Gut commensal Coprococcus comes diminishes the blood pressure‐lowering effect of ester angiotensin‐converting enzyme inhibitors

Abstract

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 ACEi's 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 Coprococcusgenus, 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.

Gut Microbiota: Friends or Foes for Blood Pressure-Lowering Drugs

“…1 Significant BP reductions with antibiotics was detected when quinapril was delivered orally, but not intravenously. 1 As a lipophilic ester prodrug, quinapril is normally absorbed in the intestine with its original form and is hydrolyzed in the liver to achieve its antihypertensive effects. Yang et al 1 revealed the gut microbiota of spontaneously hypertensive rats had an exacerbated esterase activity, leading to reduce bioavailability.…”

“…1 As a lipophilic ester prodrug, quinapril is normally absorbed in the intestine with its original form and is hydrolyzed in the liver to achieve its antihypertensive effects. Yang et al 1 revealed the gut microbiota of spontaneously hypertensive rats had an exacerbated esterase activity, leading to reduce bioavailability. Indeed, it was confirmed in vitro that intestinal bacterial lysates could increase quinapril catabolism.…”

“…To identify the specific bacteria involved, they sequenced the 16S rRNA bacterial gene. 1 The genus Coprococcus was shortlisted due to its positive correlations with quinapril catabolism, caecal esterase activity, and the level of a carboxylic-ester hydrolase that was significantly decreased with antibiotic treatment. 1 Then the team cultured Coprococcus comes , a predominant species in the Coprococcus genus, and incubated their lysates together with quinapril in vitro, where they exhibited strong esterase activities and catabolic capacity of quinapril.…”

“…12 In mouse models, deacetylation of diltiazem, another calcium channel blocker, was highly dependent on the gene bt4096 of Bacteroides thetaiotaomicron . 5 New findings described by Yang et al 1 identified a novel microbiota-drug association; they describe a mechanism by which the bacterial strain Coprococcus comes modifies the antihypertensive effect of the ester ACE inhibitor quinapril (Figure).…”

“…In the current issue of Hypertension , Yang et al 1 examined the role of the gut microbiota in the metabolism of ACE (angiotensin-converting enzyme) inhibitors both in vitro and in vivo. Here, we discuss their findings and associated studies on the interplay between the gut microbiota, antihypertensive medications, and blood pressure (BP)-lowering opportunities.…”