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Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice
Phillipp Hartmann1, Peng Chen, Hui J Wang
1Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Unlabelled:
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 (Muc) 2, 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 than 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 antimicrobial proteins regenerating islet-derived 3 beta and gamma 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.
Insights
Mice lacking mucin 2 (Muc2) showed reduced alcohol-induced liver injury. This protection stems from preventing bacterial overgrowth and lowering endotoxin translocation, crucial for mitigating alcoholic liver disease.
Area of Science:
- Gastroenterology
- Hepatology
- Microbiology
Background:
- The intestinal mucus layer, primarily composed of mucin 2 (Muc2), is vital for protecting the gut epithelium.
- Alcoholic liver disease involves bacterial product translocation across the intestinal barrier, triggering liver inflammation and steatohepatitis.
Purpose of the Study:
- To investigate the role of the intestinal mucus layer, specifically Muc2, in the development of experimental alcohol-associated liver disease.
- To determine how Muc2 deficiency impacts intestinal barrier function and microbial composition during alcohol exposure.
Main Methods:
- Utilized the Tsukamoto-French method for inducing experimental alcohol-induced liver disease in wild-type and Muc2-deficient mice.
- Assessed liver injury, steatosis, plasma lipopolysaccharide levels, and jejunal expression of antimicrobial proteins (Regenerating islet-derived 3 beta and gamma).
Main Results:
- Muc2-deficient mice exhibited significantly less alcohol-induced liver injury and steatosis compared to wild-type mice.
- Alcohol feeding led to lower plasma lipopolysaccharide levels in Muc2-deficient mice.
- Muc2-deficient mice were protected from alcohol-associated microbiome alterations and showed increased antimicrobial protein expression, leading to better control of commensal bacteria.
Conclusions:
- Mucin 2 deficiency protects against alcohol-induced intestinal bacterial overgrowth and dysbiosis.
- Reduced translocation of bacterial products like endotoxin into circulation in Muc2-deficient mice mitigates alcoholic liver disease progression.
