The role of the microbiome in NAFLD and NASH

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of cardiometabolic syndrome, which often also includes obesity, diabetes, and dyslipidemia. It is rapidly becoming the most prevalent liver disease worldwide. A sizable minority of NAFLD patients develop nonalcoholic steatohepatitis (NASH), which is characterized by inflammatory changes that can lead to progressive liver damage, cirrhosis, and hepatocellular carcinoma. Recent studies have shown that in addition to genetic predisposition and diet, the gut microbiota affects hepatic carbohydrate and lipid metabolism as well as influences the balance between pro-inflammatory and anti-inflammatory effectors in the liver, thereby impacting NAFLD and its progression to NASH In this review, we will explore the impact of gut microbiota and microbiota-derived compounds on the development and progression of NAFLD and NASH, and the unexplored factors related to potential microbiome contributions to this common liver disease.

Keywords: microbiome/microbiota; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis.

Figure 1. Gut microbiota‐derived compounds affecting liver metabolism

Microbiome‐derived compounds affect the hepatocytes via small molecules leading to highly interconnected effects including pro‐inflammatory signaling, changes in gene expression, and alteration in metabolism and toxicity. Bile acids bind their receptor in the intestinal epithelial cells leading to release of βKlotho that travels via portal vein to the liver where it binds FGFR4 on the surface of hepatocytes and leads to changes in metabolism. Bile acids also activate the TGR5 receptor on the Kupffer cells leading to secretion of pro‐inflammatory cytokines that in turn signal to hepatocytes. Bacterial pattern molecules, i.e., peptidoglycan and LPS, signal via TRL2 and TRL4. Short‐chain fatty acids act via binding to their receptors (acetate binds GPR43) and alter metabolism; additionally, butyrate is histone deacetylase (HDAC) inhibitor and regulates gene expression through modulation of chromatin state. Phenylacetate by unknown mechanism affects expression of metabolic genes such as Fasn and Lpl leading to metabolic changes. Finally, acetaldehyde, toxic derivative of ethanol, exacerbates high oxidative stress on the hepatocytes.

Figure 2. Pattern diagram featuring gut permeability, bacterial translocation, and TLR signaling in NAFLD/NASH

Gut microbiota alteration might contribute to increased gut permeability, translocation of bacteria, and microbiota products from the gut to liver through the portal vein. Different TLRs (TLR4, TLR9, TLR2, TLR5) in different cell types of the liver (Kupffer cells, hepatic stellate cells, hepatocytes) sense bacterial products and trigger downstream inflammatory responses as well as cytokine production. Different cell types, such as Kupffer cells and hepatic stellate cells, might interact with each other in inducing inflammation and fibrosis.