In 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.

Indirect 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).

Figure 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.

The 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.²⁷

A 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.

Recent 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.³⁹

The 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.

The 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.⁷

While 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.

A 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.

Currently, 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.

Finally, 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.

We 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).

Figure 2. Future prospects for leveraging the microbiota as medicine for hypertension (HT). AI indicates artificial intelligence.

Advancing 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.

Emerging 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.

Strong 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.

While 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.⁹⁸

Beyond 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.

Sex 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 but not in males.⁶⁰ These observations suggest new mechanisms for understanding how estrogens contribute to the sex-specific roles of the gut microbiota in hypertension.

There are disparities in gut microbiota between males and females in both animal models and human subjects, although these differences are not always consistent between studies.^111–114Akkermansia muciniphila shows a direct growth response to β-estradiol.¹¹⁰ The next stage would be to illustrate the distinct behavior of sex-specific gut microbiota in response to internal (host-related) and external (environmental) factors in the context of the pathogenesis of hypertension. Understanding these differences is essential for the development of sex-specific strategies for BP regulation. Gut microbial differences are typically subtle and influenced by multiple factors. Therefore, well-controlled studies on gut microbiota in experimental animals would normalize external influences and provide more mechanistic information.

The interaction between gut microbiota and medications in regulating BP is a significant and promising area of research. Antihypertensive medications can be considered as exogenous xenobiotics, which impact the gut microbiota composition and subsequently affect the host’s BP.¹¹⁵ BP-lowering medications, including angiotensin-converting enzyme inhibitors, β-blockers, and angiotensin II receptor blockers, were associated with interindividual variations in the gut microbiota.¹¹⁶ The impacts of certain drugs on different bacterial species are still uncertain because the gut microbial composition is influenced by a range of factors such as race, sex, age, diet, exercise, and circadian rhythm. However, understanding the effects of the gut microbiota on the host’s response to antihypertensive drugs is more pertinent than vice versa, as the mechanisms underlying resistant hypertension are still not well understood.¹¹⁷ The presence of the gut commensal Coprococcus comes has been demonstrated to diminish the BP-lowering impact of angiotensin-converting enzyme inhibitors with an ester group. The mechanism is likely attributed to the hydrolysis of the ester group by esterase activity in C comes, resulting in the generation of a lipophobic and less bioavailable form of angiotensin-converting enzyme inhibitors.¹¹⁸ This provides evidence for the role of gut microbial enzymes involved in drug metabolism.

The pharmacodynamics of a drug consist of its absorption, distribution, metabolism, and excretion. The involvement of the gut microbiota in the regulation of every step of the drug’s pharmacodynamics has been defined as pharmacomicrobiomics.¹¹⁹ Although this research is still in its infancy, understanding these interactions will help develop gut microbiota–targeted approaches to enhance drug efficacy and reduce drug resistance and side effects. It is evident that pharmacomicrobiomics is being progressively integrated into the development of precision medicine, and modification of the gut microbiota may present a particularly alluring prospect for optimizing the effectiveness and safety of medications on an individual basis.

Diet remains one of the top modifiable risk factors and first-line interventions for the development of hypertension and related cardiovascular diseases.¹²⁰ Diet and the gut microbiota are inextricably intertwined, where the diet can shape gut microbiota composition and, in turn, the gut microbiota reciprocally aids in the digestion, fermentation, and metabolism of macronutrients and micronutrients in the diet. Given this reciprocal relationship, several studies have examined how dietary components influence the gut microbiota and their metabolites. Salt is the most influential dietary component known to elevate BP. Pioneering studies focused on dietary salt demonstrated that the gut microbiota is altered by sodium intake, resulting in a decreased abundance of the genus Lactobacillus spp. and the microbial metabolite indole-3-lactic acid.⁶ These findings and others have prompted several exciting studies examining dietary interventions and probiotics as tools for manipulating the gut microbiota and ultimately BP.

It is known that heart-healthy diets rich in plant protein consumption confer lower BP in both observational and interventional studies, which can directly impact the gut microbiota profile.^121–125 Experimentally, animal versus plant proteins have also been shown to induce shifts in the gut microbiota composition, with causative factors that drive hypertension being specifically identified in those fed an animal protein–based diet.^15,126 Closely linked to plant-based diet consumption, fiber is a specific component largely lacking in westernized diets and has been found to critically modulate both the gut microbiota and BP.¹²⁷ The lack of prebiotic fiber predisposed mice to hypertension, which could be reversed by the administration of high-dietary fiber.^12,38 These beneficial effects are ascribed to alterations in fiber metabolism and the production of SCFAs. Aside from modulating the diet composition itself, the implications of meal timing and frequency on cardiovascular health are gaining recognition.¹²⁸ Recent studies show that the beneficial effects of intermittent fasting on BP are causally attributed to alterations to the gut microbiota and changes in bile acid metabolism.¹⁰ Additionally, a 5-day fast followed by a modified Dietary Approaches to Stop Hypertension diet reduced systolic BP in patients with hypertensive metabolic syndrome as compared with the Dietary Approaches to Stop Hypertension diet alone.¹³ While it remains essential to further elucidate the downstream effects of these dietary changes to produce more precise interventional targets, these recent investigations provide strong evidence for the promise of dietary management as a nonpharmacological, gut microbiota–centered therapeutic for hypertension.

Exercise is considered a nonpharmacological approach for the management of hypertension.^129,130 According to the current AHA guidelines, moderate-intensity aerobic exercise training is recommended as a therapeutic method to lower the BP of patients with hypertension and prevent it in the normotensive community.¹³¹ Recently, moderate-intensity exercise has been shown to increase gut microbial diversity and influence the byproducts produced by gut microbiota.¹³² Studies in both humans and animals consistently show that increased gut microbiota diversity and their metabolic potential after exercise have the potential to reverse the conditions associated with metabolic diseases such as diabetes, obesity, and hypertension.^132–134 Indeed, exercise-induced changes in the gut microbiota are beneficial to BP control, as evidenced by a recent study where fecal microbiota transfer from exercised SHR to sedentary SHR resulted in lower BP.¹³⁴ Importantly, this was associated with improvements in multiple organs (eg, the brain and intestine) that are involved in BP regulation, underlying the crucial role of gut microbiota in overall health. Veillonella spp., enriched in marathon runners postmarathon, was recently identified as a performance-enhancing microbe because of its efficient enzymatic process to convert lactate to propionate, a metabolite also produced as a byproduct of fiber intake and shown to reduce BP in mice.^38,51,135 The accumulation of lactate-producing bacteria is one of the characteristics of the gut microbiota in hypertension.⁴ Further work is needed to understand the relationships between exercise, the gut microbiota, and BP. However, this may provide an additional approach to microbiota manipulation for BP regulation.

Progress is being made toward the use of innovative gut microbiota–targeting therapeutics like fecal microbiota transplantation and bioengineered bacteria. Other than for the common treatment of gastrointestinal infections caused by Clostridium difficile, the use of fecal microbiota transplantation in the hypertension field has been primarily leveraged as a critical preclinical, experimental tool to demonstrate causality between the gut microbiota and disease.^{3,5,10,15,27,38} However, its therapeutic use for the treatment of hypertension in humans is currently being investigated. Revealing the potential of this approach, transplantation of healthy donor gut microbiota lowered BP in patients with hypertension, and there are ongoing trials dedicated to determining the efficacy and safety of fecal microbiota transplantation and gut microbiota restoration in hypertension.^136,137

Another novel avenue for modulating the gut microbiota in hypertension is via manipulation of the bacteria itself, where genetic engineering of protective bacteria like Lactobacillus spp. to overexpress human angiotensin-converting enzyme 2 demonstrated BP-lowering effects in a sex-specific manner.¹³⁸ This was the first demonstration of successfully utilizing precisely edited bioengineered bacteria to deliver an antihypertensive agent. With the currently approved therapies and medications for the management of hypertension, it is estimated that only a quarter of hypertensive individuals achieve control over their BP.¹³⁹ This clearly demonstrates the alarming need for these types of cutting-edge, innovative therapies that target unique mechanisms, like the gut microbiota and its metabolites, that are not conventionally thought to underlie the pathogenesis of hypertension.

Over the past decade, researchers have made significant strides in understanding the gut microbiota’s role in regulating BP. We have identified gut microbial alterations linked to high BP and proposed strategies to manipulate the gut microbiota for prevention and treatment. While these are substantial achievements, the field is still young and faces challenges that could hinder its full potential.

This threat arises because gut microbiota hypertension research spans diverse areas like nutrition, microbiology, gastrointestinal immunology, cardiovascular, and neurophysiology, which were largely considered unrelated a few years ago. Most laboratories studying the gut microbiota’s role in BP come from a cardiovascular physiology background. Hence, it is crucial to involve nutritionists, microbiologists, immunologists, and bioinformaticians, especially in human study designs, to ensure accuracy in analyses and interpretations. In addition, available guidelines and checklists for human studies could be better utilized.^57–59,140

The first reports suggesting potential links between the gut microbiota and host BP regulation were met with high skepticism in the field. As with any emerging field, this skepticism was healthy and warranted. In parallel, funding for these high-risk high-reward studies was limited. However, we have now demonstrated causal relationships between gut dysbiosis and hypertension in multiple animal models and patients and are beginning to unravel the mechanisms involved and propose novel therapeutic approaches. This exciting field sits at a critical stage, and without significant financial commitment comes the threat of slowed scientific progression, attrition of human resources, and delayed realization of gut microbiota–based treatments for hypertension.

The recognition that hypertension is a disorder of the host is now established as a disorder of the holobiont (host+microbiota). In the past century, while noteworthy progress has been made in understanding the role of the host, such progress is severely limiting for the critical link between the holobiont in hypertension. Ignoring the holobiont and continuing to focus merely on the host is predictable and will stifle the next century of hypertension research. Instead, combining the rapidly advancing tools like metagenomics and artificial intelligence to research the holobiont presents a transformative opportunity that holds immense potential for better personalized antihypertensive therapies and improved health care outcomes.

As a result of this strengths, weaknesses, opportunities, and threats analysis, the following is a list of our recommendations to alleviate the current weaknesses and threats pertaining to microbiota research in hypertension. We are all part of the narrative whereby there is work to be done by all of us—funders, peer researchers, and clinicians.

Increase investments in basic mechanistic and clinical research initiatives: given that hypertension is the number 1 killer of our species and that the microbiota provides a new window of opportunity to look for better cures, it is imperative that funding agencies get creative in their approach to microbiota research. Admittedly, microbiota research is still in its infancy for both basic and clinical research in hypertension. Therefore, we recommend that funding agencies for hypertension research across the globe creatively nurture this critical foundational phase with dedicated funding for both basic and clinical research. Such a call to action mirrors similar calls for global initiatives in microbiota research.¹⁴¹

Foster collaborative networks: establish platforms for researchers to share data, expertise, and resources, accelerating discoveries and their translation into clinical practice.

Join hands to recognize that research on the holobiont rather than the host per se is the next frontier for advancing the field of hypertension research from the bench to the bedside.

Recognize microbiota research in hypertension as an emerging area of research. Relative to other areas of hypertension research that are focused on the host, the host-microbiota interface is certainly a new science in the field and thereby among the least mechanistically advanced areas of research in hypertension. Recognition of this status is important for peers in hypertension to acknowledge and enthusiastically participate in conducting and supporting microbiota research, which has great potential for delivering creative new therapies for hypertension.

Educate health care professionals: equip health care providers with the knowledge and tools necessary to incorporate dietary counseling and gut microbiota insights into patient management strategies.

Empower individuals: promote public awareness about the link between gut health and hypertension, encouraging healthy lifestyle choices and preventative measures.

Together, by acting on these recommendations at this pivotal juncture of stepping into the beginning of the second centennial year of the AHA, we can bolster its mission for a healthier future for all by harnessing the true potential of the microbiota to revolutionize the way we manage and prevent human hypertension.

The authors acknowledge that BioRender.com was used to create Figure 2.

D.J Durgan was supported by an American Heart Association Transformational Project Award 23TPA1074308 and National Institutes of Health RO1HL134838. M. Vijay-Kumar was supported by National Institutes of Health R01DK134053. T. Yang was supported by an American Heart Association Career Development Award 852969 and National Institutes of Health R21AG079357. H.-B. Li was supported by the National Natural Science Foundation of China 82170443. J.M. Abais-Battad was supported by the American Heart Association Career Development Award CDA34660184. J.L. Pluznick was supported by an American Heart Association Established Investigator Award 34760253 and National Institutes of Health R21AG081683. D.N. Muller was supported by Deutsche Forschungsgemeinschaft (German Research Foundation; DFG-SFB1449) and by Deutsches Zentrum für Herz-Kreislauf-Forschung (81Z0100106). F.Z. Marques is supported by a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Charitable Foundation, a National Heart Foundation Future Leader Fellowship (105663), and a National Health and Medical Research Council Emerging Leader Fellowship (GNT2017382).

Disclosures None.

The American Heart Association celebrates its 100^th anniversary in 2024. This article is part of a series across the entire AHA Journal portfolio written by international thought leaders on the past, present, and future of cardiovascular and cerebrovascular research and care. To explore the full Centennial Collection, visit https://www.ahajournals.org/centennial

For Sources of Funding and Disclosures, see page 959–960.

The opinions expressed in this article are not necessarily those of the American Heart Association.