July/August 2024

July/August 2024 Issue

Hypertension: What’s the Gut Have to Do With It?
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 17 No. 4 P. 24

The gut microbiota plays a role regulating blood pressure, and alterations to it contribute to hypertension.

Hypertension is a significant risk factor for heart disease and stroke, two of the leading causes of death. Nearly half of the adults in the United States are hypertensive, defined as having a systolic blood pressure (BP) greater than 130 mmHg or a diastolic BP greater than 80 mmHg or taking medication for hypertension.1

Well-known contributing factors for hypertension include unhealthy lifestyle habits, age, sex, family history and genetics, race, and ethnicity. More recently, the association between gut health and chronic health conditions, including hypertension, has become increasingly recognized and is an emerging field of study. The gut microbiota (GM) plays a role regulating BP, and alterations to it contribute to hypertension.

The Gut Microbiota
The GM refers to all the microorganisms that colonize the digestive tracts of humans. The human GM consists of trillions of microbes made up of thousands of species, including bacteria, fungi, archaea, parasites, and viruses.2 It’s composed mainly of two dominant bacterial phyla, Firmicutes and Bacteroidetes (90%), followed by other phyla, including Actinobacteria (mainly Bifidobacterium), Proteobacteria, Fusobacteria, and Verrucomicrobia in lower proportion.3 GM composition is highly variable between individuals due to race, sex, body mass index, lifestyle, exercise frequency, medication use, and dietary and cultural habits.4 Maintaining a delicate balance in the GM composition is critical to numerous physiological processes, such as digestion, vitamin synthesis (eg, B1, B9, B12, and K), and immune system development and regulation.

Gut Barrier Function
A healthy GM is essential for normal gut barrier function. The gut barrier is selectively permeable, allowing nutrients to pass from the intestinal lumen into the bloodstream. It also serves a defensive “barrier function” role that prevents pathogenic microbes and other toxic substances from entering the circulation.5 When the gut barrier function is healthy, the permeability of the intestine is low, which effectively inhibits leakage of intestinal pathogens and enterotoxins into the body and reduces inflammatory damage to intestinal blood vessels, thereby maintaining normal BP. However, when the GM becomes imbalanced, this barrier becomes “leaky,” resulting in increased permeability of toxins that trigger hypertension and other chronic conditions.

Role of Short-Chain Fatty Acids (SCFAs)
SCFAs are produced by specific bacteria in the intestinal tract through the fermentation of complex carbohydrates and nondigestible dietary fibers. The three major SCFAs are acetate, propionate, and butyrate. SCFAs nourish gut cells and maintain a healthy gut barrier lining. SCFAs also affect BP regulation through multiple mechanisms, including vasodilation, anti-inflammatory properties, and immune homeostasis.

Preservation of Intestinal Barrier Integrity
SCFAs provide energy to the intestinal epithelium, promote the integrity of the intestinal epithelium, and help repair damaged epithelium. Butyrate can enhance the betaoxidation process of the cells in the intestinal mucosa, consume oxygen in the intestinal lumen, promote the growth of beneficial bacteria, and inhibit the proliferation of potential pathogenic microorganisms.6 Imbalances in GM can result in decreased SCFA-producing bacteria such as Lactobacillus spp. and Bifidobacterium spp., leading to detrimental effects on gut barrier function.7

G-protein Coupled Receptors (GPCRs)
SCFAs interact with GPCRs found in the gut, kidneys, and blood vessels, resulting in vasodilation and reduced BP. For instance, SCFAs can activate the GPCR known as olfactory receptor 78 and GPR41, leading to vasodilation and a subsequent decrease in BP.6

Immune Homeostasis and Anti-Inflammatory Properties
The immune system and excessive inflammation are known to contribute to the development of hypertension. SCFAs can mitigate the hypertension-related immune response by promoting the proliferation of regulatory T cells and reducing effector T cell response.6 Additionally, SCFAs (primarily butyrate) can also inhibit histone deacetylase activation, which helps with hypertension by preventing vascular inflammation and protecting the body from oxidative stress.6

Gut Dysbiosis
Dysbiosis refers to an imbalance or disruption of normal GM. Dysbiosis can reduce beneficial bacteria, increase the overgrowth of harmful bacteria, or cause a loss of overall bacterial diversity. These changes in gastrointestinal microbe composition can lead to disruptions of microbial metabolites, impaired gastrointestinal tract function, and increased gut leakage. Ultimately, these changes increase our vulnerability to disease. Long-term consequences of dysbiosis can be severe and may include but are not limited to the development of inflammatory bowel disease, irritable bowel syndrome, autoimmune conditions, obesity, diabetes, central nervous system disorders, cancers, hypertension, and cardiovascular disease.

Firmicutes/Bacteroidetes Ratio
The ratio of the two main phyla found in the GM, expressed as the Firmicutes/Bacteroidetes ratio (F/B ratio), is widely accepted to have an important influence on the maintenance of normal intestinal homeostasis. An increased or decreased F/B ratio is regarded as dysbiosis.8 An association between an increased F/B ratio and obesity has been reported, while a decreased F/B ratio generally indicates inflammatory bowel disease. Also, the F/B ratio increases with age, as older adults have GM enriched with proinflammatory commensals and fewer beneficial microbes.9

The Role of GM in Hypertension
Existing evidence has shown that microbiota imbalance, gut barrier dysfunction, and microbiota-derived metabolites play a crucial role in the development of hypertension.10 Additionally, hypertension can lead to GM imbalance and gut barrier dysfunction.11

Microbial Imbalance
A meta-analysis showed that probiotic fermented milk has BP-lowering effects in prehypertensive and hypertensive subjects. The study suggests that probiotic microorganisms in fermented milk, such as Lactobacillus helveticus and L. acidophilus, may influence GM composition to lower BP.12

Another meta-analysis found that probiotic consumption resulted in positive microbiota changes that reduced BP.13 This review showed that probiotic consumption with daily doses from 10⁹ to 1012 colony forming units for three to nine weeks may improve BP. The magnitude of improvement was greater among those with elevated BP when the daily dose of probiotic consumption was ≥1011 colony forming units and when the intervention lasted eight or more weeks. The study also suggested a greater effect from consuming multiple rather than single species of probiotics.

Researchers have also found that hypertension in rats and humans decreases microbiota richness, diversity, and evenness while the ratio of Firmicutes/Bacteroidetes increases.14 Hypertension was also associated with decreased SCFA bacteria. They also found that oral minocycline administration attenuated high BP and could rebalance the dysbiotic hypertension GM by reducing the F/B ratio.

In addition to decreased microbial richness and diversity, studies have shown hypertension to be associated with an overrepresentation of specific bacterial genera, especially gram-negative bacteria belonging to the genera Prevotella, Klebsiella, Parabacteroides, and Desluvibrio.15 In one study, researchers found that persons with hypertension or prehypertension have an overgrowth of bacteria such as Prevotella and Klebsiella and lower levels of Bacteroides (associated with normotensive controls).16 This indicates that gastrointestinal dysbiosis occurs early on before the development of hypertension. These researchers also showed that fecal microbiota transplant from hypertensive donors to normotensive recipients resulted in elevated BP, demonstrating that alterations to the GM community directly influenced BP and are not simply associated with elevated BP.

Intestinal Barrier Dysfunction
GM imbalance and gut barrier dysfunction are significant in persons with hypertension and are characterized by increased harmful bacteria and lipopolysaccharides (LPS), decreased beneficial bacteria and SCFAs, decreased intestinal tight junction proteins, and increased intestinal permeability, also referred to as “leaky gut.”

In addition to increased harmful and decreased beneficial bacteria, decreased SCFAs play a significant role in gut barrier dysfunction. For instance, increased opportunistic pathogens such as Klebsiella, Streptococcus, and Parabacteroides have been noted in hypertensive patients. At the same time, SCFAs producers, including Roseburia and Bacillus freundii, were higher in the control group.11

As discussed earlier, individuals with prehypertension and hypertension overexpress gram-negative bacteria. Endotoxins, also called LPS, are a major constituent of the outer cell wall of gram-negative bacteria and are released into the blood when the gut barrier is disrupted.11 LPS are responsible for the induction of sepsis, shock, and multiple organ failure due to traumatic events. When dysbiosis occurs, intestinal permeability increases and harmful microbial metabolites and toxins such as LPS are translocated across the gut barrier into the bloodstream. Consequently, proinflammatory cytokines such as interleukin (IL)-1B, IL-12, IL-6, and tumor necrosis factor alpha promote and accelerate systemic inflammation while weakening the gut barrier function. At the same time, levels of pathogenic bacteria and LPS increase, which causes a chronic inflammatory response and damage to vascular endothelial function, reducing vasodilator factors while increasing vasoconstriction factors contributing to hypertension.

Factors Contributing to Dysbiosis
Factors such as diet, exercise, and medications can influence the GM.

High-Sodium Diets
Diets high in sodium increase BP through modulation of GM, leading to an increased production of inflammatory cytokines, which directly increase BP.17 A high-salt diet also alters the GM profile by rapidly depleting Lactobacillus spp.18 Lactobacillus species benefit the host by impeding pathogen growth and activation, exhibiting anti-inflammatory properties, and optimizing gut microbial structure and composition.19 Restoring gut Lactobacillus spp. was found to reduce BP.18

Fat, Sugars, and Artificial Sweeteners
Diets that are high in fat and sugar can reduce SCFA production, leading to intestinal barrier dysfunction, resulting in increased LPS translocation and inflammation that contribute to hypertension.20 Similar findings have been seen with the use of artificial sweeteners such as aspartame.21

Fiber
Whereas low-fiber diets contribute to gut dysbiosis, high-fiber diets contribute to healthy GM and exert an antihypertensive effect. Feeding a high-fiber diet to hypertensive mice effectively reduced BP.22 Dietary fiber can modulate GM and promote the production of SCFAs.11 Hypertensive mice’s systolic and diastolic BPs were effectively decreased by supplementing the mice’s diet with high-fiber food and acetate.23

Exercise
SCFAs are lower in sedentary persons compared with those who are physically active. Exercise can increase the diversity and richness of gut bacteria, enhance the levels of SCFAs and bile acids, and improve inflammatory response.24

Medications
Some medications, including antibiotics and nonantibiotic medications such as proton pump inhibitors (PPIs), metformin, selective serotonin reuptake inhibitors, and laxatives, can influence the composition and function of the GM.25 Changes to the GM can also affect drug efficacy by altering bioavailability and drug activity.

Proton Pump Inhibitors
PPIs are used in the United States for gastroesophageal reflux disease, peptic ulcer disease, indigestion, and Helicobacter pylori infection. PPIs work by inhibiting the H+/K+ ATPase enzyme, which is responsible for acid secretion in the stomach. PPIs potently reduce stomach acid, which can lead to dysbiosis due to an overgrowth of certain bacteria that would typically be kept in check in a normal acidic environment. The resulting dysbiosis may cause or worsen hypertension. Furthermore, PPI use can interfere with certain nutrients, such as magnesium and calcium, that are essential for maintaining normal BP. Subsequent hypomagnesemia may also contribute to secondary hypertension by increasing intracellular calcium, causing vasoconstriction, which increases vascular tone and peripheral resistance.26

Treatment Resistant Hypertension
One mechanism by which gut health may influence BP is the GM’s interaction with certain BP medications. A study published in March 2024 in the Journal of Hypertension found that treatment-resistant hypertension results from specific changes in the GM and metabolites.27 The researchers found that elevated levels of Actinobacteitia and Proteobacteria characterized the treatment-resistant hypertension group. Similarly, a study from the University of Toledo found that a common gut bacterium, Coprococcus comes, can interfere with the action of some angiotensin-converting enzyme inhibitors, a prevalent class of treatments for high BP.28 Differences in GM composition between individuals may explain why some persons fail to respond to certain antihypertensive medications.

Recent Probiotic Study
A study published in October 2023 in mSystems identified two new strains of probiotics with antihypertensive properties.29 The researchers found that hypertensive mice treated with Bifidobacterium lactis and Lactobacillus rhamnosus saw their BP return to normal. For the study, the researchers tested the two probiotic strains on mice that developed high BP after consuming water mixed with fructose. Over 16 weeks, they measured the animals’ BPs every four weeks, finding that that fructose-fed mice that received either probiotic showed significantly lower BPs than did those fed a high fructose diet and not treated with probiotics. The researchers used shotgun metagenomic sequencing to probe connections between the altered GM and the change in BP. They found that a high-fructose diet in the mice led to an increase in Bacteroidetes and a decrease in Firmicutes bacteria; however, treatment with probiotics returned those populations to levels found in the control group. In addition, the analysis identified new microbial signatures associated with BP: Increased levels of Lawsonia and Pyrolobus bacteria and reduced levels of Alistipes and Alloprevotella were associated with lower BP. The researchers are planning a large clinical trial to see if the protective effect of probiotics extends to people with hypertension.

Future of Hypertension Management
Our understanding of microbiota-influenced hypertension is in its infancy and will require additional research and human clinical studies. However, it’s possible that in the future, hypertension treatment guidelines will include a combination of current antihypertensive medications along with dietary interventions, antibiotics, prebiotics, probiotics, fecal matter transplantation, and, possibly, novel gut-microbiota treatments that target an individual’s specific GM.

— Mark D. Coggins, PharmD, BCGP, FASCP, is a long term care expert and corporate pharmacy consultant for Touchstone-Communities, a leading provider of senior care that includes skilled nursing care, memory care and rehabilitation for older adults throughout Texas. He’s a past director of the American Society of Consultant Pharmacists and was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the Excellence in Geriatric Pharmacy Practice Award.