role and translational potential of gut microbiota in liver diseases. The first two reviews focused on the role of gut microbiota on NAFLD and NAFLD-HCC.1, 2 Pan and Zhang examined the evidence supporting the proposition that gut microbiota is a central player in the pathogenesis of NAFLD and NAFLD-HCC.1 A survey of recent metagenomic sequencing efforts in NAFLD and NAFLD-HCC revealed the enrichment of pathogenic Bacteroides sp. in NASH or NASH-HCC patients, whereas the beneficial commensals Akkermansia and Bifidobacterium are commonly depleted. These changes are functionally important, as proven by fecal microbiota transplantation (FMT) studies from NASH patients or mice NAFLD/NAFLD-HCC models to germ-free mice. As the Western diet is associated with gut dysbiosis and NAFLD, the authors proposed a diet-gut microbiota-NAFLD model for disease pathogenesis. Detrimental nutrients found in Western diets, such as enrichment of fats, cholesterol, and simple sugars were associated increased pathobionts and depletion of commensals. The type of fats is important, as diets rich in monounsaturated or omega-3 fatty acids promote the growth of beneficial commensals. Meanwhile, dietary fiber could exert a protective effect by promoting gut diversity and enriching probiotics. These studies imply the underlying role of diet-gut dysbiosis axis in NAFLD and NAFLD-HCC development. Dysregulated diet-gut microbiota interplay generates metabolites that are important for the development of liver diseases. Li et al. discussed the role of gut microbiota-derived metabolites in the pathogenesis of NAFLD and its related diseases.2 Bile acids are an important group of endogenous metabolites that are catabolized by gut microbes. Gut dysbiosis could modulate the balance of bile acids in the gut, which impact NAFLD via Farnesoid X receptor. Short-chain fatty acids including acetic, propionic, and butyric acids are another prominent group of gut microbiota-derived metabolites with putative beneficial effects on NAFLD and NASH. The role of gut microbes in the generation of other metabolites, such as amino acids, choline, and ethanol, that involved in the pathogenesis of NAFLD are also reviewed. Last but not least, the state-of-the-art metabolomic and bioinformatic pipelines essential for analysis of microbial metabolites are described, and the potential challenges are highlighted. The rest of the review series turn the focus on the translational significance of the gut microbiota in the management of liver disease.3-5 FMT has been proposed as a potential therapeutic approach for several liver diseases. Suk and Koh3 summarized clinical studies that examined the efficacy of FMT in the management of NAFLD, alcoholic related-liver disease, and cirrhosis. FMT reverses gut dysbiosis and mitigate NAFLD-related gut barrier dysfunction, endotoxemia, and inflammation; leading to improved liver histology in one trial. FMT also seem to improve the outcome of patients suffering from cirrhosis. Although the future of FMT therapy is bright, more clinical data are required to validate its efficacy for liver disease. Nakatsu4 reviewed another exciting area of translational research for gut microbiota—their synergies with immune blockade checkpoint therapy for HCC. Recent evidence indicates that the gut microbiota modulates tumor immune microenvironment in HCC by the recruitment of immunosuppressive myeloid-derived suppressor cells and the inactivation of T-cell populations. Nakatsu also shed light on how key microbial metabolites, short-chain fatty acids, bile acids, and lipopolysaccharide mediate the effect of gut microbiota in antitumor immunity against HCC progression. Finally, the author reviewed evidence supporting the role of gram-negative commensals in boosting immune blockade checkpoint therapy for HCC. To wrap up this review series, Sung and Wong5 provided insights into “unknowns” of FMT-based therapy. Keys gaps in FMT are identified, including (i) the uncharacterized, “dark matter” of gut microbiota; (ii) factors promoting microbial engraftment and colonization following FMT; (iii) in-depth elucidation of the active components of FMT; (iv) the lack of clinical evidence supporting use of FMT in diseases other than Clostridioides difficile infection; (v) efficacy and long-term safety considerations; and (vi) statistics and study design. Sung and Wong raised a key issue—while FMT is now the most effective strategy in reversing gut dysbiosis, non-FMT approaches should be considered, such as designer single microbes, bacteria consortia, or prebiotics. In the long run, these targeted interventions hold the key to expand the therapeutic use of the gut microbiota in other diseases including liver diseases.