ACE2 shedding exacerbates sepsis induced gut leak via loss of microbial metabolite 5-MTP

Sepsis, a critical organ dysfunction resulting from an aberrant host response to infection, remains a leading cause of mortality in ICU patients. Recent evidence suggests that angiotensin converting enzyme 2 (ACE2) contributes to intestinal barrier function, the mechanism of which is yet to be explored. The findings of this study indicate that ACE2 shedding significantly weakens the integrity of the intestinal barrier in septic conditions. Mice lacking ACE2 exhibited increased intestinal permeability and higher mortality rates post-sepsis compared to their wild-type counterparts. Notably, ACE2 deficiency was associated with distinct alterations in gut microbiota composition and reductions in protective metabolites, such as 5-methoxytryptophan (5-MTP). 5-MTP was barely detected in ABX mice, while its level was reversed by FMT of WT mice. Supplementing septic mice with 5-MTP ameliorated gut leak through enhanced epithelial cell proliferation and repairment. The relationship between intestinal barrier integrity and the expression of ACE2 in septic mice was explored in both ACE2 knockout and overexpressing mice. Intestinal barrier function was assessed through measurements of intestinal tight junction proteins and permeability tests. The resulting bacteria translocation and multi-organ dysfunction were also evaluated.