Abstract
ObjectiveAlcohol-associated liver disease is accompanied by microbial dysbiosis, increased intestinal permeability and hepatic exposure to translocated microbial products that contribute to disease progression. A key strategy to generate immune protection against invading pathogens is the secretion of IgA in the gut. Intestinal IgA levels depend on the polymeric immunoglobulin receptor (pIgR), which transports IgA across the epithelial barrier into the intestinal lumen and hepatic canaliculi. Here, we aimed to address the function of pIgR during ethanol-induced liver disease.DesignpIgR and IgA were assessed in livers from patients with alcohol-associated hepatitis and controls. Wild-type andpIgR-deficient (pIgR-/-) littermates were subjected to the chronic-binge (NIAAA model) and Lieber-DeCarli feeding model for 8 weeks. HepaticpIgRre-expression was established inpIgR-/-mice using adeno-associated virus serotype 8 (AAV8)-mediatedpIgRexpression in hepatocytes.ResultsLivers of patients with alcohol-associated hepatitis demonstrated an increased colocalisation of pIgR and IgA within canaliculi and apical poles of hepatocytes.pIgR-deficient mice developed increased liver injury, steatosis and inflammation after ethanol feeding compared with wild-type littermates. Furthermore, mice lackingpIgRdemonstrated increased plasma lipopolysaccharide levels and more hepatic bacteria, indicating elevated bacterial translocation. Treatment with non-absorbable antibiotics prevented ethanol-induced liver disease inpIgR-/-mice. Injection of AAV8 expressingpIgRintopIgR-/-mice prior to ethanol feeding increased intestinal IgA levels and ameliorated ethanol-induced steatohepatitis compared withpIgR-/-mice injected with control-AAV8 by reducing bacterial translocation.ConclusionOur results highlight that dysfunctional hepatic pIgR enhances alcohol-associated liver disease due to impaired antimicrobial defence by IgA in the gut.
Funder
Biomedical Laboratory Research & Development Service of the VA Office of Research and Development
Deutsche Forschungsgemeinschaft
Austrian Science Fund
Maag Lever Darm Stichting
ZonMw
Foundation for the National Institutes of Health
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5 articles.
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