Interactions between the intestinal microbiome and liver diseases

Abstract

The human intestine harbors a diverse community of microbes that promote metabolism and digestion in their symbiotic relationship with the host. Disturbance of its homeostasis can result in disease. We review factors that disrupt intestinal homeostasis and contribute to nonalcoholic fatty liver disease, steatohepatitis, alcoholic liver disease, and cirrhosis. Liver disease has long been associated with qualitative and quantitative (overgrowth) dysbiotic changes in the intestinal microbiota. Extrinsic factors, such as the Western diet and alcohol, contribute to these changes. Dysbiosis results in intestinal inflammation, a breakdown of the intestinal barrier, and translocation of microbial products in animal models. However, the contribution of the intestinal microbiome to liver disease goes beyond simple translocation of bacterial products that promote hepatic injury and inflammation. Microbial metabolites produced in a dysbiotic intestinal environment and host factors are equally important in the pathogenesis of liver disease. We review how the combination of liver insult and disruptions in intestinal homeostasis contribute to liver disease.

Keywords: Alcoholic Steatohepatitis; Endotoxin; Microbiota.

Figure 1. Effects of the Intestinal Microbiota on NAFLD and Progression to Steatohepatitis

High-fat diets (HFD) result in dysbiosis and intestinal bacterial overgrowth. Alterations in the intestinal microbiota increase energy extraction and fermentation of dietary fibers into oligosaccharides, monosaccharides, and short chain fatty acids (SCFA), respectively. Dietary choline is metabolized by the intestinal microbiota to TMA, resulting in choline deficiency. Hepatic choline deficiency results in decreased VLDL efflux, producing hepatic steatosis. Changes in the microbiota also produce ethanol (EtOH), which is absorbed and metabolized in the liver. The intestinal microbiota suppresses gene expression of Fiaf in intestinal epithelial cells, resulting in enhanced activity of LPL and increased levels of free fatty acids (FFA). NLRPs regulate microbial composition via changes of the effector protein IL18. Dysbiosis, in turn, causes CCL5-mediated disruption of tight junctions in enterocytes. Increased intestinal permeability leads to translocation of microbial products to the liver and causes inflammation by activating TLRs.

Figure 2. Effects of the Intestinal Microbiota on Alcoholic Liver Disease

Suppressed secretion of antimicrobial peptides and proteins (AMP), and possibly EtOH itself, contribute to bacterial overgrowth and dysbiosis. Qualitative changes in the microbiota are characterized by decreased Lactobacilli in experimental models of alcohol-induced liver disease. An altered intestinal microbiota is able to produce ethanol and metabolize it into acetaldehyde. Luminal or systemic ethanol and acetaldehyde disrupt tight junctions and increase intestinal permeability. An influx of microbial products into the liver via the portal vein results in hepatic inflammation, which synergizes with ethanol to induce alcoholic liver disease. EtOH and/or acetaldehyde-induced inflammation in the intestinal lamina propria might contribute to dysfunctional tight junctions and reduced production of antimicrobial peptides and proteins by enterocytes.