Food as Medicine for Hypertension: Microbiota as Mediators

Abstract

Hypertension is the single largest modifiable risk factor for chronic cardiovascular and renal diseases and strokes. Approximately 47% of American adults have hypertension. Despite the existence of pharmacological treatments, we remain highly vulnerable to the incidence of hypertension. Research in the past decade has identified microbiota as a previously unrecognized factor that regulates blood pressure. Because microbiota depends on the host food for its sustenance, diet presents as a potential factor to remodel microbiota composition and, thereby, affect blood pressure. Here, we survey the dietary sources of the 6 major food components: carbohydrates, proteins, fats, minerals, vitamins, and water for their ability to influence gut microbiota–mediated blood pressure regulation. Furthermore, beyond food components per se, we discuss how food additives and chemicals used in current agricultural practices could adversely remodel gut microbiota composition and contribute to hypertension. The goal of our work here is 2-prong: (1) to better understand why certain dietary components are beneficial over others for hypertensives because of their ability to remodel gut microbiota composition and (2) to advocate for further research and implementations of dietary interventions in the treatment of hypertension based on their ability to modulate gut microbiota.

Hypertension or elevated blood pressure is the single largest modifiable risk factor for chronic cardiovascular and renal diseases and strokes.¹ While pharmacological treatment options are widely available, modern humans remain highly susceptible to the incidence of hypertension.^2–4 Therefore, dietary interventions are gaining increasing attention in the management of hypertension, partly because diet plays a critical role in the prevention and management of hypertension.^5–8 Notably, the host diet determines gut microbial structure and function.⁹ Besides diet, fecal microbial transplantation is used to restore gut microbial homeostasis.^10–12 However, diet is essential for sustaining the health benefits of fecal microbial transplantation,⁹ reinforcing the central role of diet in microbiota-mediated health benefits, which, in the context of this review, is blood pressure regulation.⁹ Thus, the concept of food as medicine applied to hypertension can highlight how specific foods or nutrients can serve as nutraceutical agents to control hypertension. To this end, nutritional guidelines, such as the dietary approaches to stop hypertension diet, emphasize the consumption of fruits, vegetables, whole grains, lean proteins, and low-fat dairy products while reducing sodium, added sugars, and saturated fats.¹³ Such a diet is rich in potassium, magnesium, and antioxidants, all of which help lower blood pressure by known effects on improving host vascular function, reducing oxidative stress, and promoting sodium excretion.^13–15 However, the benefits of such diets on their potential effect on microbiota composition are relatively understudied.

Microbiota as Mediators

The mammalian host is not a single organism, but a holobiont encompassing microbiota, which consists of a diverse range of microorganisms.^16,17 The terms gut microbiota and gut microbiome are often used interchangeably, but they refer to distinct concepts: gut microbiota describes the community of microorganisms that reside primarily in the gastrointestinal tract, while gut microbiome refers to the collective genomes and functional capabilities of these microorganisms. Gut microbiota, with its microbiome, is indispensable to the host because it aids in the fermentation of food, protects against pathogens, and stimulates immune response and vitamin production.^18–20

Beyond these essential functions, in the postgenomic era, gut microbiota is increasingly recognized as a dynamic mediator of health and disease. It has been linked to the progression of chronic diseases such as inflammatory bowel disease, obesity, diabetes, and hypertension.^21–26 Recent advances demonstrate that gut microbiota is a relatively new factor capable of causally contributing to blood pressure regulation via multiple physiological processes, including metabolism, immune function, vascular, brain, and renal health.^27–36 Hence, modulating gut microbiota serves as an exciting new opportunity to lower hypertension.²⁹

The gut can be viewed as a well-coordinated system made up of various components that work together for the maintenance of a healthy gut barrier.^37–39 These components include the gut microbiota, the cells lining the intestines, the mucus lining the gut, and the immune system. They constantly communicate with microbiota using both host and microbiota-derived metabolites, which are hypothesized to be generated based on nutritional cues. In this context, it is important to recognize that microbiota is entirely dependent on our diet for its sustenance. Hence, microbiota must adapt to survive based on the types of foods that we consume, which vary constantly. As a result, microbiota adapts and routinely changes their composition.⁴⁰ Such remodeling of microbiota composition can impact levels of metabolites generated by microbiota, some of which are reported to regulate blood pressure.^41–47 Thus, microbiota plays a critical role in mediating the effects of diet on blood pressure. Viewed from this context, modulating host diet presents as an attractive strategy for altering the composition of gut microbiota to support blood pressure homeostasis of the host.

In this review, we synthesize current knowledge on the relationship between diet and hypertension viewed through the lens of microbiota as mediators. Broadly, we review the 6 major components of food, carbohydrates, proteins, lipids, vitamins, minerals, and water, on their potential influence on microbiota composition and blood pressure regulation (Table 1). Furthermore, we discuss the use of food additives and the impact of agricultural practices, which could have the potential to remodel microbiota and regulate host blood pressure.

Table 1.

Various Dietary Components and Their Effects on Hypertension

Dietary Carbohydrates

Simple Carbohydrates and Ultraprocessed Foods

Carbohydrates and ultraprocessed foods (UPFs) are major sources of added sugars, which include refined sugars and other sweeteners commonly found in processed snacks and packaged foods.^70,71 Epidemiological evidence has shown that eating too much sugar can adversely affect our health in ways that go beyond just adding extra calories, with one notable example being its association with the development of high blood pressure.^72,73 The World Health Organization describes free sugars as all monosaccharides and disaccharides that are added to foods and drinks, as well as the natural sugars found in fruits and honey.⁷⁴ These free sugars are present in different forms: they can be simple sugars, such as glucose and fructose, or disaccharides, such as sucrose, which is table sugar, or complex sugars, such as polysaccharides.⁷⁴ Excessive sugar intake has been linked to a higher risk of developing conditions such as metabolic syndrome, especially in teenagers, which is an important factor that can contribute to high blood pressure later in life.⁷⁵

Monteiro et al⁷¹ indicate that UPFs, which are mostly ready-to-eat products, contain high levels of salt, total fat, saturated fat, trans fats, free sugars, low fiber, and micronutrient content. In addition, large prospective studies evaluating dietary patterns categorized by UPF intake have identified significant associations between high UPF consumption and an unfavorable cardiometabolic risk profile.^72,76 To avoid the adverse effects of sugars, artificial sweeteners are preferred, but results are mixed on the effects of such sweeteners on blood pressure. A study with Equal and Splenda, 2 brands of sweeteners, fed to Sprague-Dawley rats for 12 months concluded that there was no effect on blood pressure.⁷⁷ While there are no direct studies of the blood pressure effects of artificial sweeteners in humans, a large clinical trial on the NutriNet-Santé cohort in France revealed a direct association between higher consumption of aspartame, acesulfame potassium, and sucralose and increased cardiovascular risk.⁷⁸ Given these conflicting and limited studies, the use of artificial sweeteners should be approached with caution and requires further research into their effects on hypertension.

The adverse effects of UPFs and sugar-rich diets are increasingly attributed to their detrimental impact on gut barrier function and gut microbial metabolites, both of which are central to the development of hypertension.^59,78–80 This is supported by evidence of a dysfunctional gut mucosal barrier and the development of leaky gut syndrome in Western diets rich in high sugar and fats.^60,81 Consistent evidence from studies in animal models demonstrates that a high glucose or fructose diet enhances intestinal inflammation, which triggers alterations in tight junction proteins.^51,82 In addition, specific alterations in microbiota with increased abundance of Pseudomonadota and decreased abundance of Bacteroidota were noted.^83,84 Other investigators have reported that administration of fructose to male Sprague-Dawley rats at different doses for 20 weeks raised the proinflammatory cytokines, IL (interleukin)-6, and TNF-α (tumor necrosis factor-alpha) while decreasing IL-10, an anti-inflammatory cytokine.^85,86 Likewise, a higher fructose intake was associated with an increased abundance of Parasutterella and Blautia and decreased Intestinimonas.⁵¹ Another study demonstrates that a 2-day exposure to a high sugar–containing diet rapidly alters microbial diversity, depletes short-chain fatty acids (SCFAs), and increases susceptibility to colitis.⁸⁷ The loss of intestinal barrier function was attributed to the direct effect of high levels of luminal sucrose linked with a decrease in SCFAs’ production, a feature noted in hypertension.^88,89

Mechanistically, gut barrier dysfunction contributes to systemic inflammation by allowing microbial products such as lipopolysaccharides to translocate into the circulation.⁹⁰ Once in the bloodstream, lipopolysaccharide is typically bound to lipopolysaccharide-binding protein or lipoproteins and interacts with pattern recognition receptors such as TLR (toll-like receptor) 4 on immune cells, triggering a robust inflammatory response.^91,92 Sustained immune activation and inflammation impair endothelial function and promote vascular dysfunction, contributing to elevated blood pressure.^93–95 While TLR4 has not been studied, another receptor, TLR5, which binds to bacterial-generated flagellin, has been demonstrated to be important for blood pressure regulation.⁹⁶ Lack of TLR5 in mice contributed to the elevation of blood pressure.⁹⁶ This cascade linking intestinal permeability, immune activation, and vascular dysregulation highlights the central role of gut barrier integrity in the pathogenesis of hypertension. Thus, diet-induced compromise of the intestinal barrier may serve as an upstream mediator of hypertension via microbially driven inflammatory pathways.

Overall, available data suggest that intake of sugar and UPFs could have a broad immunomodulatory and physiological effect by altering gut microbial composition and function and consequently blood pressure.⁹⁷ Further research is therefore required to address these potential mechanisms by which the gut microbiota could mediate the harmful effects of dietary carbohydrates and UPFs on blood pressure.

Complex Carbohydrates: Dietary Fiber, Fruits, and Vegetables

Fiber is a complex carbohydrate that is not digestible by the host but undergoes fermentation by the gut microbiota.⁹⁸ A high-fiber diet is consistently associated with positive cardiovascular and overall health outcomes.^98–100 While sodium has traditionally been viewed as the primary dietary contributor to hypertension, studies indicate that the dietary approaches to stop hypertension diet, rich in fruits, vegetables, and fiber, can effectively lower blood pressure, even in individuals consuming high-sodium diets.^15,54,101 These studies emphasize the importance of a fiber diet and point to microbiota as a central mediator of the beneficial effect of fiber.

Research comparing a Western low-fiber diet to a high-fiber diet, such as the Mediterranean diet, has revealed that those adhering to the Mediterranean diet tend to have a more beneficial microbiota profile.^102,103 This diet emphasizes the consumption of microbiota-assessable carbohydrates, which foster the growth of gut microbiota that converts these carbohydrates into SCFAs.^102,103 Currently, SCFAs are the most researched class of microbial metabolites in hypertension.^55,104–107 These SCFAs, acetate, propionate, and butyrate, activate the GPRs (G-protein–coupled receptors), GPR41 and GPR43, on the vascular endothelial and kidney cells, which leads to vasodilation (Figure 1).^108,109 GPR41 and GPR43 signalings help maintain the integrity of the gut epithelial barrier, preventing the leakage of lipopolysaccharide into the bloodstream.¹¹⁰ SCFAs also strengthen gut barrier integrity by binding GPR41 and GPR43, which increases the production of tight junction proteins such as occludins and claudins in epithelial cells.¹¹¹ The SCFAs, butyrate and acetate, are also linked to inhibition of renin release, which decreases the production of angiotensin II, leading to vasodilation, reduced blood volume, and lower blood pressure.^100,109,112 SCFAs possess anti-inflammatory properties and reduce proinflammatory cytokines, such as TNF-α, IL-6, and IL-1β. They also thwart the activation of inflammatory pathways¹¹³ and enhance the production of regulatory T cells, which suppress inflammation (Figure 1).^100,114

Figure 1.

Multifaceted mechanisms by which SCFAs, primarily acetate, propionate, and butyrate, lower blood pressure. GPR indicates G-protein–coupled receptor; IL, interleukin; and Th1, T helper cell 1.

Fruits like apples are potentially beneficial for blood pressure homeostasis because they contain pectin, which can be broken down into SCFAs.^115,116 Supplementation with prebiotic esterified pectin lowers blood pressure.¹¹⁷ Similarly, several vegetables such as broccoli, carrots, and Brussels sprouts high in fiber are demonstrated to lower blood pressure, but whether their effect is mediated by gut microbiota and SCFAs’ production remains to be determined.^118–121 Thus, there is a wide opportunity to examine the effect of these fruits and vegetables as modulators of gut microbiota composition to generate SCFAs and, thereby, contribute to blood pressure homeostasis.

A recent clinical trial has demonstrated that garlic lowers blood pressure via remodeling of gut microbiota composition.¹²² In this study, garlic was shown to increase microbial diversity with an increase in Lactobacillus and Clostridia species.¹²² This study corroborated a similar clinical trial in which 88 patients with uncontrolled hypertension were also given a daily intake of aged garlic extract. Garlic was effective in reducing both central and peripheral blood pressures in patients with uncontrolled hypertension.⁵⁷ Furthermore, garlic contains several bioactive compounds such as allicin and S-allyl cysteine that have been shown to exert antihypertensive effects by once again increasing beneficial bacteria such as Lactobacillus and reducing harmful bacteria such as Turicibacter and Staphylococcus.⁵⁸ The bioactive components also increase the production of vasodilators such as hydrogen sulfide and NO, both of which are crucial to lower blood pressure.⁵⁸

Fruits and Vegetables as Sources of Phytonutrients

Polyphenols, found abundantly in fruits and vegetables, are known for their beneficial effects on blood pressure and cardiovascular health due to their antioxidant effects.^56,123,124 They are also widely recognized for their vasodilatory properties, contributing to their antihypertensive effect (Table 2). They enhance the production and bioavailability of NO, a key regulator of endothelial function and vascular relaxation.¹²³ Beyond their role in NO signaling, polyphenols also help reduce inflammation by inhibiting the release of proinflammatory cytokines such as TNF-α and IL-6.¹²³

Table 2.

Major Polyphenols That Are Likely Beneficial for Lowering Blood Pressure via Known Cardiovascular, Anti-Inflammatory, and Immune Benefits

Polyphenols have a complex chemical structure and a high molecular weight, which makes their direct absorption in the small intestine difficult. Instead, gut microbiota in the colon breaks them down into smaller, bioactive metabolites that can be more readily absorbed and utilized by the body.¹⁴⁴ Polyphenols can be categorized into 4 primary families based on their molecular complexity, which varies in the number of phenolic rings and other structural features. The simplest of these are phenolic acids that include subclasses such as hydroxybenzoic and hydroxycinnamic acids. Another natural phenolic compound found in a variety of vegetables is protocatechuic acid; it is a major metabolite of anthocyanins. Protocatechuic acid is demonstrated to protect against the development of hypertension.¹⁴⁵ Studies on the effect of these compounds on blood pressure, especially addressing whether they occur via gut microbiota–mediated pathways, are unknown.

Glucosinolate is abundant in brassica vegetables, such as arugula, Brussels sprouts, cabbage, kale, radish, turnips, and watercress. Gut microbiota, such as Bacteroides thetaiotaomicron can metabolize glucosinolate to generate chemopreventive isothiocyanates.¹⁴⁶ While glucosinolates have been shown to lower blood pressure,¹¹⁹ research on glucosinolates and blood pressure regulation is limited, and there is only 1 report of glucosinolates lowering blood pressure in humans; whether this is mediated by gut microbiota remains unknown.

Other polyphenols such as flavanols, ellagitannins, resveratrol, and flavonols have a variety of polyphenols that are known to be metabolized by microbiota. These polyphenols also confer beneficial effects such as vasodilation, antioxidants, and anti-inflammatory effects (Table 2). Whether this beneficial effect is mediated by the microbial metabolite of these polyphenols in the context of blood pressure regulation remains a knowledge gap. Nevertheless, Table 2 tabulates the dietary sources of these polyphenols along with the metabolites generated from these polyphenols by microbiota and their potential physiological roles in regulating blood pressure.

Another key metabolite present in many fruits and vegetables, most notably bell peppers, is 1,3-butanediol, a precursor to β-hydroxybutyrate. Recent studies suggest that this precursor can help mitigate hypertension in salt-sensitive rats via epigenetic histone β-hydroxybutyrylation.¹⁴⁷ While previous studies have linked salt-sensitive hypertension to exaggerated proinflammatory T-cell function,^148–150 emerging data suggest that 1,3-butanediol may also exert its blood pressure-lowering effects through a T helper cell 17-independent mechanism.¹⁵¹ Notably, β-hydroxybutyrate has been shown to inhibit the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-contain-3) inflammasome, a key mediator of inflammation in conditions such as high-salt–dependent hypertension.^152,153 β-Hydroxybutyrate is also reported to be a potent vasodilator.¹⁵⁴ Oral feeding of 1,3-butanediol to hypertensive rats also remodeled gut microbiota composition,¹⁵¹ but the extent to which this remodeling contributed to blood pressure regulation is not clear. Nevertheless, incorporating bell peppers into the diet may offer additional benefits for individuals struggling with hypertension.

Dietary Proteins

Animal Proteins

The intake of dietary protein can directly influence the composition of the gut microbiota¹⁵⁵ and influence hypertension. Most studies show that protein consumption is positively correlated with greater total gut bacterial diversity.¹⁵⁶ The literature further suggests that rather than the quantity of protein, the source of protein can have a greater effect on the composition of gut microbiota.¹⁵⁷ Animal proteins are reported for their effect on bacterial composition.

Hentges et al¹⁵⁸ demonstrated how a diet high in beef, with an intake of 176 g/d of protein, led to a decrease in the abundance of Bifidobacterium adolescentis and an increase in Bacteroides fragilis and vulgatus compared with a meat-free diet with an intake of 90 g/d of protein. In general, focusing on animal protein consumption has been shown to increase the abundance of Bacteroides, Alistipes, and Bilophila, species that are often associated with higher inflammatory states.^97,159,160

Crimarco et al¹⁶¹ conducted a clinical trial that tracked the gut microbiota of participants who ate a diet rich with meat compared with participants with a plant-based diet. The meat-eating participants ate bacon for breakfast, cooked pork and beef for lunch, and cured meat for dinner along with some cheese. RNA sequencing revealed that eating a meat/animal-based diet had a significantly greater impact on the gut microbiota than plant-based diets.¹⁶¹

In addition to altering microbial composition, animal-based proteins influence gut microbial metabolism in ways that further exacerbate cardiovascular risk. Specifically, animal proteins contain precursors such as L-carnitine and choline that are metabolized by bacteria into trimethylamine.¹⁶² Trimethylamine is absorbed into the bloodstream and converted into trimethylamine-N-oxide (TMAO) by liver enzymes. TMAO is a proatherogenic and proinflammatory metabolite linked through several mechanisms to contribute to the disruption of gut microbiota and elevated blood pressure.^162,163 Primarily, TMAO causes endothelial cell dysfunction through a reduction of NO bioavailability, leading to vasoconstriction and impaired blood vessel dilation.^{162,164–166} TMAO also increases proinflammatory cytokines such as IL-6 and TNF-α, which contribute to vascular damage.¹⁶⁵ In addition, TMAO enhances the production of renin, which activates angiotensin II and causes systemic vasoconstriction.^167–169 This can amplify and exacerbate cardiovascular disease and hypertension. In the kidneys, TMAO affects sodium regulation, resulting in fluid buildup, retention, high blood pressure, and congestive heart failure.^162,170

Foods that promote TMAO and dysbiosis include red meat and processed meat, which are high in both L-carnitine and choline.¹⁷¹ Egg yolks are high in choline and lecithin, which also contribute to TMAO production and, therefore, oxidative stress, endothelial cell dysfunction, and hypertension.^171,172 Collectively, these data indicate that animal proteins could contribute to hypertension, which leads to the question of whether plant-based proteins are better, which is discussed in the following.

Plant-based proteins could be better than animal-based proteins for promoting microbiota composition, which allows for better blood pressure control. This could suggest that the incorporation of a diet with more vegetables and less meat and animal-based products could prevent gut dysbiosis and inhibit proinflammatory metabolites. The American Heart Association particularly recommends dietary patterns like the dietary approaches to stop hypertension diet and Mediterranean diets, which are plant-based, for their beneficial effects on blood pressure and cardiovascular health.¹⁷³

Plant Proteins

Plant protein–based diets are associated with a distinct microbiota and are linked to an improved Bacillota-to-Bacteroidota ratio, unique bacterial speciation, and greater SCFAs, all of which are beneficial for blood pressure homeostasis.^174,175 It should be noted that Bacillota-to-Bacteroidota is currently debated for the accuracy of representing good versus bad microbiota. Jia et al¹⁷⁶ found that 3-week-old Sprague-Dawley rats fed with various nitrogen-sourced diets, including casein, soybean protein, and soybean protein–derived peptides, for 35 days have enhanced gut microbiota abundance of Bifidobacterium and Akkermansia compared with the casein diet. In support, Zhao et al¹⁷⁷ demonstrated that intake of soy proteins elevated the abundance of SCFAs in the cecum of young Sprague-Dawley rats. A similar effect was observed in 4-week-old Sprague-Dawley rats fed with soy protein compared with the casein, beef, and chicken groups.¹⁷⁸

Peas are an excellent dietary protein source. They are the source of primary proteins such as globulin, albumin, prolamin, and glutelin. A randomized controlled trial conducted recently replaced meat-containing meals, 5 meals per week, with mainly a pea-based diet in 20 subjects for 4 weeks and reported an increase in butyrate-producing bacteria such as Ruminococcaceae and Lachnospiraceae, which are butyrate producers. Similarly, functional analysis showed an upregulation of butyrate-producing pathways.¹⁷⁹ Pea albumin was also beneficial when fed for 2 weeks to Wistar rats. The rats had an abundance of Bifidobacteria, Bacteroides, and Lactobacilli and were protected from gut inflammation.¹⁸⁰

Plant proteins can influence blood pressure by interacting with the gut microbiota, leading to beneficial changes that may help prevent or manage hypertension.^176,181 The relationship involves modulation of gut microbial composition, production of bioactive metabolites, and reduction of inflammation. Plant proteins, especially when hydrolyzed or fermented, release peptides that can act as prebiotics, supporting beneficial gut bacteria and increasing the production of metabolites such as SCFAs and other postbiotics.^176,181 These metabolites help regulate blood pressure by affecting the renin-angiotensin system, improving gut barrier function, and reducing inflammation and oxidative stress.^181,182 Furthermore, it is well documented in both observational and interventional studies that plant proteins help restore a healthier microbiota profile, which is correlated with improved blood pressure control.^181,183 Therefore, modulating the gut microbiota through dietary interventions, especially increasing plant protein, is potentially a promising strategy for hypertension prevention and management.

Dairy Proteins and Probiotics

One principal nonpharmacological agent for managing blood pressure is the use of probiotics. Probiotics are beneficial live microorganisms that provide health advantages to the host when consumed in adequate amounts.¹⁸⁴ The growing public interest in probiotics has resulted in their use as raw materials for functional foods, such as yogurt, fermented milk, and various dietary products.⁸⁹ These products are formulated using lactic acid from Lactobacillus spp., Bifidobacterium spp., Enterococcus spp., and Streptococcus spp.^185,186 These microorganisms serve multiple roles including secreting metabolites and altering the host immune system.¹⁸⁷ They also help protect against invading pathogenic organisms, inflammation, and hypertension.¹⁸⁷ Multiple studies revealed that probiotics significantly lower blood pressure. For instance, consuming a Lactobacillus plantarum beverage for 30 to 60 days decreases systolic blood pressure in healthy individuals.¹⁸⁸ Recently, an exploratory, randomized, double-blind, placebo-controlled, parallel-group study conducted demonstrated that Vivomixx (9×10¹¹ colony forming unit), a probiotic comprising a cocktail of bacteria, effectively lowered blood pressure in patients with grade 1 hypertension.¹⁸⁹ Women with hypertension exhibited improvement in fasting blood glucose levels, lipid profile, and autonomic modulation following 8 weeks of probiotic intake.¹⁹⁰ A meta-analysis of randomized controlled trials suggests that intake of probiotics at a daily dose of ≥10¹¹ colony forming unit improves blood pressure.¹⁹¹

Yogurt, fermented milk, and various nutritional products have been examined for their potential impact on hypertension. Buendia et al¹⁹² demonstrated that increased yogurt consumption correlates with a reduced risk of hypertension. A meta-analysis conducted by Soedamah-Muthu et al¹⁹³ indicated that the consumption of low-fat dairy was inversely correlated with the risk of hypertension. A study involving 1780 individuals demonstrated that dairy products, including yogurt, had cardiometabolic preventive effects by significantly enhancing gut microbial alpha diversity.¹⁹⁴ Other clinical investigations have documented similar results with consistent consumption of Lactobacillus fermented milk.^195,196 Many of these products comprise calcium, potassium, and other bioactive peptides that modulate blood pressure by facilitating vasodilation, enhancing sodium excretion, and inhibiting ACE (angiotensin-converting enzyme) activity.¹⁹⁷

The relationship between hypertension, gut microbiota, probiotics, and dairy consumption is complex and constitutes a triad of dietary components, microbial metabolism, and blood pressure regulation. Upon ingestion, probiotics and dairy products, particularly fermented ones, produce SCFAs, bile acids, and bile salt hydrolase.^198,199 These compounds stimulate various physiological processes, such as inhibiting NG-nitro-L-arginine methyl ester (L-NAME), ACE, and inflammatory pathways while promoting NO production to help regulate blood pressure.^200–203 Specifically, conjugated bile acids such as taurocholic acid are shown to be inversely related to hypertension in both human and animal models through yet unknown mechanisms.⁴⁴ Indeed, bile acids increase stroke volume and improve endothelium-dependent vasodilation and endothelium-independent vasodilation in humans.^{177,204–206}

Furthermore, probiotics lower blood pressure by modulating gut microbiota, diminishing the production of reactive oxygen species, and enhancing the absorption of dietary calcium.^207,208 Probiotics and dairy products have minimal or no adverse side effects and hold considerable potential for treating hypertension.

Dietary Fats

Oils

The type of fat intake plays a critical role in blood pressure regulation. A high-fat diet, particularly one rich in saturated and trans fats such as coconut oil, is strongly associated with hypertension through multiple mechanisms.²⁰⁹ High-fat diet reduces NO production and increases reactive oxygen species, resulting in inflammation and narrowing of the blood vessels.^210–212 Conversely, substituting saturated fat with unsaturated fat may result in a lower blood pressure.^213–215 Unsaturated fats such as omega-3 from fish, omega-6 fatty acids from peanut oil, and monounsaturated fats from olive oil and avocado oil improve cardiovascular function and lower blood pressure.^213,216 In addition to improving cardiovascular function, unsaturated fats improve gut microbiota diversity. Recent studies suggest that unsaturated fats elevate the abundance of SCFA-producing organisms such as Roseburia, Lactobacillus, and Faecalibacterium.²¹⁷ Increased production of SCFAs such as propionate, acetate, butyrate, and other microbial metabolites induces vasodilation and potentially lowers blood pressure.¹¹⁸ Furthermore, these SCFAs improve gut barrier integrity, reducing inflammation and oxidative stress associated with hypertension.¹¹⁸ On the other hand, excessive intake of saturated fatty acids is associated with significant gut microbial alteration by increasing Bacillota and decreasing Bacteroidota ratio.¹¹⁸ Dietary fats and oils directly shape gut microbiota composition, influencing hypertension through metabolites such as SCFAs.²¹⁸ Prioritizing anti-inflammatory fats (omega-3, omega-6, and monounsaturated fatty acid–containing oils)^37,219,220 and eschewing proinflammatory fats (saturated and trans fatty acid–containing oils) can enhance intestinal health and contribute to blood pressure homeostasis.²²¹

Nuts

Nuts are well documented to be associated with reduced risk of diseases, including obesity and cardiovascular disease, with epidemiological studies and systematic reviews highlighting their benefits for cardiovascular health.^222–224 Interestingly, early in vitro studies have demonstrated the prebiotic effect of almonds and chestnut extract on Bifidobacteria and Lactobacilli, respectively.^52,225 In addition, a randomized control trial study conducted by Holscher et al²²⁶ where they fed 18 participants with almond diet (1.5 servings/d) for 3 week suggests that consuming nuts, especially almonds, positively influences the gut microbiota by increasing beneficial bacteria such as Clostridium, Dialister, Lachnospira, and Roseburia (Figure 2) potentially important for regulating cardiovascular and metabolic health by producing SCFAs particularly butyrate,^227,228 a bacteria metabolite associated with lowering of blood pressure. It is, therefore, not surprising that the intake of almonds is linked to a reduction in blood pressure.^229,230

Figure 2.

Nut consumption induces beneficial shifts in gut bacterial composition.

An 8-week intervention with walnut consumption (43 g/d) significantly improved lipid profiles in healthy individuals, accompanied by a significant increase in the abundance of Ruminococcaceae and Bifidobacteria and a decrease in Clostridium cluster XIVa species, including Blautia and Anaerostipes.²³¹ Similarly, a study conducted in Uganda, wherein participants were fed with peanuts for 90 days, demonstrates that peanuts significantly promote the production of microbial metabolites such as SCFAs, known to reduce blood pressure.²³² Certain bacteria enriched through walnut consumption, such as Eubacterium eligens, have been inversely associated with changes in blood pressure levels.²³³ Furthermore, walnuts have been found to enhance SCFA-producing bacteria and uniquely affect specific microbes such as Gordonibacter.²³³ The randomized control crossover feeding study by Ukhanova et al²³⁴ revealed that consumption of 1.5 and 3 servings/d of pistachio increased the number of butyrate-producing bacteria while decreasing lactic acid-forming bacteria. The increased levels of butyrate produced by nuts could be attributed to the fermentation of fiber by butyrate-producing bacteria.²³⁵ Indeed, the health-related effects of nut consumption may not only be related to their contribution to energy but also their impact on beneficial gastrointestinal microbiota and overall metabolic health. In summary, while nuts remodel microbiota composition, whether such remodeling affects blood pressure remains to be determined.

Vitamins

Vitamins are key components of food, which contribute to the regulation of blood pressure. Various experiments in humans and animals have demonstrated that Vitamins B2, B6, C, D, and E^236–245 regulate blood pressure although other studies failed to support the inverse association between some of these vitamins and elevated blood pressure.^239,246,247 The reasons for such discrepancies are unknown but could stem from the fact that the relationship between vitamins and gut microbiota is bidirectional and could vary depending on the context. The gut microbiota plays a critical role in vitamin metabolism, particularly in the synthesis and regulation of B vitamins including biotin (B7), folate (B9), riboflavin (B2), niacin (B3), pantothenic acid (B5), thiamine (B1), pyridoxine (B6), and cobalamin (B12)^18,19,248 and vitamin K,¹⁹ which are vital for both microbial and host health. Conversely, vitamin D and B supplementation is noted to increase the Bacillota-to-Bacteroidota ratio, as well as the levels of Akkermansia, Bifidobacterium, and Lactobacillus.^249,250 Furthermore, vitamins C and E, which are antioxidants, enhance the growth of beneficial bacteria such as Bifidobacterium and Lactobacillus.²⁵⁰

This intricate relationship between gut microbiota and vitamins can contribute to multiple mechanisms and pathways that can influence blood pressure regulation. For instance, gut microbiota can influence the absorption and metabolism of vitamins, affecting their bioavailability and efficacy in blood pressure regulation. In addition, vitamins can modulate gut microbiota to produce SCFAs, which, in turn, can affect blood pressure through various pathways including vasodilation and inhibition of inflammation.²⁵¹ Moreover, hypertension itself may alter the gut microbial composition, creating a potential feedback loop. In conclusion, the interplay between hypertension, gut microbiota, and vitamins represents a complex system with significant potential for novel therapeutic approaches. Further research is needed to fully elucidate these relationships and develop targeted interventions for hypertension management.

Minerals

Dietary Salt

Sodium chloride is the most studied mineral that adversely affects salt-sensitive hypertension. The American Heart Association recommends a daily sodium intake of no more than 2300 mg, with an ideal limit of 1500 mg for most adults.²⁵² However, >70% of dietary sodium is from processed and packaged foods rather than from salt added during cooking or eating, leading to widespread overconsumption.^253,254 Therefore, curtailing not just added salt but also salt-loaded processed and packaged foods is an important form of preventative medicine for hypertension.

The link between salt intake and hypertension was first investigated by Dahl²⁵⁴ in the mid-20th century when his research demonstrated that chronic salt feeding in rats led to hypertension resembling that seen in humans. The Dahl salt-sensitive rat model remains a widely utilized tool in hypertension research,^255–257 reinforcing that excessive sodium intake not only increases the incidence of hypertension but also exacerbates its severity. However, a previously overlooked likely mediator in the relationship between salt sensitivity and blood pressure regulation is gut microbiota.

The gut microbiota is primarily composed of the phyla Bacillota (formerly Firmicutes) and Bacteroidota (formerly Bacteroides), with Actinobacteria and Pseudomonadota (formerly Proteobacteria) present in lower proportions.²⁵⁸ Recent evidence suggests that high dietary salt intake induces gut microbial dysbiosis, characterized by an increased abundance of Pseudomonadota, a phylum associated with proinflammatory responses.^{40,65,259,260} In line with this, Wilck et al⁶⁴ demonstrate that high salt intake significantly depletes specific members of the Bacillota phylum, particularly the genus Lactobacillus. Notably, they observed that the operational taxonomic unit abundance of Lactobacillus was restored to baseline levels when mice were reintroduced to a normal-sodium diet, indicating the reversible nature of salt-induced microbial composition perturbations. In support, adverse gut microbiota remodeling is reported in patients with salt-sensitive hypertension,²⁵⁹ further linking the effect of salt on microbial composition to blood pressure regulation. This evidence suggests that high salt intake disrupts the composition of the gut microbiota, leading to an imbalance between beneficial and harmful microbial populations, with specific microbial profiles correlating with the severity of hypertension.

Beyond compositional changes, high salt intake can also influence the functional capacity of gut microbiota, particularly microbial metabolism. Salt acts as a physiological stressor not only for humans but also for bacteria residing in the gut. In response to elevated sodium levels, bacteria undergo adaptive changes, altering their metabolic output to survive in this high-salt environment. This shift in microbial metabolism can have significant downstream effects on host physiology, including blood pressure regulation.¹⁰⁰ One key aspect of this adaptation is the modification of microbial metabolite production.⁶⁵ Studies indicate that mice on a high-salt diet exhibit reduced intestinal levels of butyrate, potentially due to enhanced butyrate uptake by colonocytes as a compensatory protective mechanism.²⁶¹

Similarly, Yang et al⁸⁹ found that hypertensive rats had significantly lower levels of butyrate-producing bacteria compared with their normotensive counterparts. Consistently, in humans, microbial metabolites are also altered, and individuals with hypertension have reduced butyrate production, reflected in a lower abundance of butyrate-producing bacteria, including Butyricicoccus, Eubacterium, Faecalibacterium, and Fusobacterium.²⁶² However, in contrast to butyrate levels, fecal acetate and propionate, as well as plasma acetate, have been reported to increase under high-salt conditions in rodents.²⁶²

Furthermore, studies have demonstrated that dietary sodium restriction increases circulating levels of SCFAs, which enhance arterial compliance and lower blood pressure through multiple mechanisms including receptor-mediated signaling discussed earlier in the review.²⁵⁹ A key pathway involves SCFA activation of GPRs, particularly GPR41 and GPR43, which modulate vasodilation, suppress inflammation, and regulate the renin-angiotensin system.²⁵⁹ These findings underscore the intricate relationship between dietary salt intake, gut microbial metabolites, and host cardiovascular physiology in blood pressure regulation.

Growing evidence strongly supports that immune system activation and chronic low-grade inflammation are key drivers of elevated blood pressure.²⁶³ A high-sodium diet not only affects blood pressure but also contributes to a cascade of inflammatory responses, boosting proinflammatory cytokine levels and triggering immune cell infiltration in vascular tissues.²⁶⁴ Mice fed with a high-salt diet show a surge in inflammatory cells in the gut, likely driven by the formation of isolevuglandins protein adducts in antigen-presenting cells, which amplify IFN-γ (interferon-gamma) and IL-17A production.²⁶⁵ Furthermore, studies have demonstrated that transferring fecal material from high-salt–fed mice to germ-free mice leads to increased inflammation and hypertension, underscoring the critical role of gut microbiota in modulating immune responses and hypertension.²⁶⁶ These findings collectively highlight the intricate interplay between dietary salt intake, gut microbiota, immune homeostasis, and blood pressure regulation.

Other Minerals/Micronutrients

There is increasing evidence that suggests that dietary minerals other than salt (sodium chloride) may influence gut microbiota.²⁶⁷ The literature suggests that minerals including calcium, phosphorus, magnesium, zinc, and iron can sway the balance between so-called good and bad microbiota, which can set the stage for the development of hypertension.^268,269 Calcium supports the growth of beneficial bacteria, such as Bifidobacteria and Lactobacilli, and helps maintain gut integrity⁶⁶; low calcium levels can lead to imbalanced microbiota and increased inflammation, both of which are linked to hypertension.^66,270 Phosphorus is crucial for energy metabolism, and while adequate levels can support beneficial bacteria, excessive intake, especially from processed foods, can promote an imbalance that fosters inflammation and potentially contributes to high blood pressure.⁶⁷ Magnesium is essential for enzymatic functions and maintaining a diverse gut microbiota composition; deficiency can increase inflammation and oxidative stress, exacerbating vascular dysfunction.^271,272 Similarly, zinc is vital for immune function and gut health, and its deficiency can lead to microbiota imbalance and impaired gut barrier function, raising systemic inflammation and hypertension risk.^273,274

Iron, while necessary for many bacteria, can create an imbalance when excessive, leading to the overgrowth of harmful bacteria that promote inflammation.^275,276 In contrast, iron deficiency can also alter microbiota composition and contribute to cardiovascular illnesses.^277–279 Together, these results emphasize the importance of a balanced diet with optimal levels of minerals/micronutrients to support gut health and mitigate the risk of hypertension.²⁵⁰

However, besides sodium, research linking dietary minerals directly to blood pressure regulation via microbiota is limited and presents an attractive prospect.

Water

Water intake plays a crucial role in blood pressure regulation. Adequate hydration sustains optimal blood volume, which directly affects blood pressure.²⁸⁰ Dehydration may result in decreased blood volume, potentially leading to hypotension. Inadequate water intake triggers vasopressin release, resulting in vasoconstriction and increased blood pressure.²⁸¹ In addition, dehydration activates renin angiotensin aldosterone system, enhancing sodium retention and vasoconstriction.²⁸² On the contrary, a randomized placebo-controlled, parallel-group study conducted over 12 weeks by Nakamura et al²⁸⁰ demonstrated that increasing water intake by 2.0 L/d lowered systolic blood pressure in normotensive individuals.²⁸³ Water intake influences gut microbiota composition and function through its effects on intestinal environment, mucus integrity, and microbial metabolism. Adequate hydration maintains the gut’s protective mucus layer, which supports commensal bacteria such as Akkermansia muciniphila, a mucin degrader, and inhibits pathogen adhesion.²⁴⁷ Water has also been reported to facilitate the transport of fermentable substrates such as fiber to colonic bacteria such as Bifidobacteria and Roseburia, boosting production of SCFAs.^69,284 In addition, it regulates colonic pH, favoring lactic acid bacteria (eg, Lactobacillus) over alkaliphilic pathogens.^69,284 A 2023 randomized controlled trial revealed that adults drinking >3 liters of water per day exhibited 15% elevated fecal Bifidobacterium and Faecalibacterium compared with low-intake groups (≤1.5 liters per day).²⁴⁷

Food Additives

Food additives are chemical compounds that are critically essential to the formulation of UPFs for enhancing appearance, palatability, and shelf life. About 60% of foods purchased by Americans contain food additives, including coloring or flavoring agents, preservatives, and sweeteners.²⁸⁵ Prevalence of food additives is on the rise with the mean number of additives contained in purchased food and beverage products from 3.7 in 2001 to 4.5 in 2019.²⁸⁵ Despite this upsurge in usage, it is disconcerting that the health consequences of these food additives are not fully researched.²⁸⁵ As such, most of these additives are considered to have no negative health effects. However, emerging research indicates that some food additives disrupt gut microbiota composition with potential downstream consequences on cardiovascular and metabolic health. Such findings are reported with limited food additives such as antibiotics, emulsifiers, and artificial sweeteners, which are elaborated on in the following.

However, the specific effects of food additives on blood pressure regulation mediated by microbiota are understudied.

Antibiotics

Antibiotic-fortified animal feed leads to the presence of antibiotics in poultry and meat products. Consumption of such antibiotic-containing foods can disrupt the gut microbiota. We have demonstrated that in rat models of hypertension, the antibiotics neomycin, vancomycin, and minocycline elevated blood pressure via modulation of the gut microbiota composition.²⁸⁶ On the other hand, minocycline and amoxicillin are demonstrated to lower blood pressure.^89,287,288 These reports while conflicting clearly demonstrate that antibiotics can influence blood pressure. Further research is, therefore, warranted to delineate the effects of antibiotics-fortified foods and their potential effects on gut microbiota–mediated blood pressure regulation.

Emulsifiers

Emulsifiers are additives whose effect on the human body currently raises many questions. These molecules are widely used by the food industry because of their ability to bind both fat and water-forming micelles, allowing them to give a smooth and homogeneous texture to UPFs. Emulsifiers, especially polysorbates, carboxymethylcellulose, and carrageenan, are thought to disrupt gut microbiota composition, which can lead to inflammation and other metabolic disturbances.^289–296 Moreover, the ability of these emulsifiers to dissolve fats could disrupt certain protective barriers whose function requires insolubility in water. For example, the layer of mucus that covers the surface of the intestine must remain intact to prevent hundreds of billions of intestinal bacteria from coming into contact with the bloodstream and causing uncontrolled activation of the immune system, which can lead to an inflammatory reaction.^297–299 A study in animal models suggests that the addition of polysorbate 80 or carboxymethylcellulose to the diet causes inflammation in the intestine, as a result of bacterial infiltration through the mucus barrier, and these inflammatory conditions could promote the development of various pathologies.³⁰⁰

A recent study suggests that a high intake of emulsifiers could also increase the risk of cardiovascular disease.³⁰¹ This study of 95 442 healthy French adults examined the potential association between intake of emulsifiers from UPFs and the incidence of cardiovascular disease via coronary heart disease and stroke over the following 7 years. Positive associations were found between the consumption of 5 specific emulsifiers, widely used in processed foods, namely, cellulose, carboxymethylcellulose, sodium triphosphate, and monoglyceride and diglyceride esters of citric and lactic acids^300,302,303 and the risk of cardiovascular disease. More recently, a study showed that the administration of carboxymethyl cellulose for 11 days to human volunteers caused an increase in inflammatory markers and reduced the diversity of the microbiota.³⁰⁴ Given the crucial role of inflammation in the development of cardiovascular disease, it is possible that the adverse effects of these emulsifiers on cardiovascular health are linked to the promotion of chronic inflammation caused by a disruption of the intestinal microbiota. An additional mechanism of action of emulsifiers could be via their introduction into the digestive system, causing rearrangement in the composition of bile acids, which are the natural emulsifiers of the host. We and others have shown that bile acid composition regulates blood pressure.^44,305 While emulsifiers are likely to influence the host via the plausible mechanisms described above, none have been tested for their effects on microbiota-mediated blood pressure regulation. However, a high intake of emulsifiers is correlated with an increased risk of cardiovascular disease in humans and requires mechanistic studies.³⁰¹

Monosodium Glutamate and Other Food Additives

Monosodium glutamate is yet another widely used flavor-enhancing additive in Chinese and Eastern Asian cuisines. Monosodium glutamate is banned in many parts of the world due to its documented carcinogenic effects.³⁰⁶ However, monosodium glutamate is also reported to promote hypertension.³⁰⁷ Whether this is via microbiota-mediated mechanisms remains unknown and requires attention.

To the best of our knowledge, other food additives have not been reported specifically for their effects on blood pressure regulation and cardiovascular health. Furthermore, none have been tested for their potential effects on microbiota-mediated blood pressure regulation. Given that certain dyes cause hyperactivity in some children,^308–310 it is plausible that the gut-brain axis, which also affects blood pressure regulation, could be mediating such effects. Similarly, artificial sweeteners such as aspartame or sucralose disrupt glucose metabolism, which can also be due to an altered gut microbiota composition as noted in hypertension.^50,311,312 Overall, from a food safety perspective, because food additives are extensively used xenobiotics, which may affect gut microbiota composition, it is important to reexamine their safety on cardiovascular health with emphasis on microbiota-mediated effects on host hemodynamics.

Food Contamination With Current Agricultural Practices and Organic Foods

The Food and Agriculture Organization of the United Nations broadly defines organic agriculture as a system that relies on ecosystem management rather than external agricultural inputs.³¹³ In the United States, organic foods are certified by the US Department of Agriculture in accordance with federal regulations that encompass various criteria, such as soil health, animal welfare, and sustainable pest and weed management, as well as restrictions on synthetic additives.³¹⁴ Organic producers are expected to rely primarily on natural substances and physical, mechanical, or biological farming methods.³¹⁴ Epidemiological studies have demonstrated that regular consumers of organic products exhibit healthier physiological profiles overall.³¹⁵ Furthermore, existing literature indicates a correlation between increased organic food intake and a diminished risk of cardiovascular diseases, highlighting potential health advantages that transcend mere nutrient composition.^316,317 A significant study conducted in 2020 by Ludwig-Borycz et al,³¹⁸ which analyzed a cohort with a mean age of 64.3 years (54.4% female), revealed an inverse relationship between organic food consumption and key inflammatory biomarkers such as CysC (cystatin C) and CRP (C-reactive protein). However, whether there are differences in microbiota composition between organic food and conventional food consumption is unknown. The rationale for this thought is that current agricultural practices use a variety of herbicides and pesticides, which can influence microbiota composition. Therefore, another important factor to consider is that modern agricultural practices could affect our food. To increase the yield of crops, we use a variety of herbicides and pesticides. Some of these are known to be detrimental to microbes but were developed in the 20th century when awareness about humans being holobionts was nonexistent. As an example, glyphosate, which is the most widely used broad-spectrum herbicide in the history of agriculture, is detrimental to both plants and microbes.³¹⁹ The latter was ignored during its development. Human exposure to glyphosate occurs through dermal contact, inhalation, and diet. Recently, an analysis of glyphosate from urine samples obtained from the US general population from the 2013 to 2014 National Health and Nutrition Examination Survey revealed that glyphosate was detected in a staggering 81% of the US population aged ≥6 years.³²⁰ Because chemicals such as glyphosate can be detrimental to microbiota, further research is needed to understand if they are indeed causative of hypertension. Until then, organic foods, which are cultivated in the absence of such herbicides, are likely better for consumption by subjects with hypertension.

Conclusions

Emerging evidence on the interplay between diet, gut microbiota, and hypertension emphasizes the critical role of dietary interventions in managing blood pressure. The concept of food as medicine is increasingly validated by studies demonstrating how specific nutrients influence gut microbiota composition, thereby affecting key physiological processes such as immune function, metabolism, and vascular health.

As research continues to unravel the impact of macronutrients such as carbohydrates, proteins, and lipids on gut microbiota, the focus shifts from caloric intake alone to the broader concept of dietary quality. Processed and UPFs, rich in added sugars and unhealthy fats, disrupt gut microbial balance, contributing to inflammation and hypertension. Conversely, fiber-rich and probiotic-enhancing foods, such as fermented dairy products and plant-based proteins, foster beneficial microbial populations that generate SCFAs, which play a key role in lowering blood pressure. The notion that humans are holobionts presents the opportunity to prioritize the composition of food components that positively influence blood pressure homeostasis via resetting microbiota composition to generate beneficial metabolites. However, significant gaps in knowledge persist for defining underlying gut microbiota–mediated mechanisms of all food groups on blood pressure regulation.

Future research should also focus on personalized nutrition approaches, leveraging gut microbiota profiling to tailor dietary interventions for individuals at risk of hypertension. In addition, there is a need for well-designed clinical trials to validate microbiota-targeted dietary strategies and translate these findings into practical guidelines. By deepening our understanding of diet-microbiota interactions, we can pave the way for innovative, microbiota-targeted therapies that complement conventional pharmacological treatments to lower hypertension.

Article Information

Acknowledgments

Biorender.com was used for the design of the figures.

Sources of Funding

The authors acknowledge funding from the National Institutes of Health to B. Joe (grant R01-HL171401).

Disclosures

None.