Loss of intestinal Akt elicits rapid mortality via intestinal damage which is rescued by mTORC1 activation

Combined Akt1 and Akt2 systemic deletion in adult mice elicits rapid mortality, preceded by body weight loss, diarrhea, and inflammation. Here, we show that lethality induced by systemic Akt1/Akt2 deletion is caused by intestinal damage, as intestinal Akt1/Akt2 deletion induces mortality phenocopying systemic deletion. Consistently, Akt ablation impairs intestinal organoid formation in vitro. Both in vivo and in vitro results show that Akt is essential for the survival of Paneth cells and survival and proliferation of Lgr5⁺ and transit-amplifying cells. Additional intestinal deletion of either FoxO1 or Tsc1 activates mTORC1 and rescues this phenotype. Thus, mTORC1 emerges as the most critical downstream effector of Akt in maintaining intestinal integrity. Indeed, mTORC1 inhibition by Raptor deletion phenocopies intestinal deletion of Akt1/Akt2. Remarkably, systemic Akt1/Akt2 deletion is tolerated when FoxO1 is deleted concurrently. This study unravels a critical role for Akt in maintaining intestinal homeostasis and the interplay between its downstream effectors FoxO1 and mTORC1.