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.
- alcoholic liver disease
- mucosal immunology
- liver immunology
- immune-mediated liver damage
Data availability statement
Data are available on reasonable request. Data are available on reasonable request to the corresponding authors.
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Correction notice This article has been corrected since it published Online First. A second corresponding author has been added.
Contributors TH designed and performed the studies, acquired and analysed the data, wrote and edited the manuscript. SL performed studies, acquired and analysed the data and critically revised the manuscript. DR, YW, SM, KK and ZM provided technical assistance and acquired part of the data. BS serves as guarantor, designed the studies, analysed the data, wrote and edited the manuscript.
Funding TH was supported by a Veni grant (ZonMw, NWO; 91619012), ‘Right-On-Time’ grant (MLDS; W019-28) and Zukunftskollegs grant (FWF; ZK81B). SL was supported in part by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) fellowship (LA 4286/1-1) and the 'Clinical and Translational Research Fellowship in Liver Disease' by the American Association for the Study of Liver Diseases (AASLD) Foundation. This study was supported in part by NIH grants R01 AA24726, R37 AA020703, U01 AA026939, U01 AA026939-04S1, S10OD021831, by Award Number BX004594 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development, and a Harrington Discovery Institute Foundation Grant (to BS) and services provided by NIH centres P30 DK120515 and P50 AA011999.
Competing interests BS has been consulting for Ambys Medicines, Ferring Research Institute, Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals and Takeda. BS is founder of Nterica Bio. UC San Diego has filed several patents with BS as inventor related to this work. BS’s institution UC San Diego has received research support from Artizan Biosciences, Axial Biotherapeutics, BiomX, CymaBay Therapeutics, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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