c-Jun N-Terminal Kinase-2 Mediates Alcohol and Corticosterone-Induced Tissue Injury at the Gut-Liver Axis

The Gut-Liver axis plays a vital role in the pathogenesis of alcoholic hepatitis. Chronic stress andcorticosterone are exacerbating factors in alcohol-induced gut barrier dysfunction and liver damage.However, the mechanisms involved in alcohol and stress comorbidity are poorly defined. This studyinvestigates the potential role of the c-Jun N-terminal Kinase (JNK2) in alcohol and corticosteronemediatedtissue injury at the Gut-Liver axis in vivo. We used JNK2 knockout mice (JNK2-KO) and achronic ethanol feeding model with or without corticosterone administration. Results show that chronicethanol feeding-induced gut barrier dysfunction, epithelial tight junction disruption, and mucosalinflammatory responses were potentiated by corticosterone administration in WT mice. These effects ofethanol and corticosterone were absent in JNK2-KO mice. Gut microbiota analysis showed elevated adiversity,distinct b-diversity, and higher abundance of the beneficial Akkermansia and Lactobacillusgenera in JNK2-KO mice. JNK2 deficiency blocked ethanol and corticosterone-induced Paneth celldysfunction, endotoxemia, and systemic inflammation. Ethanol-induced liver injury and its potentiationby corticosterone were also absent in JNK2-KO mice. These data demonstrate that JNK2 is pivotal inethanol-induced tissue injury at the gut-liver axis and its potentiation by the stress hormonecorticosterone, thus identifying it as a potential therapeutic target for treating alcoholic hepatitis.