Balance of AKT isoforms in intestinal barrier function. Implications for IBD therapy.

The leakiness of the intestinal epithelial barrier plays a major role in the development of inflammatory bowel disease. We show that either Akt1 overexpression or Akt2 chemical inhibition have similar effects on intestinal epithelial cells, enhancing the permeability of the barrier and affecting the expression and/or localization of the tight junctions' proteins whereas Akt1 inhibition or Akt2 overexpression show the opposite results. Akt1 overexpression or Akt2 inhibition also promotes activation of beta-Catenin and Lgr5. Moreover, mouse intestinal organoids treated with Akt1 inhibitors present dissembled and disorganized structures that mimic IBD features. Importantly, in DSS-induced IBD mice, Akt2 inhibition strongly ameliorates disease, presenting healthy-like crypts, having tightened colon epithelial cells expressing TJP, and an anti-inflammatory M2 macrophage phenotype. In contrast, treatment with Akt1 inhibitors enhances histological damage, TJP disorganization, reduces Lgr5+ expression and promotes a more proinflammatory milieu further favoring the disease. Those results suggest that balance between Akt1 and Akt2 regulates the functionality of the intestinal epithelial barrier, cell renewal and inflammation and that Akt2 inhibition can be considered as a new therapy for IBD. ### Competing Interest Statement The authors have declared no competing interest.