Balance of AKT isoforms in intestinal barrier function. Implications for inflammatory bowel disease therapy

WORKING MODEL The leakiness of the intestinal epithelial barrier plays a major role in the development of inflammatory bowel disease (IBD). We show that either Akt1 overexpression or Akt2 chemical inhibition have similar effects on intestinal epithelial cells, enhancing the permeability of the epithelial barrier and affecting the expression and/or intracellular localization of the tight junctions’ proteins (TJP) whereas Akt1 inhibition or Akt2 overexpression show the opposite results. Akt1 overexpression or Akt2 inhibition also promotes activation of β-Catenin and Lgr5. Moreover, mouse intestinal organoids treated ex vivo with Akt1 inhibitors present dissembled and disorganized structures that mimic IBD histological features. Importantly, in DSS-induced IBD in mice, Akt2 inhibition strongly ameliorates disease with animals presenting healthy-like crypts, having tightened colon epithelial cells expressing TJP, and presenting 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 development of the disease. Those results suggest that a 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. THE PAPER EXPLAINED Inflammatory bowel disease (IBD), that includes Crohńs disease and ulcerative colitis, needs better therapeutic options. Importantly, IBD is a risk factor for the development of colorectal cancer. IBD is associated with epithelial barrier dysfunction, decreasing its permeability, and finally leading to chronic inflammation and disease. We show that the Akt1 and Akt2 protein kinase isoforms play different and opposite roles in the integrity of intestinal epithelial barrier by affecting the expression and/or the intracellular localization of tight junction proteins (TJP) responsible for barrier formation and reducing anti-barrier ones when Akt1 is overexpressed or Akt2 is inhibited. Those results were confirmed in ex vivo organoids, a system that mimics intestinal tissue organization, where Akt1 inhibition resulted in dissembled and disorganized structures that resembled those found in IBD patients. There is a balance between Akt1 and Akt2 activation on the epithelial cells, and when Akt1 is less abundant than Akt2, the barrier is disrupted by the dysregulation of the tightness of the barrier by the TJPs, leading also to an acute phase of inflammation. Epithelial cells are also incapable of renewing themselves by the absence of active Akt1, making the damage more severe, creating a pro-inflammatory niche that derives on chronic inflammation and severe IBD. Interestingly, those in vitro and ex vivo results can be translated to the whole animals. IBD disease and colon inflammation and histological alterations induced in mice by an irritant DSS could be either worsened with an Akt1 inhibitor or much improved with treatment with an Akt2 inhibitor, respectively. The inhibition of Akt2 may be considered as a treatment or co-treatment of IBD by regulating this balance to an Akt1 predominance environment. Thus, the use of Akt2 inhibitors, already developed, could be an alternative way to treat this disease.