Hepatic pIgR-mediated secretion of IgA limits bacterial translocation and prevents ethanol-induced liver disease in mice

Abstract

Objective: Alcohol-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.

Design: pIgR and IgA were assessed in livers from patients with alcohol-associated hepatitis and controls. Wild-type and pIgR-deficient (pIgR^-/- ) littermates were subjected to the chronic-binge (NIAAA model) and Lieber-DeCarli feeding model for 8 weeks. Hepatic pIgR re-expression was established in pIgR^-/- mice using adeno-associated virus serotype 8 (AAV8)-mediated pIgR expression in hepatocytes.

Results: Livers 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 lacking pIgR demonstrated increased plasma lipopolysaccharide levels and more hepatic bacteria, indicating elevated bacterial translocation. Treatment with non-absorbable antibiotics prevented ethanol-induced liver disease in pIgR^-/- mice. Injection of AAV8 expressing pIgR into pIgR^-/- mice prior to ethanol feeding increased intestinal IgA levels and ameliorated ethanol-induced steatohepatitis compared with pIgR^-/- mice injected with control-AAV8 by reducing bacterial translocation.

Conclusion: Our results highlight that dysfunctional hepatic pIgR enhances alcohol-associated liver disease due to impaired antimicrobial defence by IgA in the gut.

Keywords: alcoholic liver disease; immune-mediated liver damage; liver immunology; mucosal immunology.