Lifestyle modifications are often effective adjuncts in preventing and treating hypertension. More recently, research supports a role for the gut microbiome in regulating blood pressure. This blog will describe the potential mechanisms of this relationship and the evidence for the role of probiotics to reduce the risk of hypertension.
Hypertension, in brief
Hypertension is diagnosed when the pressure of blood pushing against your artery walls is too high (140/90 mmHg or higher). The first number (systolic) signifies the pressure within blood vessels during the heart's contraction or beats, while the second number (diastolic) indicates the pressure in the vessels when the heart is at rest between beats. For individuals with cardiovascular disease, diabetes, or chronic kidney disease, the recommended blood pressure target is below 130/80 mmHg.
Risk factors for hypertension that can be altered include poor dietary habits (such as high salt, saturated fat, and trans fats intake, and low consumption of fruits and vegetables), tobacco and alcohol consumption, lack of physical activity, and being overweight or obese. Environmental stresses such as noise can also increase the risk of hypertension.
Factors that cannot be modified include a family history of hypertension, being over 65 years old, and the presence of concurrent conditions like diabetes or kidney disease.
Common antihypertensive medications include diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin-2 receptor blockers (ARBs).
The gut microbiota and hypertension
Both humans and animals with hypertension have been observed to have reduced gut microbial richness and diversity along with disrupted microbial structure and function. Specific gut bacteria show a higher presence in individuals with hypertension compared to those with normal blood pressure. A recent review found that “hypertensive patients were shown to have lower alpha diversity, lower abundance of SCFA-producing microbiota, and higher abundance of gram-negative bacteria, which are a source of LPS. Animal studies point towards a direct role for SCFAs in blood pressure regulation and show that LPS has pro-inflammatory effects.”
Many risk factors for hypertension impact gut microbiota composition, providing a potential link to the disease. For example, a higher salt intake may alter short-chain fatty acid (SCFA) production, which in turn affects blood pressure.
Strikingly, gut microbiota has been observed to have a direct impact on host blood pressure: fecal transplantation from hypertensive human donors to germ-free mice demonstrated the transfer of elevated blood pressure via microbiota.
Dysbiosis effects in hypertension
An imbalance of gut microbiota and a change in metabolites are key factors impacting blood pressure control. Dysbiosis can lead to failure of the gut epithelial barrier which can elicit systemic inflammation. These changes can trigger processes typically linked to the regulation of blood pressure, including the renin-angiotensin-aldosterone system, the autonomic nervous system, and the immune system.
In addition, dysbiosis can alter the metabolite mix (detailed below) which can negatively engage various downstream signaling pathways crucial in controlling blood pressure.
Gut microbiota modifications and effect on hypertension
Probiotics are thought to regulate hypertension through several mechanisms:
1: Mitigation of vascular oxidative stress
It is widely acknowledged that oxidative stress and a reduced ability to eliminate free radicals play a role in causing hypertension. An excess of reactive oxygen species (ROS) results in reduced nitric oxide (NO) availability and vasoconstriction, thereby fostering the development of arterial hypertension.
Probiotics such as lactobacilli and Bifidobacterium and their metabolites exhibit antioxidative activities that regulate oxidative stress and protect cells from oxidative damage.
In one study on rats with hypertension induced by chronic nitric oxide blockade, administration of the probiotic Limosilactobacillus fermentum prevented dysbiosis and vascular oxidative stress.
2: Production of metabolites
The gut microbiota can secrete various metabolites that cross into the systemic circulation and act as signaling molecules to help regulate blood pressure. The key microbiota-derived metabolites concerning blood pressure include short-chain fatty acids (SCFAs), vasoactive hormones, trimethylamine (TMA) and trimethylamine N-oxide (TMAO), and uremic toxins, such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS).
Short-chain fatty acids
Derived from gut microbial fermentation of dietary fiber and resistant starch, SCFAs (primarily composed of acetic, propionic, and butyric acid) are linked to the prevention of hypertension. They have demonstrated a protective role in safeguarding the heart and blood vessels from damage.
SCFAs traverse the gut barrier and act via various mechanisms, including interactions with G protein-coupled receptors (GPCRs) which are central in regulating blood pressure.
The connection between metabolites produced by gut microbes and the regulation of blood pressure has been confirmed in animal models. In one example of many, research demonstrates an increased Firmicutes/Bacteroidetes ratio and decreases in acetate- and butyrate-producing bacteria in rats with hypertension.
One study on spontaneously hypertensive rats observed that the administration of SCFA-producing probiotics Limosilactobacillus fermentum and Bifidobacterium brevis prevented increases in blood pressure.
While SCFA supplementation shows great promise in animal models of hypertension, its efficacy in treating human hypertension is yet to be determined.
Vasoactive hormones
Research shows that several commensal gut microbes can produce vasoactive hormones, such as serotonin, dopamine, and norepinephrine. As vasoactive hormones, they play a role in regulating blood vessel constriction or dilation, influencing blood pressure.
Trimethylamine N-oxide (TMAO)
A gut microbiota-derived metabolite produced from foods such as red meat, eggs, and milk, TMAO is involved in the intricate process of blood pressure regulation but not in a positive way.
One 2022 analysis provided “evidence of a causal relationship of TMAO and its precursors with BP, suggesting that mediating the generation of TMAO would be beneficial for lowering BP.”
Reducing blood TMAO concentrations reduced blood pressure levels in several studies. One meta-analysis suggested that the intake of probiotics could have a slight positive impact on blood pressure, especially when initial are higher, and when a variety of probiotic strains are ingested.
Uremic toxins, such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS
The gut microbiota creates uremic toxins—such as indoxyl sulfate and p-cresyl sulfate— by breaking down dietary components like proteins, amino acids, and other compounds. When kidney function is impaired, these toxins can accumulate in the body, leading to arterial calcification and oxidative stress. Blood vessel function, salt and water balance, and hormonal regulation are affected, all of which can influence blood pressure.
A systematic review and meta-analysis suggested that treatment with probiotics, prebiotics, and synbiotics may help alleviate uremic toxin levels.
3: Improving endothelial cell dysfunction
Vascular endothelial cell dysfunction and hypertension are interlinked in a detrimental cycle, where the cells' secretions play a crucial role in regulating blood vessel function. Hypertension affects these secretions leading to endothelial damage that can make hypertension worse.
In animals, in one study using a strain of Lactobacillus coryniformis, improvement in endothelial dysfunction and reduced oxidative stress was reported, suggesting a potential for benefits in hypertension.
In a small clinical study, probiotic supplementation with Lactiplantibacillus plantarum improved vascular endothelial function and reduced systemic inflammation in men with coronary artery disease.
4: Reducing vascular inflammation
Chronic inflammation is strongly linked to vascular diseases, contributing to endothelial dysfunction and exacerbating hypertension and cardiovascular issues.
The gut microbiota may influence host hypertension by pro-inflammatory pathways, possibly via lipopolysaccharide (LPS), a component of gram-negative bacteria such as Escherichia coli which is positively correlated with hypertension in humans and is used to induce endothelial dysfunction and vascular inflammation in animal models.
One review found that animal intervention studies suggested an improvement in vascular inflammation and hypertension following probiotic supplementation, which was mediated by the downregulation of LPS-induced pathways. Also cited were clinical studies showing evidence for the anti-inflammatory effect of probiotics with antihypertensive effects.
The role of gut microbiota in the prevention and treatment of hypertension is multifaceted. From the evidence suggesting multiple mechanisms at play, gut microbiota-targeted antihypertensive therapy is a promising strategy.
In addition to studies cited previously, a 2022 umbrella meta-analysis of 14 meta-analyses with 15,494 participants indicated significant decreases in both systolic and diastolic blood pressure following probiotics supplementation. Greater reductions in systolic were observed in older participants and in those receiving a longer duration of intervention.
A list of probiotic interventions in clinical and experimental models and results related to hypertension was assembled in another review.
Takeaway
Hypertension affects over a billion adults worldwide, and its complications can lead to serious health issues like stroke and heart disease.
Recent studies reveal the vital influence of gut microbiota on blood pressure regulation through the production of metabolites like short-chain fatty acids, vasoactive hormones, and uremic toxins. Probiotics show promise in potentially mitigating risk of hypertension by influencing oxidative stress, metabolite production, endothelial function, and vascular inflammation.
While more research is needed, targeting the gut microbiota for antihypertensive therapy is an emerging and promising approach.
Key references
Bartolomaeus, Hendrik et al. “Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage.” Circulation vol. 139,11 (2019): 1407-1421. doi:10.1161/CIRCULATIONAHA.118.036652
Bier, Ariel et al. “A High Salt Diet Modulates the Gut Microbiota and Short Chain Fatty Acids Production in a Salt-Sensitive Hypertension Rat Model.” Nutrients vol. 10,9 1154. 23 Aug. 2018, doi:10.3390/nu10091154
Chen, Zouquan et al. “Probiotics: functional food ingredients with the potential to reduce hypertension.” Frontiers in cellular and infection microbiology vol. 13 1220877. 3 Jul. 2023, doi:10.3389/fcimb.2023.1220877
Gatarek, Paulina, and Joanna Kaluzna-Czaplinska. “Trimethylamine N-oxide (TMAO) in human health.” EXCLI journal vol. 20 301-319. 11 Feb. 2021, doi:10.17179/excli2020-3239
Graboski, Amanda L, and Matthew R Redinbo. “Gut-Derived Protein-Bound Uremic Toxins.” Toxins vol. 12,9 590. 11 Sep. 2020, doi:10.3390/toxins12090590
Grylls, Alina et al. “Link between microbiota and hypertension: Focus on LPS/TLR4 pathway in endothelial dysfunction and vascular inflammation, and therapeutic implication of probiotics.” Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie vol. 137 (2021): 111334. doi:10.1016/j.biopha.2021.111334
Hahad, Omar et al. “The Cardiovascular Effects of Noise.” Deutsches Arzteblatt international vol. 116,14 (2019): 245-250. doi:10.3238/arztebl.2019.0245
Khalesi, Saman et al. “Effect of probiotics on blood pressure: a systematic review and meta-analysis of randomized, controlled trials.” Hypertension (Dallas, Tex. : 1979) vol. 64,4 (2014): 897-903. doi:10.1161/HYPERTENSIONAHA.114.03469
Li, Jing et al. “Gut microbiota dysbiosis contributes to the development of hypertension.” Microbiome vol. 5,1 14. 1 Feb. 2017, doi:10.1186/s40168-016-0222-x
Li, Jing et al. “The Role and Mechanism of Intestinal Flora in Blood Pressure Regulation and Hypertension Development.” Antioxidants & redox signaling vol. 34,10 (2021): 811-830. doi:10.1089/ars.2020.8104
Lin, Wen-Yang et al. “Probiotics and their Metabolites Reduce Oxidative Stress in Middle-Aged Mice.” Current microbiology vol. 79,4 104. 14 Feb. 2022, doi:10.1007/s00284-022-02783-y
Mahdavi-Roshan, Marjan et al. “The Effects of Probiotics on Inflammation, Endothelial Dysfunction, and Atherosclerosis Progression: A Mechanistic Overview.” Heart, lung & circulation vol. 31,5 (2022): e45-e71. doi:10.1016/j.hlc.2021.09.006
Malik, Mobin et al. “Lactobacillus plantarum 299v Supplementation Improves Vascular Endothelial Function and Reduces Inflammatory Biomarkers in Men With Stable Coronary Artery Disease.” Circulation research vol. 123,9 (2018): 1091-1102. doi:10.1161/CIRCRESAHA.118.313565
Martinez-Quinones, Patricia et al. “Hypertension Induced Morphological and Physiological Changes in Cells of the Arterial Wall.” American journal of hypertension vol. 31,10 (2018): 1067-1078. doi:10.1093/ajh/hpy083
Nguyen, Thi Thuy Uyen et al. “Effects of Probiotics, Prebiotics, and Synbiotics on Uremic Toxins, Inflammation, and Oxidative Stress in Hemodialysis Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.” Journal of clinical medicine vol. 10,19 4456. 28 Sep. 2021, doi:10.3390/jcm10194456
O'Donnell, Joanne A et al. “The gut microbiome and hypertension.” Nature reviews. Nephrology vol. 19,3 (2023): 153-167. doi:10.1038/s41581-022-00654-0
Ojangba, Theodora et al. “Comprehensive effects of lifestyle reform, adherence, and related factors on hypertension control: A review.” Journal of clinical hypertension (Greenwich, Conn.) vol. 25,6 (2023): 509-520. doi:10.1111/jch.14653
Opdebeeck, Britt et al. “Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate.” Toxins vol. 12,1 58. 19 Jan. 2020, doi:10.3390/toxins12010058
Pluznick, Jennifer L. “Microbial Short-Chain Fatty Acids and Blood Pressure Regulation.” Current hypertension reports vol. 19,4 (2017): 25. doi:10.1007/s11906-017-0722-5
Poll, Brian G et al. “Gut Microbial Metabolites and Blood Pressure Regulation: Focus on SCFAs and TMAO.” Physiology (Bethesda, Md.) vol. 35,4 (2020): 275-284. doi:10.1152/physiol.00004.2020
Rashid, Sherzad K et al. “Probiotics (VSL#3) prevent endothelial dysfunction in rats with portal hypertension: role of the angiotensin system.” PloS one vol. 9,5 e97458. 15 May. 2014, doi:10.1371/journal.pone.0097458
Robles-Vera, Iñaki et al. “Microbiota and Hypertension: Role of the Sympathetic Nervous System and the Immune System.” American journal of hypertension vol. 33,10 (2020): 890-901. doi:10.1093/ajh/hpaa103
Robles-Vera, Iñaki et al. “Probiotics Prevent Dysbiosis and the Rise in Blood Pressure in Genetic Hypertension: Role of Short-Chain Fatty Acids.” Molecular nutrition & food research vol. 64,6 (2020): e1900616. doi:10.1002/mnfr.201900616
Robles-Vera, Iñaki et al. “The Probiotic Lactobacillus fermentum Prevents Dysbiosis and Vascular Oxidative Stress in Rats with Hypertension Induced by Chronic Nitric Oxide Blockade.” Molecular nutrition & food research vol. 62,19 (2018): e1800298. doi:10.1002/mnfr.201800298
Senoner, Thomas, and Wolfgang Dichtl. “Oxidative Stress in Cardiovascular Diseases: Still a Therapeutic Target?.” Nutrients vol. 11,9 2090. 4 Sep. 2019, doi:10.3390/nu11092090
Soehnlein, Oliver, and Peter Libby. “Targeting inflammation in atherosclerosis - from experimental insights to the clinic.” Nature reviews. Drug discovery vol. 20,8 (2021): 589-610. doi:10.1038/s41573-021-00198-1
Stier, Charles T Jr. “Serotonin and dopamine in essential hypertension.” American journal of hypertension vol. 26,2 (2013): 151. doi:10.1093/ajh/hps085
Tokarek, Julita et al. “Does the Composition of Gut Microbiota Affect Hypertension? Molecular Mechanisms Involved in Increasing Blood Pressure.” International journal of molecular sciences vol. 24,2 1377. 10 Jan. 2023, doi:10.3390/ijms24021377
Toral, Marta et al. “The probiotic Lactobacillus coryniformis CECT5711 reduces the vascular pro-oxidant and pro-inflammatory status in obese mice.” Clinical science (London, England : 1979) vol. 127,1 (2014): 33-45. doi:10.1042/CS20130339
Verhaar, Barbara J H et al. “Gut Microbiota in Hypertension and Atherosclerosis: A Review.” Nutrients vol. 12,10 2982. 29 Sep. 2020, doi:10.3390/nu12102982
Wang, Han et al. “Trimethylamine N-oxide and its precursors in relation to blood pressure: A mendelian randomization study.” Frontiers in cardiovascular medicine vol. 9 922441. 22 Jul. 2022, doi:10.3389/fcvm.2022.922441
Yang, Tao et al. “Gut dysbiosis is linked to hypertension.” Hypertension (Dallas, Tex. : 1979) vol. 65,6 (2015): 1331-40. doi:10.1161/HYPERTENSIONAHA.115.05315
Yang, Zhihua et al. “Gut microbiota and hypertension: association, mechanisms and treatment.” Clinical and experimental hypertension (New York, N.Y. : 1993) vol. 45,1 (2023): 2195135. doi:10.1080/10641963.2023.2195135
Yuan, Lin et al. “Effects of probiotics on hypertension.” Applied microbiology and biotechnology vol. 107,4 (2023): 1107-1117. doi:10.1007/s00253-023-12369-8
Zarezadeh, Meysam et al. “Effects of probiotics supplementation on blood pressure: An umbrella meta-analysis of randomized controlled trials.” Nutrition, metabolism, and cardiovascular diseases : NMCD vol. 33,2 (2023): 275-286. doi:10.1016/j.numecd.2022.09.005
Zhou, Donghao et al. “Uncontrolled hypertension increases risk of all-cause and cardiovascular disease mortality in US adults: the NHANES III Linked Mortality Study.” Scientific reports vol. 8,1 9418. 20 Jun. 2018, doi:10.1038/s41598-018-27377-2
The International Probiotics Association (IPA) is a global non-profit organization bringing together, through its membership, the sector's stakeholders, including but not limited to academia, scientists, healthcare professionals, consumers, industry, and regulators. The IPA's mission is to promote the safe and efficacious use of pre-, pro-, and post-biotics worldwide. Holding NGO status before Codex Alimentarius, the IPA is also recognized as the unified "Global Voice of Pre-, Pro- and Post-biotics" around the world.
Clare Fleishman, MS RDN, bridges the gap between science and health across most platforms: major newspapers, magazines, books (Globesity), workshops, social media, and websites. In 2010, she launched www.ProbioticsNow.com to share the cascade of new discoveries in the microbiome. Always amazed at this "forgotten organ," Fleishman has also created white papers, blogs, videos, and social media for the International Probiotics Association. She recently published Fertility: Why Microbes, Weight & Nutrition Matter.
