Gut Microbiota Modulate the Efficacy of Angiotensin‐converting Enzyme Inhibitor Captopril

Abstract

Introduction: About 15-20% of the hypertensive population are resistant to antihypertensive drugs for reasons that remain unknown. Recent knowledge regarding the ability of gut microbiota to metabolize a variety of drugs led us to hypothesize that antihypertensive medications, such as the angiotensin-converting enzyme (ACE) inhibitor Captopril (CAP), are degraded by gut microbiota resulting in a loss of efficacy to lower blood pressure (BP). The goal of our study was to test this hypothesis and identify the bacteria involved. Methods: Once per day for 5 consecutive days, 16-week-old male spontaneously hypertensive rats (SHR) were administered with or without antibiotics (SHR±ABX) via oral gavage. Two days after the final ABX oral gavage, all SHR were provided CAP-containing drinking water (250 mg/day/kg) for the following 11 days. Systolic BP, diastolic BP, and mean arterial pressure (MAP) were periodically recorded during the 11 days via radio-telemetry. Fecal microbiota was profiled by 16S RNA sequencing at the beginning and end of the study. Results: Upon CAP treatment, there was a significantly greater reduction in systolic BP in the SHR+ABX, compared with SHR, on day 3 (SHR -10.92 mmHg vs SHR+ABX -23.05 mmHg, p=0.039, Fig. A) and day 4 (SHR -13.83 mmHg vs SHR+ABX -27.54 mmHg, p=0.05, Fig. A). Two-way ANOVA analysis demonstrated that CAP significantly contributed to the differences in systolic BP (Fig. A), diastolic BP (Fig. B) and MAP (Fig. C) between the groups (p<0.0001). Upon CAP treatment, gut microbiota of SHR+ABX showed a significantly increased diversity (SHR 5.11 vs SHR+ABX 6.18, p=0.006, Fig. D) and evenness (SHR 0.59 vs SHR+ABX 0.71, p=0.008, Fig. E). The gut microbiota of SHR+ABX upon CAP treatment showed a significantly reduced relative abundance of the Allobaculum genus (SHR 40.8% vs SHR+ABX 15.5%, p=0.001, Fig. F) of the Erysipelotrichaceae family. Conclusion: A significantly greater BP-lowering effect by CAP in the SHR+ABX group, in comparison to the SHR group, provides clear evidence for the involvement of gut microbiota in the modulation of antihypertensive drug efficacy. Further, the BP-lowering effect by CAP was negatively linked to the abundance of the genus Allobaculum, indicating that bacteria belonging to this genus contribute to the catabolism of CAP. Our study lends support to the potential for improved maintenance of blood pressure homeostasis and reduction of the prevalence of resistant hypertension via manipulation of gut microbiota.