Microbiota and Fatty Liver Disease-the Known, the Unknown, and the Future

Abstract

The liver communicates with the intestine via the portal vein, biliary system, and mediators in the circulation. Microbes in the intestine maintain liver homeostasis but can also serve as a source of pathogens and molecules that contribute to fatty liver diseases. We review changes in the gut microbiota that can promote development or progression of alcohol-associated and non-alcoholic fatty liver disease-the most common chronic liver diseases in Western countries. We discuss how microbes and their products contribute to liver disease pathogenesis, putative microbial biomarkers of disease, and potential treatment approaches based on manipulation of the gut microbiota. Increasing our understanding of interactions between the intestinal microbiome and liver might help us identify patients with specific disease subtypes and select specific microbiota-based therapies.

Keywords: ALD; NAFLD; NASH; alcohol use disorder; alcohol-associated liver disease; alcoholic hepatitis; metagenomics; microbiome; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis.

Figure 1.. Dysregulated interactions between the intestine and liver in patients with fatty liver disease.

Alterations in the gut microbiota in (A) alcohol-associated liver disease and (B) non-alcoholic fatty liver disease. Gut-derived pathogen-associated molecular patterns (PAMP) that reach the liver through the portal vein are recognized by pattern recognition receptors such as toll-like receptors. The activation ultimately results in steatosis, cell death, inflammation, and fibrosis. Alternatively, direct hepatocyte damage can be induced. Bile acids (BA), produced by the liver, are secreted in the intestine via the bile duct. In NAFLD, insulin resistance, macrophage recruitment and adipocyte dysfunction can be modulated by intestinal derived BA signaling, lipopolysaccharide (LPS) delivery and glucagon like peptide-1 (GLP-1), which in turn affect NAFLD development. C4, 7-alpha-hydroxy-4-cholesten-3-one; IL-22, interleukin-22; REG3G, regenerating islet derived protein 3 gamma; IgA, immunoglobulin A; SCFAs, short-chain fatty acids; TMAO, trimethylamine N-oxide; PAA, phenylacetic acid; FXR, farnesoid X receptor; FGF19, fibroblast growth factor 19.

Figure 2.. Targeting the gut microbiota for treatment of liver disease (bugs as drugs).

Additive approaches include fecal microbiota transfer (FMT), transplanting entire microbe communities; and administration of probiotics (living bacteria), prebiotics (group of nutrients that enhance growth of specific bacteria), synbiotics (combination of probiotics and prebiotics), and engineered bacteria, which can produce beneficial metabolites or metabolize toxins into non-toxic products (drug the bug). Specific pathogens or pathobionts can be eliminated using bacteriophages (phages) targeting specific bacterial strains. Pathogenic microbes, such as those with the ability to generate high levels of ethanol or ammonia could be targeted with antibiotics or antifungals (drugs from bugs). Supplementation of microbe-derived molecules or their derivatives such as farnesoid X receptor (FXR) agonists, FGF19 analogs, or short-chain fatty acids (SCFA), can replace lost metabolic activity of microbes. Microbial bile acid metabolizing enzymes include bile salt hydrolases that catalzye deconjugation, enzymes for hydroxylation, epimerization, esterification and desulfation, which eventually leads to the transformation of primary bile acids (P-BA) to secondary bile acids (S-BA). G/T represents glycine/taurine conjugates, OH represents hydroxy groups.

Figure 3.. Precision therapies for fatty liver disease.

Microbiome studies might identify new pathways and factors that contribute to progression of fatty liver diseases; these might be used to assign patients to subgroups and identify those associated with specific alterations to the gut microbiota. Integration of this knowledge into diagnostic analyses might increase diagnostic and prognostic accuracy, and lead to personalized microbiota-based therapeutics. These approaches could increase therapeutic efficacy and reduce treatment-associated side effects, compared with standard approaches.