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Metformin enhances intestinal epithelial health through activation of AMPK

The intestinal epithelium is a vital barrier that is consistently renewed. The balance among proliferation, migration, and differentiation are tightly regulated, which is critical for intestinal epithelial homeostasis. The objective of this study was to evaluate the beneficial role of metformin, a widely used antidiabetic drug, on epithelial health using interleukin‐10 deficient (IL10KO) mice. Metformin supplementation increased the abundance of E‐cadherin, a core component of the adhesion junctions, in both WT and IL10KO mice. In addition, metformin supplementation suppressed macrophage pro‐inflammatory activity in IL10KO mice as indicated by reduced M1 macrophage abundance as well as decreased pro‐inflammatory cytokine IL‐1b, TNF‐a and INF‐g expression. As a target of metformin, AMP‐activated protein kinase (AMPK) phosphorylation was enhanced, which might explain the suppression of inflammation in metformin group. Bone morphogenetic protein (BMP) signaling is one of the key pathways regulating gastrointestinal development and homeostasis. Consistently, metformin supplementation enhanced BMP signaling in IL10KO mice. Furthermore, the expression of two key transcription factors promoting epithelial differentiation, Hes1 and Math, was promoted by metformin. To confirm the mediator role of AMPK, we further over‐expressed AMPK in Caco‐2 cells and found that the expression of BMP4 and the phosphorylation of Smad, which is a down‐stream effector of BMP signaling, was enhanced in AMPK over‐expressed Caco‐2 cells. In addition, AMPK activity was correlated with the mRNA expression and/or protein content of Notch1, Math, Hes1, which are key transcription factors regulating epithelial differentiation. In conclusion, our data demonstrated that metformin suppresses inflammation and enhanced intestinal epithelial differentiation via enhancing AMPK signaling.