Abstract 087: Genetically Engineered Gut Microbiota For Delivery Of Angiotensin Converting Enzyme 2 Attenuates Hypertension

Abstract

Engineered gut microbiota represents a new frontier in medicine, in part, serving as a vehicle for the delivery of therapeutic biologics to treat a range of host conditions. Since gut microbiota plays a significant role in blood pressure (BP) regulation, using engineered gut microbiota for treatment of hypertension is a promising novel prospect. In this study, we hypothesized that genetically engineered Lactobacilli that biosynthesize human ACE2 (Lacto-hACE2) target AngII in the gut to lower BP. To test this hypothesis, a novel Ace2 knockout (KO) rat (r Ace2 -/- for female rats, r Ace2 -/y for male rats) was generated using the CRISPR/Cas9 technology. Age and sex-matched Ace2 KO rats were surgically implanted with radiotelemetry transmitters to monitor BP and administered either Lacto-hACE2 (n=8 male; n=8 female) or wild-type Lactobacillus (Lacto-Control, n=7 male, n=8 female) for 3 weeks. BP was monitored by radiotelemetry. ACE2 activity and AngII levels were compared in both sexes. As expected, compared to non-founder control rats, Ace2 KO rats of both sexes had a significantly higher mean arterial pressure (MAP) (females: control vs. r Ace2 -/- , 132±2 mmHg vs 167±10 mmHg, p<0.0001; males: control vs. r Ace2 -/y , 116±2 mmHg vs 132±6 mmHg, p<0.0001). Moreover, both renal and colonic Ang II levels were elevated in the Ace2 KO rats (Renal: females-control vs. rAce 2 -/- , p<0.05; males-control vs. r Ace2 -/y , p<0.0001; Colon: females-control vs. r Ace2 -/- , p<0.001; males-control vs r Ace2 -/y , p<0.05). However, treatment with Lacto-hACE2 showed a sex-specific lowering of BP in females (MAP, control vs. treated, 158±7 mmHg vs 150±7 mmHg, p<0.01), which was not observed in males. The treatment effect was largely due to a significant decrease in diastolic BP (control vs . treated, 145±8 mmHg vs 133±9 mmHg, p<0.001). Interestingly, only colonic AngII, but not renal AngII, was lowered in the treated rats. In conclusion, this study is the first to demonstrate the therapeutic benefit of a commensal microbe engineered to deliver human ACE2 to the colon to lower BP in Ace2 KO rats. Our study is the first to highlight the potential of targeting the colon with engineered bacteria to develop microbiome medicine as the treatment of hypertension.