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

Chronic stress and the stress hormone corticosterone are exacerbating factors in alcohol-induced gut and liver injury; however, the underlying mechanisms are poorly defined. This study investigates the potential role of c-Jun N-terminal kinase 2 (JNK2) in alcohol- and corticosterone-mediated gut and liver injury. The effects of chronic ethanol feeding and corticosterone administration on gut and liver injury were evaluated in JNK2 knockout (JNK2-KO) and wild-type mice. We measured gut permeability to FITC-inulin in vivo; epithelial tight junction (TJ) integrity by immunofluorescence confocal microscopy; microbiota dysbiosis by 16S rRNA sequencing; mucosal inflammatory responses by cytokine mRNA assay; endotoxemia by plasma lipopolysaccharide (LPS) levels; systemic inflammation by cytokine ELISA; and liver damage by multiple assays. Data show that chronic ethanol feeding-induced gut barrier dysfunction, epithelial TJ disruption, and colonic mucosal inflammatory responses were potentiated by corticosterone in the wild-type mice, but not in JNK2-KO mice. Microbiota analyses indicated that the gut microbiota composition in pair-fed and ethanol-fed JNK2-KO mice is distinctly different from that of wild-type mice. The effects of ethanol and its potentiation by corticosterone on Paneth cell-specific genes were absent in JNK2-KO mice. Ethanol-induced intestinal mucosal inflammatory responses, endotoxemia, and systemic inflammation, and their potentiation by corticosterone, were absent in JNK2-KO mice. Ethanol-induced liver injury and its potentiation by corticosterone, as assessed by plasma AST/ALT, liver triglyceride, histopathology, and cytokine expression, were also absent in JNK2-KO mice. These data demonstrate that JNK2 plays a pivotal role in ethanol-induced tissue injury at the Gut-Liver axis and that this effect is potentiated by corticosterone.