Depletion of Esterase‐Harboring Bacteria Increases Antihypertensive Efficacy of ACE Inhibitor Quinapril

Abstract

Listen

Translate article

Introduction Resistant hypertension (rHTN) is a critical impediment to successful control of high blood pressure (BP) and hypertension-linked pathophysiology in 15-20% of all hypertensive patients. rHTN is of importance in African American patients because they experience early onset, increased prevalence and severe outcomes. The mechanisms for drug resistance in rHTN remain unknown. Eggerthellaceae family harbors biotransformative enzymes including esterase, which influences drug catabolism in the gut prior to absorption. Thus, we hypothesized that an increased abundance of bacteria with catabolic capacity for an antihypertensive drug will decrease its efficacy (Fig. A) and may thereby serve as a novel treatment target for rHTN. Methods Ten human feces (4 controlled HTN (cHTN), 6 rHTN) were analyzed by metatranscriptomics. 16-week old male Spontaneously Hypertensive Rats (SHR) were gavaged with (N=12) or without (N=6) Vancomycin, Meropenem, and Omeprazole (VMO), at 50 mg/kg/day for five days to deplete the gut microbiota. To test the quinapril efficacy, a single 8mg/kg dose was gavaged to both SHR and SHR+VMO before BP recording via telemetry. Quinapril catabolism was quantified by liquid chromatography-mass spectrometry. Bacterial esterase activity was monitored by the hydrolysis of p-nitro-phenylbutyrate. Cecal microbiota was analyzed by 16S rDNA. Pearson r correlation was plotted using GraphPad. Results Patients with rHTN showed ~3-fold more Eggerthellaceae compared to cHTN (p=0.0027, Fig. B). With 50% reduction in bacterial 16S copy numbers (P<0.0001, Fig. C), the SHR+VMO group showed (1) reduced Eggerthellaceae (P<0.0001, Fig. D); (2) lower esterase activity per gram of cecal microbiota to hydrolyze quinapril (p=0.0065, Fig. E); (3) a 50% lower reduction in quinapril quantity (Δquinapril, nmol) after incubation with 1mg of cecal lysate (P<0.0001, Fig. F); (4) decreased bacterial genes in KEGG drug metabolism pathway (P<0.0001, Fig. G). The abundance of Eggerthellaceae positively correlated with Δquinapril (P=0.029, Fig. H) and genes in drug metabolism (P<0.0001, Fig. I). Importantly, administration of quinapril to the SHR+VMO led to lowering of BP, compared to SHR (Fig. J). Conclusion Eggerthellaceae was enriched ~3-fold in rHTN. Using SHR, we showed that depletion of Eggerthellaceae and esterase activity of the gut microbiota by VMO increased the antihypertensive efficacy of quinapril, due to protection of quinapril from catabolism in the gut. Therefore, our study, for the first time, provides evidence for a previously unrecognized role of gut microbiota in rHTN. Innovative approaches can now be considered for rHTN based on strategies to protect antihypertensive drugs from catabolism by gut bacteria before reaching the systemic circulation for improved efficacy.