Metformin improves ileal epithelial barrier function in interleukin‐10 deficient mice

Background Accumulating evidence shows that gut epithelial integrity and barrier function is a central predisposing factor in the pathogenesis of inflammatory bowel disease. The proper intestinal epithelial proliferation and differentiation is crucial for maintaining gut homeostasis and intestinal integrity. Objective To evaluate the protective role of metformin in ileal epithelial barrier function using interleukin‐10 deficient (IL10KO) mice. Results Metformin supplementation had no effect body weight gain and feed intake, but decreased intestinal permeability in IL10KO mice associated with reduced expression of p ore forming tight junction protein, claudin 2 and enhanced expression of barrier forming tight junction protein, claudin 3. Histological analysis showed that IL‐10 depletion elongated crypt depth and increased mucosal thickness, resulting in decreased Villi/Crypt ratio, which was restored by metformin supplementation. Consistent with increased crypt depth, proliferation of epithelial cells in IL10KO mice with or without metformin supplementation was enhanced compared to that of WT mice, while metformin supplementation decreased the number of proliferative cells per crypt in IL10KO mice as assayed by Ki67 staining and in vivo BrdU labeling. The density of Paneth cells was increased in metformin treated mice regardless of genotypes, but the Paneth cell density was decreased dramatically in IL10KO mice when compared to those of WT mice regardless of metformin supplementation. Consistently, t he density of goblet cells was much lower in the intestinal epithelium of IL10KO mice compared to that of the WT mice , while metformin supplementation increased the goblet cell density in both WT and IL10KO mice. Conclusion Our data demonstrate that metformin supplementation inhibits cell proliferation, promotes secretory cell lineage differentiation and further improves epithelial barrier function in IL10KO mice. Support or Funding Information R15HD073864