P054 Metformin protects against intestinal barrier disruption via AMPKα1-dependent inhibition of JNK signaling pathway
Deng J., Chen Y., Zeng L.
Nanfang Hospital, Southern Medical Universit, Department of Gastroenterology, Guangzhou, China
The intestinal epithelium serves as an important barrier to prevent intestinal penetration of luminal bacteria, toxins and antigens. The disruption of intestinal epithelial barrier contributes to IBD pathogenesis. C-Jun N-terminal kinase (JNK) is involved in the disruption of epithelial barrier. There is increasing evidence that metformin has additional beneficial effects including anti-inflammation and upregulation of blood-brain barrier functions. The aim of the current study is to investigate whether metformin protects against intestinal barrier disruption and the potential mechanisms in colitis.
we used confluent Caco-2 cell monolayers and C57BL/6 mice treated with 3% DSS to induce intestinal barrier disruption
Metformin treatment significantly alleviates DSS-induced the loss of TEER and the increasing flux of FD4 in Caco-2 cell monolayers. Western blot and immunofluorescence staining showed that the level of TJs occludin and Zo-1 reduced by DSS were reversed by metformin treatment. In DSS-induced acute colitis of mice, metformin can significantly ameliorate the induction of colitis, prevent the reduction of body weight, colon length, reduce DAI score and inhibit the production of inflammatory factors IL-6, TNF-α and IL-1β. The intestinal barrier function of mice was maintained by metformin in DSS-induced colitis, as metformin protected against the loss of TJS occludin and Zo-1 and reduced the permeability of FD4 in colon. Also, metformin significantly reduced the commensal bacterial translocation in colitis. DSS-induced JNK activation in Caco-2 cell monolayers and in colon of mice, while metformin treatment inhibited the activation of JNK and promoted the phosphorylation of AMPKα. The inhibition effect of JNK activation by metformin was disappeared when AMPKα1 was silenced by siRNA, but not AMPKα2. Metformin couldn't maintain the barrier function of AMPKα1- silenced cell monolayers after DSS administration.
Metformin can protect against DSS-induced intestinal barrier disruption. The potential mechanism is involved in the inhibition of JNK activation via a AMPKα1-dependent signaling pathway.