Angiotensin-Converting Enzyme 2 Deficiency Increases Translocation of Gut Bacteria by Depletion of Bone Marrow-Derived Circulating Angiogenic Cells

A healthy microbiome is central to good nutrition and efficient metabolism both of which can be altered in diabetes. Disruption of gut-vascular integrity may lead to translocation of microbial antigens and bacteria into the circulation. Bone marrow-derived circulating angiogenic cells (CACs) are essential to maintain vascular integrity. We tested the hypothesis that angiotensin-converting enzyme 2 (ACE2), the key enzyme in the vasoprotective axis of renin-angiotensin system (RAS), acts to regulate the infiltration of bone marrow-derived CACs in the gut and to maintain gut-vascular integrity in diabetes and could influence the systemic translocation of pathogenic antigens and bacteria from the gut.

Diabetic ACE2 knockout (ACE2^-/y)/C57BL/6-Ins2^WT/C96Y (Akita) mice were examined at 9 months after the onset of diabetes and compared to age-matched controls. Beta diversity analysis of the gut microbiome revealed a distinct bacterial profile among the different genotypes (n=9-17 per group, p=0.002). The fecal samples from ACE2^-/y-Akita group compared to Akita group were enriched with a great diversity of bacterial taxa that have been reported to contribute to the pathogenesis of diabetes and showed activation of peptidoglycan biosynthesis pathways by metatranscriptome analysis (n=4 per group, p=0.005). Flow cytometry analysis showed that loss of ACE2 led to reduced infiltration of bone marrow-derived CACs (CD45⁺Flk-1⁺CD31⁺) into the gut (n=8-14 per group, p<0.0001), without modifying levels of proinflammatory or immune cell phenotypes. The CAC depletion mediated by ACE2 deficiency was associated with increased levels of gut bacteria in the blood as assessed by SourceTracker analysis (n=9 per group). These data suggested a loss of the protective arm of RAS contributes to the depletion of CACs and disruption of gut-vascular barrier that may promote bacterial translocation in diabetes.