Introduction:Treatment resistant hypertension (rHTN) is present in ~20% of all hypertensive patients. rHTN is critical in African American patients who experience early onset, severe outcomes, and weak responsiveness to angiotensin converting enzyme inhibitor (ACEi). The mechanism for drug resistance is unknown. Gut microbiota harbors biotransformative enzymes such as esterase, which may hydrolyze ACEis, reducing absorption. Our study was to identify microbe responsible for ACEi resistance. Methods:16-week-old male Spontaneously Hypertensive Rats (SHR) were gavaged with (N=12) or without (N=6) Vancomycin, Meropenem, and Omeprazole (VMO) 50 mg/kg/day for five days to deplete the gut microbiota. A single 8mg/kg dose of quinapril was given to SHR and SHR+VMO before blood pressure (BP) recording via telemetry. Quinapril catabolism was quantified by liquid chromatography-mass spectrometry. Bacterial esterase activity was monitored by hydrolysis of p-nitro-phenylbutyrate. Cecal microbiota was analyzed by 16S rDNA. Fecal microbiota were analyzed by metagenomics in 29 (16 black, 13 white) HTN patients. Results:Quinapril lowered BP more in the SHR+VMO than SHR ( P<0.0001). With a 50% reduction in bacterial 16S copy numbers ( P<0.0001), the SHR+VMO group showed (1) reduced Coprococcus( P<0.0001); (2) lower esterase activity per gram of cecal microbiota to hydrolyze quinapril ( P=0.0065); (3) a 50% lower reduction in quinapril quantity (nmol) after incubation with 1mg of cecal lysate for 3 hr ( P<0.0001); (4) decreased bacterial genes in KEGG drug metabolism pathway ( P<0.0001). The abundance of Coprococcuspositively correlated with genes in drug metabolism ( P<0.0001). Importantly, co-administration of quinapril with C. comes,a species in Coprococcusgenus, reduced the BP-lowering effects of quinapril in the SHR ( P<0.0001). Comparison of human microbiota demonstrated a higher abundance of C. comesin the black hypertensives (poor ACEi responder) than the white (ACEi responder) ( P=0.0167). Conclusion:We, for the first time, demonstrate a previously unrecognized role of gut microbes in reducing ACEi effectiveness. This serves a foundation for expanding clinical management of antihypertensive drug resistance via manipulation of gut microbiota.
- HYPERTENSION Journal
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