(844.3) Gut commensal Coprococcus comes diminishes the blood pressure-lowering effect of ester angiotensin-converting enzyme inhibitors

Poster Board Number: B166

Tao Yang (University of Toledo), Xue Mei (University of Toledo), Ethel Tackie-Yarbo (University of Toledo), Millicent Tambari Akere (University of Toledo), Jun Kyoung (University of Toledo), Blair Mell (University of Toledo), Ji-Youn Yeo (University of Toledo), Xi Cheng (University of Toledo), Jasenka Zubcevic (University of Toledo), Elaine Richards (University of Florida), Carl Pepine (University of Florida), Mohan Raizada (University of Florida), Isaac Schiefer (University of Toledo), Bina Joe (University of Toledo)

Introduction

Drug resistant HTN (rHTN) affects around 15% to 20% of hypertensive (HTN) patients. The underlying mechanisms of resistance to treatment remain poorly understood. The majority of angiotensin-converting enzyme inhibitors (ACEi) are esters, whereby we hypothesized that select gut microbiota hydrolyze ACEi rendering lower efficacy (Figure 1A). To test this hypothesis, we investigated if and which gut microbe modulates the effectiveness of ACEi.

Methods

Vancomycin, Meropenem and Omeprazole (VMO) were given to 16-week-old male Spontaneously Hypertensive Rats (SHR) at 50 mg/kg/day for five days. A single dose of 8mg/kg Quinapril was orally administered to both SHR and SHR+VMO, and blood pressure (BP) was recorded via radio-telemetry. Liquid chromatography–mass spectrometry was used to measure the catabolism of quinapril. The hydrolysis of p-nitro-phenylbutyrate was used to measure the activity of bacterial esterase. 16S rRNA sequencing was used to study the microbial composition. At last, ester ACEi ramipril and non-ester lisinopril were co-administered with Coprococcus comes, respectively, to generalize the effect of C. comes on ACEis effectiveness.

Results

Compared to the SHR, depletion of gut microbiota in the SHR+VMO group preserved the BP lowering effect of Quinapril, an ester ACEi (Figure 1B). The SHR+VMO group showed (1) reduced Coprococcus (Figure 1C); (2) lower esterase activity per gram of cecal microbiota to hydrolyze quinapril (Figure 1D); (3) a 50% lower reduction in quinapril quantity (nmol) after incubation with 1mg of cecal lysate for 3 hr (Figure 1E). C. comes, a species in Coprococcus genus, catabolized quinapril in vitro and reduced its BP-lowering effects in the SHR (Figure 2A-B). Importantly, C. comes also reduced the BP-lowering effects of ramipril (ester), but not lisinopril (non-ester) in the SHR (Figure 2C-D).

Conclusion

These observations  constitute the first report of an unrecognized role of a select gut microbe, C. comes, in reducing the effectiveness of ester ACEi. As such, this mechanistic study serves as the foundation for expanding clinical management of antihypertensive drug resistance via manipulation of gut microbiota.

Support or Funding Information

This work was supported by the Biocodex Microbiota Foundation USA grant, the University of Toledo fellow to faculty transition funds and the American Heart Association Career Development Award 852969 (T. Yang), National Institute of Health R01HL143082 (B. Joe).





Figure 1. (A) Hydrolysis of quinapril. (B) Recording of Mean Arterial Pressure (MAP). Red arrow indicates oral gavage. BP recording was started 30 min after gavage. (C) Enrichment of bacterial genera in each group. (D) Esterase activity assay. (E) Reduction of quinapril after incubation with cecal bacterial protein. Two way ANOVA in Figure 1B. Unpaired t test in Figure 1D-E.; Figure 2. (A) Reduction in quinparil after incubation with extracted protein of C. comes. (B) Changes in MAP after oral gavage. (C) MAP of gavaged with C. comes, ramipril (ester) and both. (D) MAP of gavaged with C. comes, lisinopril (non-ester) and both. Red arrow indicates oral gavage. BP recording was started 30 min after gavage. Unpaired t test in Figure 2A. Two way ANOVA in Figure 2B-D.