Prospects for Leveraging the Microbiota as Medicine for Hypertension

HomeHypertensionVol. 81, No. 5Prospects for Leveraging the Microbiota as Medicine for Hypertension Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBProspects for Leveraging the Microbiota as Medicine for Hypertension David J. Durgan, Jasenka Zubcevic, Matam Vijay-Kumar, Tao Yang, Ishan Manandhar, Sachin Aryal, Rikeish R. Muralitharan, Hong-Bao Li, Ying Li, Justine M. Abais-Battad, Jennifer L. Pluznick, Dominik N. Muller, Francine Z. Marques and Bina Joe David J. DurganDavid J. Durgan https://orcid.org/0000-0002-3358-1935 Department of Integrative Physiology and Anesthesiology, Baylor College of Medicine, Houston, TX (D.J.D.). , Jasenka ZubcevicJasenka Zubcevic Center for Hypertension and Precision Medicine, Toledo, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). Microbiome Consortium, Toledo, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). , Matam Vijay-KumarMatam Vijay-Kumar https://orcid.org/0000-0002-8732-0167 Center for Hypertension and Precision Medicine, Toledo, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). Microbiome Consortium, Toledo, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). , Tao YangTao Yang https://orcid.org/0000-0002-4182-9793 Center for Hypertension and Precision Medicine, Toledo, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). Microbiome Consortium, Toledo, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). , Ishan ManandharIshan Manandhar https://orcid.org/0000-0001-6772-2540 Center for Hypertension and Precision Medicine, Toledo, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). Microbiome Consortium, Toledo, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). , Sachin AryalSachin Aryal https://orcid.org/0000-0002-1939-6338 Center for Hypertension and Precision Medicine, Toledo, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). Microbiome Consortium, Toledo, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, OH (J.Z., M.V.-K., T.Y., I.M., S.A., B.J.). , Rikeish R. MuralitharanRikeish R. Muralitharan Hypertension Research Laboratory, School of Biological Sciences, Monash University, Melbourne, Australia (R.R.M., F.Z.M.). Victorian Heart Institute, Monash University, Melbourne, Australia (R.R.M., F.Z.M.). Baker Heart and Diabetes Institute, Melbourne, Australia (R.R.M., F.Z.M.). , Hong-Bao LiHong-Bao Li https://orcid.org/0000-0002-1600-9590 Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, PR China (H.-B.L., Y.L.). , Ying LiYing Li https://orcid.org/0000-0002-9042-4768 Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, PR China (H.-B.L., Y.L.). , Justine M. Abais-BattadJustine M. Abais-Battad Department of Physiology, Medical College of Georgia at Augusta University (J.M.A.-B.). , Jennifer L. PluznickJennifer L. Pluznick https://orcid.org/0000-0003-3621-2665 Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD (J.L.P.). , Dominik N. MullerDominik N. Muller Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (D.N.M.). Experimental and Clinical Research Center, a cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Germany (D.N.M.). Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (D.N.M.). DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany (D.N.M.). , Francine Z. MarquesFrancine Z. Marques https://orcid.org/0000-0003-4920-9991 Hypertension Research Laboratory, School of Biological Sciences, Monash University, Melbourne, Australia (R.R.M., F.Z.M.). Victorian Heart Institute, Monash University, Melbourne, Australia (R.R.M., F.Z.M.). Baker Heart and Diabetes Institute, Melbourne, Australia (R.R.M., F.Z.M.). and Bina JoeBina Joe Correspondence to: Bina Joe, University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Block Health Science Bldg, Rm 310, Toledo, OH 43614. Email E-mail Address: [email protected] https://orcid.org/0000-0002-2385-7061 Department of Integrative Physiology and Anesthesiology, Baylor College of Medicine, Houston, TX (D.J.D.). Originally published17 Apr 2024https://doi.org/10.1161/HYPERTENSIONAHA.124.21721Hypertension. 2024;81:951–963In 1924, the distinguished Dutch physiologist Willem Einthoven was awarded the Nobel Prize in Physiology or Medicine for his research and invention of the ECG. Coincidentally, the same year marked the birth of the American Heart Association (AHA), whose central mission, as the name indicates, was also focused on heart health. By then, the term essential hypertension (essentielle hypertonie) was already coined by Eberhard Frank to describe elevated blood pressure (BP).1 However, at that time, the relationships between the heart and essential hypertension were murky.2 Fast-forward to 2024, and as we celebrate the centennial year of the AHA, it is clear that essential hypertension persists as the single most significant risk factor for heart diseases, which are the major contributors to human morbidity and mortality. Therefore, finding solutions to curb essential hypertension is central to achieving the mission of the AHA, which is to be a relentless force for a world of longer, healthier lives.AHA's commitment to hypertension research is evident not just through research funding but also through the addition of a journal aptly called Hypertension to its publication portfolio. Since its inception 45 years ago, research published in Hypertension has centered on human or animal models of hypertension. However, recent understanding of the host as a holobiont—that is, inclusive of the trillions of microorganisms, specifically in the distal part of the gastrointestinal tract—prompted early investigations into potential relationships between gut microbiota and host hypertension. In 2015, 3 seminal publications from our groups, 2 of which were published in Hypertension, reported critical links between gut microbiota and hypertension.3–5 In 2017, another study reported that sodium intake regulates BP via the gut microbiota.6 Over the past 9 years, these impactful works alone have been highly cited over 2700×, which speaks to the community of researchers embracing this new discipline as a previously ignored, important factor in hypertension research.7 Later studies provided the necessary evidence for the causality of BP regulation by gut microbiota and for the existence and modulation of such relationships in human hypertension.6,8–19 The next step for leveraging the gut microbiota as a target for combating hypertension is an exciting prospect for this relatively young field. Targeting microbiota has led to tremendous successes in other fields, implying that the prospects for microbiota medicine are growing. However, what lies ahead for the untapped potential of the microbiota as a target for hypertension is dependent on several variables. Having contributed to this science, here we address these variables via a strengths, weaknesses, opportunities, and threats analysis and present a critical appraisal of the prospects of microbiota research to combat essential hypertension.STRENGTHSPast and Current AccomplishmentsIndirect evidence for the involvement of microbiota in BP homeostasis was available as early as the 1980s through the demonstration that antibiotics attenuated experimental hypertension.20–23 However, formal demonstrations had to wait until the advent of next-generation sequencing, which revealed a much more complex gut community than originally realized and provided a mechanism to track changes to community members that were unculturable. This led to a surge of studies examining potential links between gut microbiota, host physiology, and pathophysiology. Most findings related to the gut microbiota and BP fields began in the 2010s. We reviewed the literature and identified, in our opinion, the top findings that have significantly advanced the field (Figure 1).Download figureDownload PowerPointFigure 1. Highlights of findings that have significantly advanced the field of gut microbiota and blood pressure (BP) regulation. Ace2 indicates angiotensin-converting enzyme 2; ACEi, angiotensin-converting enzyme inhibitor; AI, artificial intelligence; Ang II, angiotensin II; CVD, cardiovascular disease; GPR109A, G-protein–coupled receptor 109A; GPR41, G-protein–coupled receptor 41; GPR43, G-protein–coupled receptor 43; L helveticus, Lactobacillus helveticus; LPS, lipopolysaccharide; OLFR78, olfactory receptor 78; RCT, randomized controlled trial; SCFA, short-chain fatty acid; SHR, spontaneously hypertensive rat; TLR4, toll-like receptor 4; TLR5, toll-like receptor 5; and WKY, Wistar Kyoto.Gut Dysbiosis in Hypertension: From Association to CausationThe first descriptions of alterations to the gut microbiota were described in 3 separate rat genetic models of hypertension in 2015.3–5 Importantly, fecal microbiota transplant from hypertensive donors to normotensive recipients resulted in BP elevations.5,8 These studies demonstrated that alterations to the gut microbiota community were causal in, and not simply associated with, elevated BP. Further compelling causal function of microbiota in BP regulation was obtained through cohousing studies of germ-free rats with conventional rats, wherein acquisition of microbiota restored vascular tone and BP homeostasis in otherwise hypotensive germ-free rats.18 In 2019, 2 independent human studies reported associations of gut microbiota with BP.24,25 The following year, the HELIUS study (Healthy Life in an Urban Setting) demonstrated that gut microbiota associations with BP were distinct between ethnic groups.26 Fecal microbiota transplantation from hypertensive patients into germ-free mice resulted in elevated BP, further demonstrating that the gut microbiota indeed regulates BP.27A third line of early evidence for the microbiota to be integral to BP regulation is evidenced by studies of the host receptors, TLR4 (toll-like receptor 4) and TLR5 (toll-like receptor 5), which recognize bacterial lipopolysaccharide and flagellin, respectively. Pharmacological inhibition of TLR4 signaling lowered BP,28 whereas genetic deletion of TLR5 caused gut microbiota dysbiosis with indices of metabolic syndrome and elevated BP in mice.29 Although with disparate conclusions, these studies demonstrate links between microbiota-derived ligands and host receptors as contributors to BP regulation.Gut Microbiota–Derived Metabolites as Mediators of BP RegulationRecent studies have suggested that ≈50% of circulating metabolites originate from, or are modified by, the gut microbiota and that circulating metabolites are distinct in hypertension.30,31 Not surprisingly, many of these microbially derived metabolites and host-microbe–derived cometabolites are emerging as potential mediators of microbe-host interactions in BP regulation.32 One class of microbial metabolites, called short-chain fatty acids (SCFAs), was the first to be reported as regulators of BP. SCFAs are the byproducts of gut bacterial fermentation of plant-derived complex fibers, which are resistant to digestion by the host. In the 1990s, SCFAs were shown to induce vasodilation ex vivo in human colonic and rat caudal arteries.33,34 These were followed by reports in the past decade that acute and chronic administration of SCFAs caused a decrease in BP in animal models and, more recently, in humans.11,12,35,36 These findings are congruent with a 1979 report showing that interventions with dietary fiber lower the BP in humans.37 Gut microbiota, which thrive in response to a low-fiber diet, increase BP via modulation of the SCFA receptors GPR41 (FFAR3), GPR43 (FFAR2), GPR109A (HCA2), and OLFR78, combined with other systems.12,35,38 In recent studies, bile acids, which are transacted metabolites between the host and gut microbiota, were studied, and conjugated bile acids were identified as nutritionally reprogrammable antihypertensive metabolites.39Microbiota and the Immune SystemThe microbiota is fundamentally important for the induction, training, and function of the host immune system. This is a bidirectional interaction, whereby signals from the microbiota educate the host immune system and, in turn, the immune system responds to members of the microbiota with a tolerogenic or inflammatory response.40–42 While there is exciting ongoing research on the contributions of the immune system to hypertension, most of these studies do not currently consider the bidirectional alliance between the microbiota and the host immune system.43–47 One group of studies to consider this relationship demonstrates that dietary salt alters the microbiota, including reducing gut lactobacilli.6,48 In this salt-sensitive model, these shifts in the microbiota were mechanistically linked to elevated host T helper 17 (Th17) cells and hypertension.6 Second, the SHR (spontaneously hypertensive rat), which harbors a dysbiotic microbiota, was recently reported to lack IgA in both systemic and mucosal compartments, including milk, which is a major host factor required for gut microbiota homeostasis.49 Finally, in a model of obstructive sleep apnea–induced hypertension, it was shown that the alterations to the gut microbiota increase Th17 cells in the gut, and these gut-derived lymphocytes migrate to tissues that influence BP, including the brain.9 These reports likely represent the tip of the iceberg of our understanding of the microbiota's influence on host immune function and, in turn, BP.Interactions Between Host Gut Microbiota and Abiotic FactorsThe early, key studies that first established the connection between the gut microbiota and hypertension followed best practices by faithfully controlling for potential abiotic factors, for example, by controlling for variables such as age and time of the day. However, now that the connection between the host gut microbiota and BP regulation has been established, a next level in our understanding will be to uncover how these abiotic factors interact with microbes to amplify (or diminish) microbial signals. There is good reason to expect interactions here: for circadian rhythm, for example, gut microbiota–derived SCFAs (shown previously to lower BP) act to entrain peripheral tissues.11,38,50,51 Additionally, a comparison of metabolomic signatures of dippers versus nondippers showed significantly elevated SCFAs in nondipping men and women.25,52,53 There are also studies showing that the diurnal abundance of a subset of gut microbes is independently associated with BP and that BP variability (including nighttime dipping and systolic variability) is associated with specific taxa.54,55 Conversely, changes in the circadian rhythm can impact the gut microbiota, and key host factors that influence gut microbes (eg, stool consistency and transit time) are rarely recorded. For aging, it is well established that BP increases with aging and that gut microbes are likewise altered in aging.56 Thus, achieving a higher level understanding of how circadian rhythms, sex, age, and other abiotic factors impinge on these host-microbe interactions can reveal unique aspects of physiology. A deeper understanding of these interactions would yield key insight into how to best design gut microbiota–based treatments and how to interpret differences in efficacy between different subjects.Together, some of these findings culminated in the addition of the gut microbiota to the revised Page's Mosaic Theory of Hypertension in 2021, which is transformative to acknowledge that it is the holobiont that one should focus on rather than exclusively focusing on the host as the target for treatment of hypertension.7WEAKNESSESTechnological ChallengesWhile many fields have shifted their focus to exploring nonbacterial components (eg, gut mycobiome and virome) of the gut microbiota, 16S rRNA gene sequencing (which only allows identification of bacteria) remains a pivotal technology in hypertension research. Combined with small sample sizes, particularly for animal studies, this represents a limitation for the advancement of research in this area: 16S rRNA falls short in providing subspecies-level information, can miss bacteria of low abundance, and overlooks other crucial members of the gut microbiota, such as fungi, viruses, and bacteriophages.57 To propel the field forward, there is a pressing need for more studies to use shotgun metagenomic sequencing. Yet, this approach comes with higher costs, increased labor, and demands advanced bioinformatics skills as well as substantial resources, including data storage capacity.Mismatched Human ResourcesA critical issue associated with technological challenges is that there is a mismatched workforce between the large magnitude of the effects of the gut microbiota and the small critical mass of research teams in this area of hypertension research. This lack of capacity results in the slow advancement of the field and the translation of the findings from bench to bedside. A potential solution lies in establishing a consortium or network of researchers working collaboratively to advance the field. By leveraging shared resources, data, and expertise across the network, collaborative studies can be prioritized for funding, thereby promoting the acceleration of discoveries and translation. This approach would foster a more unified and comprehensive effort to address the challenges associated with gut microbiota research in the context of hypertension.Deficiencies of Human StudiesCurrently, human studies on this subject have been conducted across various geographic locations, which is commendable. However, there exists a disparity in the standards used in these studies, despite the availability of guidelines for their conduct.58,59 To effectively identify the effects of the gut microbiota on hypertension as a phenotype, large, well-characterized clinical cohorts are imperative. For instance, to date, few studies have used 24-hour ambulatory BP measurement as a diagnostic tool.36,60,61 Additionally, dietary components such as salt, prebiotics, and probiotics, which are prominent modifiers of the gut microbiota, have not been considered in most studies. Inclusion of diet as a highly variable factor is necessary, and clinical trials must be conducted so that the effect of these variables in gut microbiota hypertension research can be assessed. Moreover, findings should undergo replication in independent cohorts; due to the lack of well-characterized cohorts, this is still not possible in many cases.Lack of Diversity in Microbiota DataFinally, similar to human genome studies, publicly available human gut microbiota data are mostly available from high-income countries: 71% of samples come from the United States, Canada, and Europe, which represent only 4.3% of the global population.62,63 Considering that low-income countries have a higher hypertension burden, we need to invest resources into studying gut microbiota from underrepresented populations.OPPORTUNITIESWe have identified the following topics as areas of great opportunity and high potential for advancing our understanding of the microbiota-BP relationship and developing treatment strategies (Figure 2).Download figureDownload PowerPointFigure 2. Future prospects for leveraging the microbiota as medicine for hypertension (HT). AI indicates artificial intelligence.Tools for Examining the Gut Microbiota-BP RelationshipAdvancing our understanding of the gut microbiota's role in BP regulation will demand a multifaceted approach. Leveraging cutting-edge tools like metagenomics, artificial intelligence, machine learning, germ-free models, and the gut microbiota–editing capabilities of CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9) will allow for detailed interrogation of the mechanisms underlying microbiota regulation of host BP.Metagenomics, the sequencing of all DNA within a sample, can unveil the vast and diverse communities residing in our gut. Artificial intelligence and machine learning can then be used to sift through these large genomic data sets to identify bacterial strains and metabolic pathways potentially influencing BP. Currently, there are only a few studies using both artificial intelligence and gut microbiota data to assess insights on BP toward microbiota-targeted therapeutics or diagnosis.26,61,64 Germ-free rodents, devoid of any microbes, will serve as crucial blank slates, allowing researchers to introduce specific bacterial strains and monitor their impact on BP, isolating their effects from the complex interplay of the existing microbiota. Finally, CRISPR-Cas9, the precise gene-editing tool, adds another layer of sophistication. By selectively manipulating gut bacteria, researchers can probe specific microbial functions and their influence on BP regulation. This targeted approach will allow for a deeper understanding of cause-and-effect relationships, illuminating the intricate mechanisms by which the microbiota exerts its influence.By synergistically using these diverse tools, researchers can move beyond simply observing correlations between the microbiota and BP. They can dissect the underlying mechanisms, pinpoint key bacterial players, and even explore the potential for targeted gut microbiota modulation as a future therapeutic strategy for hypertension. This multifaceted approach holds immense promise for unlocking the secrets of the gut microbiota, ultimately paving the way for personalized interventions to regulate BP.Gut-Brain Axis in HypertensionEmerging research has shed light on the profound impact of the gut microbiota on the gut-brain axis, an intricate communication system between the gastrointestinal tract and the central nervous system.65,66 This axis presents an exciting area of research for hypertension. The gut-brain axis operates through signaling pathways that encompass neural, hormonal, and immunologic mechanisms. The gut microbiota actively participates in these interactions, as it can produce and influence the host's production of neuroactive metabolites. These may influence neural function in the periphery or centrally by crossing the blood-brain barrier, thereby affecting brain activity and behavior. Studies have demonstrated alterations in the gut microbiota in various neurological and psychiatric disorders, including anxiety, depression, and neurodegenerative diseases.67–69 Conversely, interventions aimed at modulating the gut microbiota, such as probiotics and prebiotics, have shown promise in promoting mental well-being and cognitive function.67,70–72 Moreover, the gut-brain axis is implicated in the regulation of stress responses and the modulation of the immune system.9 A bidirectional interaction between the immune system and gut microbiota exists, whereby the gut microbiota can modulate the immune responses and vice versa.73–76 Studies have also linked gut microbiota with elevated sympathetic drive, but precise mechanisms remain unknown.77–79 SCFAs can directly regulate the activity of the sympathetic ganglia and modulate BP centrally by affecting the brain cardioregulatory regions.80,81 In addition, SCFAs can modulate vagal parasympathetic activity and regulate sensory neural feedback both directly and indirectly via the release of neuroactive gastrointestinal peptides.82–86 Understanding these complex multisystem interactions may open new avenues for therapeutic interventions in cases of treatment-resistant hypertension associated with gut dysbiosis and autonomic dysfunction.Gut Epithelial Permeability and HypertensionStrong evidence from the past 2 decades supports a role for the immune system in the development of hypertension, particularly via an increase in systemic and tissue-specific (eg, kidney and brain) inflammation.87 A key question that remains to be addressed is what triggers and where these inflammatory processes start. Due to the key role of the gut microbiota in priming the immune system, it is plausible that at least part of the inflammatory processes that result in high BP start in the gut. These processes would likely start with the breakdown of the gut epithelial barrier, the monolayer of epithelial cells, and the associated mucus layer that separates the microbiota from the host.88 This process can be triggered by many factors, including diet.89 If this essential barrier is disrupted, it allows the passage of microbial substances such as lipopolysaccharide from the gut to the systemic circulation, where it can bind to the TLR4 and activate inflammatory pathways.88 Indeed, blockage of TLR4 reduces BP in the SHR and in the angiotensin II model, including in knockout mice that lack receptors to sense SCFAs, which are fundamental for maintaining the gut epithelial barrier intact.28,90 Studies in experimental models of hypertension suggest that the intestinal barrier is disrupted, with higher passage of fluorescein isothiocyanate dextran from the gut to the host's circulation and lower levels of tight junction proteins that maintain epithelial cells together and reduce the passage of lipopolysaccharide, as observed in the SHR relative to WKY (Wistar Kyoto) rats, but only after hypertension is established.91 Studies in human hypertension remain less conclusive, as only biomarkers (eg, zonulin and lipopolysaccharide) have been measured, and recent literature points to doubts about their accuracy.92,93 More robust studies in humans are urgently needed to address (1) whether the intestinal barrier is indeed disrupted, (2) how long it remains that way during hypertension, and (3) whether restoring the barrier also reduces BP.Players Beyond Gut BacteriaWhile bacteria have been extensively studied in the context of cardiovascular health, the broader impact of other biota members, including fungi, viruses, bacteriophages, and archaea, remains unknown. Among the diverse biota, bacteriophages, viruses that infect bacteria, are gaining recognition for their potential impact on human health, including hypertension.94,95 Recent studies have highlighted the abundance and diversity of bacteriophages in the human microbiota.96 These viruses can modulate the composition of bacterial communities, influencing the production of bioactive metabolites that in turn may affect cardiovascular function.Fungal dysbiosis has emerged as another intriguing area of hypertension research.97 The gut mycobiota, comprising various fungal species, releases bioactive molecules that could influence BP. Understanding the interplay between fungal communities and cardiovascular health could uncover novel therapeutic avenues for hypertension. A link between archaea and cardiovascular health has also been proposed, highlighting the need for a more comprehensive understanding of biota interactions that may regulate cardiovascular function.98Beyond the gut, the mouth harbors the oral microbiota, which may play a role in BP regulation. Recent research suggests links between specific oral bacteria and systolic BP, diastolic BP, and hypertension prevalence.99 A prospective study reported associations between oral bacterial species, baseline BP, and the risk of developing hypertension in postmenopausal women.100,101 These associations are still being explored, but understanding the functional relationships between oral bacteria and BP regulation will be an important next step. One promising pathway involves oral bacteria capable of converting nitrate into NO, a molecule impacting blood vessel function and BP.102 Studies in rats and humans show that dietary sodium nitrate supplementation lowers BP.103 Interestingly, a clinical study using antiseptic mouthwash that reduced nitrate-converting bacteria led to an increase in BP.104 While more research is needed, studying the oral microbiota's role in hypertension could pave the way for novel preventive or therapeutic strategies.Gut Microbiota as a Driver of Population Differences in Hypertension Susceptibility and TreatmentSex Differences of Gut Microbiota in HypertensionSex differences in the prevalence of hypertension are observed across different life stages; in fact, there are sex differences between men and premenopausal women even in normotension.105,106 Men have a higher incidence of hypertension at an earlier age than women. During menopause, the decline in estrogen levels is associated with an increase in the prevalence of hypertension in females, surpassing that of males.107 The physiological changes associated with estrogen levels, such as the renin-angiotensin system and sympathetic activity, have been documented in the context of BP regulation.108,109 A recent study revealed that female sex hormones have a dominant influence over male sex hormones and sex chromosomes in determining the composition of the gut microbiota.110 In a Chinese cohort of untreated patients, alterations to the gut microbiota were found to be strongly associated with 24-hour ambulatory BP in females