Alcoholic liver disease: the gut microbiome and liver cross talk

Abstract

Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. Alcoholic fatty liver disease can progress to steatohepatitis, alcoholic hepatitis, fibrosis, and cirrhosis. Patients with alcohol abuse show quantitative and qualitative changes in the composition of the intestinal microbiome. Furthermore, patients with ALD have increased intestinal permeability and elevated systemic levels of gut-derived microbial products. Maintaining eubiosis, stabilizing the mucosal gut barrier, or preventing cellular responses to microbial products protect from experimental ALD. Therefore, intestinal dysbiosis and pathological bacterial translocation appear fundamental for the pathogenesis of ALD. This review highlights causes for intestinal dysbiosis and pathological bacterial translocation, their relationship, and consequences for ALD. We also discuss how the liver affects the intestinal microbiota.

Keywords: Alcoholic Liver Disease; Bacterial Translocation; Intestinal Bacterial Dysbiosis; Metabolome; Microbiome.

Figure 1. Contributing factors to intestinal dysbiosis after chronic alcohol consumption

Chronic alcohol administration results in a quantitative increase of intestinal bacteria and a qualitative change in the bacterial composition of the microbiota. Several factors might contribute to alcohol-associated dysbiotic changes in the intestine.

Figure 2. Consequences of intestinal dysbiosis relevant to the pathogenesis of alcoholic liver disease

Chronic alcohol consumption leads to intestinal bacterial overgrowth and dysbiosis. Metabolomic changes such as lower bacterial synthesis of long-chain fatty acids (LCFA) result in smaller amounts of ‘good’ bacteria, e.g. Lactobacillus spp. Yet unknown microbial metabolites or products cause intestinal inflammation. While anti-inflammatory properties of intestinal lactobacilli suppress intestinal inflammation during health, reduced amounts of lactobacilli associated with chronic alcohol administration are not any longer able to maintain intestinal homeostasis. Inflammatory cells of the intestinal lamina propria are activated and secrete tumor necrosis factor (TNF)-alpha. TNF-alpha then binds to its receptor TNFR1 on enterocytes, which results in a disruption of tight junctions, partly mediated via myosin-light chain kinase (MLCK). Ethanol and its metabolite acetaldehyde might contribute to a dysfunction of the gut barrier. Microbial products can therefore translocate from the intestinal lumen to the portal venous blood. Translocated microbial products activate hepatic stellate cells and Kupffer cells, and damage hepatocytes. This synergizes with a direct hepatotoxic effect of alcohol and its metabolites to cause progression of alcoholic liver disease.