Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice

Abstract

The intestinal mucus layer protects the epithelium from noxious agents, viruses, and pathogenic bacteria present in the gastrointestinal tract. It is composed of mucins, predominantly mucin-2 (Muc2), secreted by goblet cells of the intestine. Experimental alcoholic liver disease requires translocation of bacterial products across the intestinal barrier into the systemic circulation, which induces an inflammatory response in the liver and contributes to steatohepatitis. We investigated the roles of the intestinal mucus layer, and in particular Muc2, in development of experimental alcohol-associated liver disease in mice. We studied experimental alcohol-induced liver disease, induced by the Tsukamoto-French method (which involves continuous intragastric feeding of an isocaloric diet or alcohol) in wild-type and Muc2−/− mice. Muc2−/− mice showed less alcohol-induced liver injury and steatosis that developed in wild-type mice. Most notably, Muc2−/− mice had significantly lower plasma levels of lipopolysaccharide than wild-type mice after alcohol feeding. In contrast to wild-type mice, Muc2−/− mice were protected from alcohol-associated microbiome changes that are dependent on intestinal mucins. The anti-microbial proteins Reg3b and Reg3g were expressed at significantly higher levels in the jejunum of Muc2−/− mice fed the isocaloric diet or alcohol, compared with wild-type mice. Consequently, Muc2−/− mice showed increased killing of commensal bacteria and prevented intestinal bacterial overgrowth. Conclusion: Muc2−/− mice are protected from intestinal bacterial overgrowth and dysbiosis in response to alcohol feeding. Subsequently, lower amounts of bacterial products such as endotoxin translocate into the systemic circulation, decreasing liver disease.

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

“…Presently, the identity of the endogenous lipid antigens that contribute to chronic-plus-binge ethanol-induced hepatic iNKT cell activation is unknown. It is known that chronic ethanol feeding induces gut bacterial overgrowth and increases gut permeability, [29][30][31] which may result in elevated hepatic levels of bacterial products, such as glycosphingolipids, which can induce CD1d-dependent NKT cell activation. 32 Interestingly, a recent study reported that incubation with physiological concentrations of ethanol stimulated NKT cell activation by enhancing CD1d glycolipid loading.…”

Intestinal fungi contribute to development of alcoholic liver disease

“…Approximately 50% of cirrhosis-related deaths are due to alcohol abuse (2). Chronic alcoholism can lead to intestinal bacterial overgrowth and dysbiosis, a leaky gut barrier, and increased systemic levels of bacterial products (3)(4)(5)(6)(7). Although the intestinal microbiome contains bacteria, fungi, and viruses, research in the field of alcohol-associated disease has almost exclusively focused on the interaction between the host and bacteria.…”

Alcoholism and mental illness: overlapping diseases requiring a renewed focus

“…These methods are employed to encourage animals to consume a specific amount of substance in a particular timeframe, a motivation that is distinct from those that drive human consumption of alcohol. In other models of alcoholism, animals do not willingly consume alcohol at all, but are rather injected intraperitoneally or subcutaneously, or receive ethanol via gavage or intubation (Girard, Xing, Ward, & Wainwright, 2000;Hartmann et al, 2013;Tran, Cronise, Marino, Jenkins, & Kelly, 2000). Moreover, due to species-specific differences in metabolism and scale, the quantity of alcohol consumed by laboratory animals does not easily translate to realistic quantities consumed by adult humans (Zorzano & Herrera, 1990).…”