From intestinal dysbiosis to alcohol-associated liver disease

Abstract

Alcohol-associated intestinal dysbiosis and bacterial overgrowth can lead to a dysregulation of tryptophan metabolism and lower production of indoles. Several of these indole derivatives are aryl hydrocarbon receptor ligands that, in turn, are involved in antimicrobial defense via induction of interleukin-22 (IL-22). IL-22 increases the expression of intestinal regenerating islet-derived 3 (Reg3) lectins, which maintain low bacterial colonization of the inner mucus layer and reduce bacterial translocation to the liver. Chronic alcohol consumption is associated with reduced intestinal expression of Reg3β and Reg3γ, increased numbers of mucosa-associated bacteria and bacterial translocation. Translocated microbial products and viable bacteria reach the liver and activate the innate immune system. Release of inflammatory molecules promotes inflammation, contributes to hepatocyte death and results in a fibrotic response. This review summarizes the mechanisms by which chronic alcohol intake changes the gut microbiota and contributes to alcohol-associated liver disease by changing microbial-derived metabolites.

Intestinal Barrier in Human Health and Disease

“…Studies have documented that ethanol causes a downregulation of REG3G and REG3B in the small intestine [ 193 ] and that the liver is protected against alcoholic steatohepatitis in case of REG3G hyper-expression [ 194 ]. This reinforces the evidence that dysbiosis leads to ALD through intestinal bacterial translocation and systemic inflammation [ 195 ]. Indeed, patients show higher serum levels of LPS and pro-inflammatory cytokines than healthy controls [ 189 ].…”

Gut Microbiota at the Intersection of Alcohol, Brain, and the Liver

“…Therefore, it seems reasonable to assess whether these prompt proinflammatory responses are initiated by bacterial products translocation through the intestinal barrier. In addition, gut microbiota can metabolize the physiologically vital amino acid tryptophan into indole and its derivatives; this process can limit the availability of tryptophan [ 68 ], and recently this mechanism was thoroughly reviewed by Beatriz et al, where they affirmed the dysregulation of tryptophan metabolism in alcohol-related liver diseases [ 69 ].…”

Interleukin-17 in Liver Disease Pathogenesis

“…93 IL-27 antagonizes expansion of Th17 directly or via inhibition of IL-23-producing cells. 93 Regulation of IL-17 production by intestinal microbiome: the development of the metabolic syndrome, obesity, 96,97 and progression of NAFLD 98,99 and AALD 100,101 in humans and experimental models of diet-induced obesity 102,103 was linked with intestinal microbiome dysbiosis. 104,105 Changes in the intestinal microbiota composition stimulate proinflammatory activation of immune cells, including Th17 cells.…”