Population-Based Gut Microbiome Associations With Hypertension
Authors: Hamdi Jama, David M. Kaye, Francine Z. Marques
Journal: Circulation Research (2018)

HomeCirculation ResearchVol. 123, No. 11Population-Based Gut Microbiome Associations With Hypertension Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBPopulation-Based Gut Microbiome Associations With HypertensionThe Need for More Detailed Phenotypes Hamdi Jama, David M. Kaye and Francine Z. Marques Hamdi JamaHamdi Jama From the Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia (H.J., D.M.K., F.Z.M.) Department of Pharmacology (H.J.), Monash University, Melbourne, Australia , David M. KayeDavid M. Kaye From the Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia (H.J., D.M.K., F.Z.M.) Central Clinical School (D.M.K.), Monash University, Melbourne, Australia Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.). and Francine Z. MarquesFrancine Z. Marques Correspondence to Francine Z. Marques, PhD, Heart Failure Research Group, Baker Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, Victoria 3004, Australia. Email E-mail Address: [email protected] From the Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia (H.J., D.M.K., F.Z.M.) School of Biological Sciences (F.Z.M.), Monash University, Melbourne, Australia Originally published8 Nov 2018https://doi.org/10.1161/CIRCRESAHA.118.313792Circulation Research. 2018;123:1185–1187The past 5 years have seen a blooming interest in the contribution of the microbes that inhabit our colon, collectively known as the gut microbiota, to cardiovascular disease. A recent study published in Nature Communications determined the gut microbiota profile in >2700 participants of the British TwinsUK cohort. Besides being one of the largest microbiome datasets analysed to date, this study associated 38 self-reported common diseases and 51 medications. Amongst these diseases and relevant to cardiovascular disease was hypertension and 5 types of blood pressure (BP)-lowering medication. The findings, however, were not exciting for hypertension. Here, we discuss their data and propose an explanation for their mostly negative results.It is increasingly evident that our gut microbiome is important for the preservation of human health and the progression of pathological disease states, including cardiovascular disease. Population-based and experimental studies, including by the use of gnobiotic (ie, germ-free) mice, suggest maintenance of BP may indeed be influenced by the composition, richness, and diversity of the gut microbiota (reviewed in detail in Marques et al).1 A recent study published in Nature Communications assessed the gut microbiome profiles by sequencing of the 16S rRNA gene of >2700 older (60±12 years), mostly female (89%) participants from the TwinsUK cohort, which has been followed for 25 years.2 They were able to show specific associations between the gut microbiome and 38 self-reported diseases, including hypertension, with 17 diseases having significant correlation with ≥1 bacteria taxa. In agreement with previous studies, decreased α diversity (which compares the number of microbes between individuals) was associated with most diseases, including hypertension (ie, Shannon index and phylogenetic diversity whole tree). Of the total number of participants in the study, 756 (27.6%) replied yes to the question of whether a doctor or health professional had ever diagnosed hypertension. Given that hypertension is often a silent, undiagnosed disease,3 it would be reasonable to assume the rates of hypertension within this aged cohort might, in fact, be higher. As expected, hypertensive subjects were older and had higher body mass index than their average subject. Both of these factors have been previously associated with gut microbiome composition.4,5 The association between hypertension and α diversity was no longer significant when the analysis was adjusted by age and body mass index. The considerable overlap between diseases, medications, and microbes as expected in a human population made it difficult to tease apart confounding effects. These could account for the lack of strong correlation between the gut microbiome and hypertension.Gut Microbiome Is Influenced by Diet and LifestyleThe TwinsUK cohort represents an attractive model to study difference and significance of the gut microbiome. However, the lack of dietary information in this study, lifestyle habits, and gut metabolites data (all linked to both microbiota and hypertension prevalence) limit functional implication of these results in the context of hypertension. The Dietary Approaches to Stop Hypertension and Mediterranean diets have been shown to markedly reduce BP in hypertensive subjects.6,7 Furthermore, specific dietary intake has a large impact on the composition of the commensal bacteria, with a Western-style diet considered detrimental to cardiovascular health.8 Indeed, compared with a control diet, the Dietary Approaches to Stop Hypertension diet leads to a different metabolite profile in prehypertensive and hypertensive subjects.9 This supports the need for large cohort studies to take into consideration the numerous ways in which dietary habits could influence the changes observed in the microbiome, especially when trying to grasp how these changes might influence complex disease.The Importance of Proper BP Measurement for Diagnosis of HypertensionSelf-reporting hypertension poses a significant issue, especially when results from the recent 2017 May Measurement Month report are taken into consideration.3 Europe had some of the highest prevalence of hypertension in the world (43.5% in Europe compared with 24.2% worldwide), and ≈16.5% of participants from this study were previously undiagnosed hypertensives.3 This is further confounded by prevalence of masked hypertension (estimated between 8 and 38% of the adult population) and misdiagnosed patients with white coat hypertension (20%–25%). At least an accurate measurement of BP in the clinical setting in addition to 24-hour ambulatory BP and self-measured BP at home are able to discern between these subtypes and essential hypertension, and it is unclear if these participants had either. Although more homogenous (albeit smaller in size) cohorts of hypertensive subjects have reported associations between hypertension, BP, and gut microbes,10–12 we still lack studies that have properly characterized subjects by the use of ambulatory BP with matched-age and matched–body mass index controls. Jackson et al2 noted the limitations of the use of self-reported nontime-matched questionnaires for diseases and medications and that their results were likely underestimations of true effects. Combined with evidence from previous studies of an association between gut microbiota and essential hypertension and the importance of proper BP measurement for the diagnosis of hypertension, it is plausible that this study underestimated the effect of the gut microbiota in hypertension. Cohorts of similar size with proper diagnosis of hypertension are needed to address this question.BP-Lowering Medication and the Gut MicrobiomeThe study by Jackson et al2 also examined relationships between 52 common prescription medications and bacteria taxa. Of these, 5 were medications used to manage hypertension, including β-blockers (reported in n=128), ACE (angiotensin-converting enzyme) inhibitors (n=202), Sartan (n=118), calcium-channel blockers (n=222), and α-blockers (n=47). For β-blockers significance was only detected when looking at Firmicutes, which have been traditionally reported as a marker of gut dysbiosis.13 Similarly, they found significant association between the reported use of α-blockers and proteobacteria, another phylum linked to gut dysbiosis. Gut biosis include normalization of resident commensal communities relative to normotensive subjects, as well as an improvement in the gut epithelial barrier. These findings might be in the opposite direction as expected because these medications are used to lower BP, and one would expect they would improve, and not decrease, gut biosis. Jackson et al2 did not find significant associations for the remaining 3 medications, with no drug surviving false discovery rate adjustment. This is contradictory to another population-based metagenomic analysis in 1135 individuals that reported a positive correlation between microbiota composition and the use of ACE inhibitor and β-blockers.14 Indeed, it has been recently shown that almost all commonly orally administered drugs affect our gut microbiome as the gastrointestinal tract is an important site for their metabolism.15 The gut microbiota produces several enzymes that have a role in the metabolism of xenobiotics that might impact the excretion, transport, and bioavailability of antihypertensive medications (reviewed in Choi et al16). For example, in rats, the metabolism of the calcium-channel blocker amlodipine was modified by the use of antibiotics, which increased the systemic availability of amlodipine.17 This suggests that the gut microbiota may be involved. Moreover, spontaneously hypertensive rats treated with ACE inhibitor captopril displayed reduced gut dysbiosis, including decreased intestinal permeability and fibrosis, and improved villi length.18 Thus, it would be reasonable to assume these antihypertensive drugs also alter the communities of gut microbes, perhaps helping us to get rid of opportunistic and adverse bacterial species. Although these studies shed light on the drug-microbiota interactions, more comprehensive analyses characterizing large cohorts with and without BP-lowering drugs and interventions with these drugs are necessary to understand the consequences of specific antihypertensive medication, the gut microbiome, and disease outcome.Another major complication in the treatment of hypertension is the lack of compliance: on examination of urine, 25% to 53% of patients have been found to be nonadherent to their prescribed antihypertensive medication.19,20 This would have a major impact in the analyses reported by Jackson et al2 and may explain, at least in part, the lack of association between antihypertensive drugs and the gut microbiota. Moreover, there is limited evidence that hypertensive patients who are resistant to antihypertensive drugs might benefit from treatment with antibiotics. A case-study reported an improvement in BP control after intensive antibiotic therapy in a patient with treatment-resistance hypertension.21 Ongoing clinical trials (http://www.clinicaltrials.gov. Unique identifiers: NCT02133872 and NCT02133885) should address this question in the next years. However, manipulation of the gut microbiota with prebiotics, such as resistant starches22 and gut metabolites, such as short-chain fatty acids, which are produced by fermentation of prebiotics, have been shown to lower BP in experimental models.22–24Significance and Future DirectionsOur understanding of the complex and interconnected nature of microbial-host interactions is still rudimentary. Although this study described novel and previously unrecognized interactions between our gut microbiome, self-reported diseases, and drug consumption, it highlights the importance for more comprehensive studies to better understand the influence the gut microbiome has in the progression and maintenance of hypertension in humans. As confirmed by the study of Jackson et al,2 several commonly taken drugs alter the microbiota and to no surprise are clearly a confounding factor when studying complex phenotypes, such as hypertension. Thus, it is paramount to characterize the microbiome of different phenotypes (such as essential, masked, and white coat hypertension), while taking into account medication, compliance, dietary and lifestyle history (Figure). Additionally, most studies, including the one by Jackson et al,2 analyse only the bacterial 16S rRNA gene. Complete analysis of the gut microbiota through metagenomics, which would generate information about microbiome function, as well as presence of archaea, viruses (particularly bacteriophages), and fungi, should also be performed to determine the microbial communities and specific genera present in the hypertensive gut. These analyses would be better suited to understand the interactions between gut microbiota and complex diseases, such as hypertension, which might not be reflected in global changes detected as α and β diversity. Finally, studies in the field need to take into consideration the importance of metabolites produced by the gut microbiota because several have been shown to have protective or detrimental effects on the pathogenesis of cardiovascular disease (reviewed in Marques et al1).Download figureDownload PowerPointFigure. Well-characterized phenotypes, including intake of blood pressure (BP)-lowering drugs, diet, and other lifestyle factors, combined with 24 h ambulatory BP, are important in determining the association between essential, masked, or white coat hypertension and gut microbes.Sources of FundingH. Jama was supported by a Baker Institute's Bright Sparks scholarship and is now supported by a Research Training Program Scholarships; D.M. Kaye is supported by a National Health and Medical Research Council of Australia Program Grant and fellowship; and F.Z. Marques is supported by a National Heart Foundation Future Leader and Baker Fellowships. The Baker Heart and Diabetes Institute is supported in part by the Victorian Government's Operational Infrastructure Support Program.DisclosuresNone.FootnotesThe opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association.Commentaries serve as a forum in which experts highlight and discuss articles (published here and elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine.Commentaries are edited by Aruni Bhatnagar & Ali J. Marian.Correspondence to Francine Z. Marques, PhD, Heart Failure Research Group, Baker Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, Victoria 3004, Australia. Email francine.[email protected]edu.auReferences1. Marques FZ, Mackay CR, Kaye DM. Beyond gut feelings: how the gut microbiota regulates blood pressure.Nat Rev Cardiol. 2018; 15:20–32. doi: 10.1038/nrcardio.2017.120CrossrefMedlineGoogle Scholar2. 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November 9, 2018Vol 123, Issue 11 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.118.313792PMID: 30571464 Originally publishedNovember 8, 2018 PDF download Advertisement SubjectsDiet and NutritionHigh Blood PressureHypertensionRisk Factors