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

Abstract

HomeHypertensionVol. 79, No. 8Gut Microbiota: Friends or Foes for Blood Pressure-Lowering Drugs Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBGut Microbiota: Friends or Foes for Blood Pressure-Lowering Drugs Tenghao Zheng and Francine Z. Marques Tenghao ZhengTenghao Zheng Hypertension Research Laboratory, School of Biological Sciences, Monash University, Melbourne, Australia (T.Z., F.Z.M.). Search for more papers by this author and Francine Z. MarquesFrancine Z. Marques Correspondence to: Francine Z. Marques, 25 Rainforest Walk, Clayton, Monash University, VIC Australia 3800. Email E-mail Address: [email protected] Hypertension Research Laboratory, School of Biological Sciences, Monash University, Melbourne, Australia (T.Z., F.Z.M.). Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia (F.Z.M.). Search for more papers by this author Originally published13 Jul 2022https://doi.org/10.1161/HYPERTENSIONAHA.122.19609Hypertension. 2022;79:1602–1604This article is a commentary on the followingIdentification of a Gut Commensal That Compromises the Blood Pressure-Lowering Effect of Ester Angiotensin-Converting Enzyme InhibitorsSee related article, pp 1591–1601In the current issue of Hypertension, Yang et al1 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. The bidirectional interactions between the gut microbiota and oral pharmaceuticals is increasingly recognized.2 Pharmaceuticals, even nonantibiotic drugs, have the capacity to shift the gut microbiome composition.3,4 Meanwhile, evidence supports the gut microbiota can also affect the metabolism of orally delivered drugs.5 More than 10% of hypertensive patients are estimated to be resistant to BP-lowering medications.6 While the cause of resistant hypertension and the underlying pathophysiological mechanisms are still poorly understood, a few models have been proposed that include obesity, ageing and excessive dietary salt.7 Considering antihypertensive medications are usually taken orally, thus being absorbed in the gastrointestinal tract, a novel possibility is that the gut microbiota may be involved. Little is known, however, about the mechanisms behind their complex interactions.Dating from 2016, there are multiple lines of evidence in humans supporting antihypertensive medications modulate the composition of the gut microbiome (Figure). Metagenomic analyses of 1135 stool samples described associations between β-blockers and ACE inhibitor with variations of gut microbiome composition.8 A high-throughput drug screening discovered antibiotic-like effects on the gut microbiota with use of the calcium channel blockers felodipine and bepridil.3 Finally, antihypertensive medications may have additive effects: diuretics combined with β-blockers, ACE inhibitor, or aspirin were associated with enriched abundance of Roseburia,4 a bacterium involved in the production of the metabolite butyrate, shown to lower BP in animal models.9 While we still do not understand the impact of these changes to BP, evidence in spontaneously hypertensive rats support the action of the ACE inhibitor captopril10 and angiotensin II type 1 receptor blockers losartan11 may be dependent on the gut microbiota.Download figureDownload PowerPointFigure. Bidirectional interactions between the gut microbiome and antihypertensive agents. Left: Known interactions between the gut microbiome and antihypertensive agents reported in cohort studies. Right: Novel mechanism of how the gut microbiome may impact the effect of ester ACE (angiotensin-converting enzyme) inhibitors such as quinapril.While it is plausible that antihypertensive drugs may impact the composition of the gut microbiota, the impact of the baseline gut microbiota on the efficacy of antihypertensive medications is unclear. Using human and rat faecal suspensions, the gut microbiota reduced the drug bioavailability of amlodipine, a calcium channel blocker, by 21.3% after 72-hours.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 al1 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).How the Gut Microbiota May Impact Ester ACE InhibitorsFirstly, Yang et al observed that treatment with antibiotics increased quinapril effectiveness to reduce BP in spontaneously hypertensive rats.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 al1 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.1 These findings linked the attenuated antihypertensive effects of quinapril in spontaneously hypertensive rats to premature hydrolysis of ester quinapril in the intestine and its decreased bioavailability.1To 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.1 Co-administration of quinapril with C. comes significantly reduced quinapril’s BP-lowering effect compared with sole administration of quinapril. Importantly, this was replicated using ramipril, another ester ACE inhibitor, but not using lisinopril, a nonester ACE inhibitor.1Finally, they investigated the translational potential of the C. comes-ester ACE inhibitor association in a small cohort of essential hypertensive patients. Using metagenomic data of faecal samples, they compared the levels of Coprococcus between 13 White Americans and 16 Blacks, who have poorer responses to ACE inhibitor.1 They observed an enrichment of Coprococcus and C. comes in Black patients, although this was not statistically significant after adjustment for multiple comparisons.1 Taken together, the novel findings from Yang et al offer proof-of-principle evidence of how commensal gut bacteria may impact bioavailability and efficacy of BP-lowering drugs, particularly ester ACE inhibitor (Figure). This supports further pharmacomicrobiomics investigations targeting other antihypertensive drugs.Limitations and Future DirectionsUnderstanding the complex mechanisms behind bidirectional microbiota-drug interactions is challenging. Although recent advances in genome sequencing technologies and bioinformatic tools allow us to identify gut microbiome composition and gene functions, the microbiota gene pool is ≈100× larger than the human genome. This adds to the complexity of selecting a potential gut microbe target, particularly for common diseases such as hypertension. Considering the number of different types of antihypertensive agents, pinpointing the effect of the gut microbiome for each agent will represent a major but important research effort. Given that each drug involves individual metabolic pathways that may interact with the gut microbiota in different manners, the works from Yang et al1 could serve as a foundation for studying the microbiota-drug interactions in other class of antihypertensive drugs, especially for those already known to affect gut microbiome compositions, as discussed above. Untangling the complex microbiota-drug interactions may lead to novel personalized diagnostic and therapeutic approaches for hypertensive patients. In the future, the gut microbiota may be used as a noninvasive biomarker for evaluating efficacy or toxicity of antihypertensive treatments. There is also potential to improve effectiveness of antihypertensive drugs by altering the abundance of certain gut bacterial species.13Moreover, together with the microbiota-drug interactions, host genetics, dietary habits and other social-environment factors are known to contribute to the diversity of the gut microbiota.8 Gut microbiota compositions vary in different ethnicity groups, while current human microbiome studies are mainly performed in Europe, the United States, and Canada. Further large-scale human gut microbiome studies covering more ethnicities are in urgent need before bringing any microbiota-drug hints into clinical considerations. Yang et al described a nonsignificant enrichment of Coprococcus and C. comes in Blacks compared with White Americans and suggested that Coprococcus could be responsible for their poor responses to ACE inhibitor. However, these findings were obtained from a small, mostly medicated cohort with up to 4 different antihypertensive medications, and there was no comparison between patients on ester or nonester ACE inhibitor. Further studies in larger cohorts are needed to confirm the role of C. comes in ester ACE inhibitor in resistant hypertension and Black patients.More comprehensive models which integrate the gut microbiota with other potential contributing factors such as dietary habits and host genetics should also be considered. Diet, in particular, is a powerful modulator of both the gut microbiota and BP.9 Gut microbiota-derived metabolites, such as short-chain fatty acids, produced from microbial fermentation of dietary fibre, are an important link. These reduce BP in experimental models9 and are currently being tested in a randomized clinical trial.14 Short-chain fatty acids downregulate the cardiorenal renal angiotensin system,9 with exception of renal ACE2, which is upregulated by the short-chain fatty acid acetate.15In conclusion, the gut microbiota has a bidirectional role modifying and being modified by antihypertensive agents. It represents an important opportunity for the development of novel therapies for hypertension, both pharmacologically and nonpharmacologically.Article InformationSources of FundingF.Z. Marques is supported by a National Heart Foundation Future Leader Fellowship (101185, 105663) and a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Charitable Foundation.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1604.Correspondence to: Francine Z. Marques, 25 Rainforest Walk, Clayton, Monash University, VIC Australia 3800. Email francine.[email protected]edu.au