Background: Despite the availability of various classes of antihypertensive medications, a large proportion of hypertensive individuals remain resistant to treatments. The reason for what contributes to low efficacy of antihypertensive medications in these individuals is elusive. The knowledge that gut microbiota is involved in pathophysiology of hypertension and drug metabolism led us to hypothesize that gut microbiota catabolize antihypertensive medications and compromised their blood pressure (BP)-lowering effects. Methods and Results: To test this hypothesis, we examined the BP responses to a representative ACE (angiotensin-converting enzyme) inhibitor quinapril in spontaneously hypertensive rats (SHR) with or without antibiotics. BP-lowering effect of quinapril was more pronounced in the SHR+antibiotics, indicating that gut microbiota of SHR lowered the antihypertensive effect of quinapril. Depletion of gut microbiota in the SHR+antibiotics was associated with decreased gut microbial catabolism of quinapril as well as significant reduction in the bacterial genus Coprococcus . C. comes , an anaerobic species of Coprococcus , harbored esterase activity and catabolized the ester quinapril in vitro. Co-administration of quinapril with C. comes reduced the antihypertensive effect of quinapril in the SHR. Importantly, C. comes selectively reduced the antihypertensive effects of ester ramipril but not nonester lisinopril. Conclusions: Our study revealed a previously unrecognized mechanism by which human commensal C. comes catabolizes ester ACE inhibitors in the gut and lowers its antihypertensive effect.

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.

Microbiota colonization begins at birth and continuously reshapes throughout the course of our lives, resulting in tremendous interindividual heterogeneity. Given that the gut microbiome, similar to the liver, houses many categories of catalytic enzymes, there is significant value in understanding drug-bacteria interactions. The discovery of this link could enhance the therapeutic value of drugs that would otherwise have a limited or perhaps detrimental effect on patients. Resistant hypertension is one such subset of the hypertensive population that poorly responds to antihypertensive medications, resulting in an increased risk for chronic cardiovascular illnesses and its debilitating effects that ultimately have a detrimental impact on patient quality of life. We recently demonstrated that the gut microbiota is involved in the metabolism of antihypertensive drugs and thus contributes to the pathophysiology of resistant hypertension. Due to a lack of knowledge of the mechanisms, novel therapeutic approaches that account for the gut microbiota may allow for better therapeutic outcomes in resistant hypertension. Therefore, the purpose of this review is to summarize our current, albeit limited, understanding of how the gut microbiota may possess particular enzymatic activities that influence the efficacy of antihypertensive drugs.

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Background The gut and gut microbiota, which were previously neglected in blood pressure regulation, are becoming increasingly recognized as factors contributing to hypertension. Diseases affecting the gut such as inflammatory bowel disease (IBD) present with aberrant energy metabolism of colonic epithelium and gut dysbiosis, both of which are also mechanisms contributing to hypertension. We reasoned that current measures to remedy deficits in colonic energy metabolism and dysbiosis in IBD could also ameliorate hypertension. Among them, 5‐aminosalicylic acid (5‐ASA; mesalamine) is a PPARγ (peroxisome proliferator‐activated receptor gamma) agonist. It attenuates IBD by a dual mechanism of selectively enhancing colonic epithelial cell energy metabolism and ameliorating gut dysbiosis. Methods and Results A total of 2 groups of 11‐ to 12‐week‐old male, hypertensive, Dahl salt‐sensitive (S) rats were gavaged with (n=10) or without (n=10) 5‐aminosalicylic acid (150 mg/kg) for 4 weeks. Rats receiving 5‐aminosalicylic acid treatment had a lower mean blood pressure than controls (145±3 mm Hg versus 153±4 mm Hg; P <0.0001). This reduction in blood pressure was accompanied by increased activity of PPARγ, increased expression of energy metabolism–related genes, and lowering of the Firmicutes/Bacteroidetes ratio in the colon, the reduction of which is a marker for the correction of gut dysbiosis. Furthermore, these data were consistent with the American Gut Project wherein the Firmicutes/Bacteroidetes ratio of non‐IBD (n=611) patients was significantly lower than patients with IBD (n=631). Conclusions 5‐Aminosalicylic acid could be repurposed for hypertension by specifically enhancing the gut energy metabolism and correction of microbiota dysbiosis.