Deficiency of Intestinal α1-2-Fucosylation Exacerbates Ethanol-Induced Liver Disease in Mice

Background Fucosyltransferase 2 (Fut2)-mediated intestinal alpha 1-2-fucosylation is important in maintaining a symbiotic host-microbiota relationship and can protect against several pathogens. Intestinal dysbiosis is an important factor for the progression of experimental ethanol (EtOH)-induced liver disease, but the role of Fut2 in modulating the intestinal glycocalyx during alcohol-associated liver disease is unknown. We investigated the role of Fut2-mediated intestinal alpha 1-2-fucosylation for the development of alcohol-associated liver disease. Methods Immunohistochemistry staining was applied to evaluate alpha 1-2-fucosylation in duodenal biopsies from patients with alcohol use disorder. Wild-type (WT) andFut2-deficient littermate mice were subjected to Lieber-DeCarli models of chronic EtOH administration and the chronic-binge EtOH diet (NIAAA model). Results Intestinal alpha 1-2-fucosylation was down-regulated in patients with alcohol use disorder. Lack of alpha 1-2-fucosylation inFut2-deficient mice exacerbates chronic EtOH-induced liver injury, steatosis, and inflammation without affecting EtOH metabolism. Dietary supplementation of the alpha 1-2-fucosylated glycan 2 '-fucosyllactose (2 '-FL) ameliorates EtOH-induced liver disease inFut2-deficient mice in the NIAAA model. Despite no direct effects on growth ofEnterococcus faecalisin vitro, intestinal alpha 1-2-fucosylation reduces colonization of cytolysin-positiveE. faecalisin the intestine of EtOH-fed mice. Conclusions Intestinal alpha 1-2-fucosylation acts as a host-protective mechanism against EtOH-induced liver disease. 2 '-FL is an oligosaccharide naturally present in human milk that could be considered as therapeutic agent for alcohol-associated liver disease.