Balance the Gut Microbiome to Prevent Cardiovascular Disease

Balance the Gut Microbiome to Prevent Cardiovascular Disease

February is American Heart Month – an opportune time to discuss cardiovascular health and the prevention of cardiovascular disease with your patients. Did you know cardiovascular health begins in the gut microbiome?

The gut microbiome is a diverse community of microorganisms that reside in the GI tract and influence systemic health. Research shows the gut microbiome has impacts far beyond nutrient absorption and digestion, including the modulation of metabolic processes, immune responses, and neurological function.¹

Numerous studies suggest the gut microbiome could also play a significant role in heart health and the development of cardiovascular disease (CVD).² Understanding the intricate crosstalk and connection between the gut and the cardiovascular system holds promise for novel therapeutic strategies in the prevention and management of CVD. This connection is often referred to as the gut-heart axis. The gut-heart axis is a bidirectional communication between the gut and the heart through which immune signals and gut microbiota-derived metabolites can affect cardiovascular health.¹

The Gut-Heart Axis

CVD includes many conditions that impact the heart and blood vessels, such as stroke, coronary artery disease (CAD), heart failure, and other health concerns. There are also several known risk factors for CVD, including dyslipidemia, inflammation, and hypertension.² The richness of the gut microbiome and the levels of metabolites produced by the gut microbiome are associated with the development of hypertension, dyslipidemia, inflammation, atherosclerosis, heart failure, and other cardiovascular conditions.^3,4

Significant dysbiosis with lower microbial richness and diversity in the gut microbiome has been identified in hypertensive animal populations. Animal studies reveal that antibiotic therapy depletes the gut microbiota and elevates blood pressure (BP), suggesting the direct involvement of the gut microbiome in controlling blood pressure.² Research also shows that transferring gut microbiota from patients with hypertension to animals significantly increases BP in the animals.⁵ Furthermore, research shows mice models that lack microbiota experience the hastened formation of atherosclerotic plaques and the onset of heart disease. Dysbiosis also correlates with the magnitude of CVD risk and alters the development of CVD in animal studies.²

The Gut-Heart Axis – Evidence from Clinical Research

The underlying pathophysiology of gut microbiome-induced CVD is still being investigated in clinical trials but includes aberrations in oxidative stress, host energy metabolism, immunological control, and programmed cell death pathways. The composition of the gut microbiome and the production of metabolites by the microbiome, such as trimethylamine N-oxide (TMAO), phenylacetylglutamine, short-chain fatty acids (SCFAs), stearoyl ethanolamide (SEA), lipopolysaccharides (LPS), and secondary bile acids (BA), are also implicated in gut microbiome-induced cardiovascular disorders.^2,5

Recent clinical trials confirm that blood levels of the gut microbiome metabolites TMAO and phenylacetylglutamine are associated with the development of cardiovascular disease.² TMAO is a unique metabolite produced by the gut microbiome. Bacteria in the gut microbiome metabolize L-carnitine, choline, and betaine into trimethylamine (TMA). Hepatic enzymes then oxidize the TMA into TMAO. The amount of TMA and TMAO produced by the gut microbiome depends upon nutrient precursor availability and the abundance of the bacteria that metabolize the nutrients into TMA.⁶

Research shows that TMAO facilitates the progression of atherosclerosis by inducing endothelial dysfunction, impairing cholesterol metabolism, and contributing to platelet hyperactivity.² Bacteria that contribute to TMAO production include members of the Clostridiaceae family, E. coli, other members of the Enterobacteriaceae family, Acinetobacter baumannii, Thomasclavelia ramosa (previously known as Clostridium ramosum), and Emergencia timonensis.^6,7

Another potentially harmful substance released by the gut microbiome is lipopolysaccharide (LPS), also known as endotoxin. LPS has pro-inflammatory effects, and increased gut permeability (leaky gut) fosters its translocation from the gut into the systemic circulation. Clinical research shows that hypertensive patients have a higher abundance of gram-negative bacteria, which is the source of LPS.⁸

Clinical research also suggests a link between general atherosclerosis and bacterial populations in the mouth and gut. One case-control study discovered that patients with atherosclerotic cardiovascular disease had higher levels of certain gut bacterial populations than controls. Furthermore, research suggests that the presence of coronary artery disease and alterations in plasma metabolites in obese people is caused by the interaction of the immune system and the bioactive metabolites produced by the gut microbiome.²

Heart Failure and Gut Microbiome Dysbiosis

Emerging research on the factors contributing to the development and progression of heart failure (HF) is broadening the understanding that HF is influenced by complex interactions between cardiac function, systemic physiology, and environmental factors. The gut microbiome is a novel and intriguing factor in the pathophysiology of HF, according to Petruzziello et al.¹

HF patients have less beneficial, SCFA-producing bacteria compared to controls.¹ Research also shows individuals with HF have a greater abundance of pathogenic and opportunistic bacteria, including:

• Campylobacter
• Clostridium
• Escherichia
• Klebsiella
• Salmonella
• Shigella
• Yersinia¹

Inflammation is an underlying cause of HF progression, contributing to cardiac remodeling and dysfunction. One inflammatory effect of dysbiosis is the movement of inflammatory LPS from the gut into the systemic circulation. The gut microbiome’s role in immune system modulation may also lead to the production of proinflammatory cytokines, further exacerbating inflammation. Thus, dysbiosis-driven inflammation could fuel the systemic inflammatory state observed in patients with HF.¹

Dysbiosis also increases oxidative stress by producing reactive oxygen species (ROS) and modulating host antioxidant systems to disturb the delicate equilibrium systemically and within the cardiovascular system. This oxidative imbalance can further exacerbate cardiac remodeling, endothelial dysfunction, and the progression of cardiovascular disease. The gut microbiome also alters immune responses and metabolic pathways. Dysregulated immune responses and cytokine profiles due to an unhealthy gut microbiome contribute to adverse cardiac remodeling by promoting hypertrophy, fibrosis, and ventricular dysfunction.¹

Klebsiella, Hypertension (HTN) & Cardiovascular Disease

Hypertension (HTN) is the #1 leading preventable risk factor that contributes to all-cause mortality and cardiovascular disease. Estimates suggest HTN affects over 30% of the population worldwide, or approximately 1.39 billion individuals as of 2010.⁹

Researchers are beginning to investigate the effects of the gut-brain-microbiota axis in the etiology of hypertension, and data suggest gut microbial dysbiosis could be an underlying cause.² As noted above, several animal studies have linked specific gut microbial signatures to HTN. Research also shows that the transfer of intestinal flora from patients with hypertension to germ-free mice reliably increases the blood pressure in the mice. Furthermore, angiotensin II does not induce HTN in germ-free mice, suggesting the gut microbiome could play a direct role in increasing blood pressure.⁵

Altered gut microbiome composition and a significant decrease in microbial richness and diversity are also associated with the development of hypertension in humans. Research suggests a high-salt diet may induce hypertension via the intestinal flora. In other words, dysbiosis could be the underlying cause of the increased blood pressure, not the dietary sodium intake. Overall, a healthy gut microbiome appears essential for vascular contractility and the maintenance of optimal blood pressure.⁵

Researchers have also sought out specific organisms that might be associated with hypertension. One organism that continues to raise eyebrows is Klebsiella pneumoniae. Research shows enrichment of the gut microbiome with K. pneumoniae tends to be present in those with hypertension. Furthermore, bacteriophage KP32, which coexists with K. pneumoniae, is considered a biomarker for hypertension.⁵

An animal study conducted by Li et al. discovered the inoculation of mice with K. pneumoniae contributed to significant increases in systolic blood pressure, resistant arterial vasoconstriction, and mild cardiac hypertrophy. In general, an abundance of K. pneumoniae is associated with significant inflammation of the gut; therefore, pathological changes were also observed in the gastrointestinal tract during the study. Klebsiella pneumoniae induced a decrease in stearoyl ethanolamide (SEA), which is an anti-inflammatory metabolite produced by the gut microbiome. The production of tight junction proteins and the expression of the intestinal gene PON-1 were also suppressed in the animal study. PON-1 protects against the development of hypertension and plays a role in innate immunity. Investigation of the kidneys revealed the presence of K. pneumoniae, which contributed to shifts in the renal transcriptome. Altogether, the results of this pre-clinical research suggest that K. pneumoniae is a pathogenic bacterium that directly contributes to hypertension via several pathways.⁵

The gut, once viewed as a distant organ system designed for digestion and nutrient absorption, is now recognized as a significant source of inflammatory stimuli and other compounds that can harm the vascular endothelium and the heart.¹ The emerging understanding of the link between the gut microbiome and CVD offers clinical implications for novel management approaches. Targeting the gut microbiome and related metabolic pathways could result in new treatment options for some cardiovascular diseases.^1,2

Improve the Health of the Gut Microbiome & Prevent Cardiovascular System Disease with a Healthy Diet

Diet is a key, modifiable component that interacts with the gut microbiome and could impact the development of CVD.² The gut microbiome produces beneficial and toxic metabolites. Evidence suggests healthy dietary modifications could increase the production of the nourishing, beneficial metabolites while decreasing the levels of the harmful metabolites.⁶

Clinical research demonstrates a high-fiber diet is associated with reducing the risk of developing obesity, type 2 diabetes mellitus (T2DM), and CVD. The increased intake of dietary fiber promotes the production of short-chain fatty acids (SCFAs) by the gut microbiome.² SCFAs have several benefits, including regulating the immune system and the anti-inflammatory response, modulating lipid metabolism, and maintaining the integrity of the intestinal barrier.⁶ Research suggests the plasma level of SCFAs from the gut microbiome is more clinically relevant to CVD risk than the SCFA level in the stool.⁴

The Mediterranean diet has been shown to promote the growth of beneficial commensal bacteria that preserve gut barrier function and have anti-inflammatory effects. On the other hand, research shows a Western diet that is rich in saturated fats and added sugars is associated with gut dysbiosis and diminished microbial diversity, which increases vulnerability to developing CVD, obesity, and hypertension. The Western diet also contributes to the development of atherosclerosis via the deleterious impacts on the integrity of the gut lining. The overconsumption of red meat, common with a Western diet, can generate TMAO. Research shows that TMAO facilitates the progression of atherosclerosis by inducing endothelial dysfunction, impairing cholesterol metabolism, and contributing to platelet hyperactivity.²

Compared to a diet mostly composed of animal-derived foods, a diet rich in dietary fiber and plant foods could be highly beneficial for reducing the production of harmful compounds by the gut microbiome. Healthy dietary changes are an essential therapeutic strategy to reduce CVD, according to many researchers. Research suggests that a plant-based diet is directly associated with less production of LPS, inflammatory cytokines, uremic toxins, and other toxic metabolites, reduced growth of opportunistic bacteria, and increased levels of the beneficial gut microbiota that produce SCFAs.⁶

Support Healthy Gut Flora and Optimize Cardiovascular Health with Probiotics

Therapeutic strategies that modulate and optimize the composition of the gut microbiome, such as probiotic interventions, offer a promising avenue for improving cardiovascular health. Probiotics, also known as friendly, beneficial, or commensal organisms, have gained significant attention for their ability to confer health benefits.¹

Research shows dysbiosis is characterized by the loss of beneficial commensals and healthy diversity and the harmful proliferation of pathogens and opportunistic pathogens. Dysbiosis leads to the increased production of LPS and other toxins that promote inflammation and immune system dysregulation while increasing the risk of developing many diseases, including inflammatory bowel disease, CVD, CKD, autism, diabetes mellitus, and obesity.⁶

Clinical studies suggest probiotics display potential for mitigating cardiovascular disease risks by improving glycemic control, blood pressure levels, dysbiosis, and lipid profiles. Probiotic supplementation significantly improves glycemic control in patients with T2DM and obesity compared to dietary interventions alone. A recent meta-analysis demonstrated probiotic supplements significantly decrease the total cholesterol and low-density lipoprotein (LDL) cholesterol levels in hypercholesterolemic adults.²

Research also highlights the potential of probiotics as beneficial adjuncts to standard weight loss interventions since they yield reductions in BMI and weight. Moreover, supplementation with probiotics significantly reduces blood pressure in healthy, obese, diabetic, and even hypertensive patients by modulating the gut microbiome and balancing various factors that regulate the renin-angiotensin system.²

Probiotic supplements could prevent or directly treat CAD. Research shows that some beneficial strains enhance lipid profiles, reduce inflammation and oxidative stress, and mitigate the effects of metabolic endotoxemia in individuals with CAD.²

Probiotic supplementation has also been shown to significantly enhance the quality of life and exercise tolerance in patients with HF. The results of pre-clinical studies show probiotic supplementation reduces left ventricular hypertrophy, attenuates fibrosis, and enhances cardiac contractility in HF. Awoyemi et al. determined specific probiotic strains improve the composition of the gut microbiome and the left ventricular ejection fraction in patients with HF. Furthermore, Moludi et al. conducted a clinical trial that demonstrated probiotic supplementation fostered improvements in inflammatory markers and metabolic profiles. These pre-clinical and clinical findings underscore the potential therapeutic relevance of probiotic supplementation in heart failure management and the prevention of CVD.¹

The Best Probiotic Supplements for the Gut Microbiome & Heart Health

Research shows probiotics could promote the health of the gut-heart axis by:

• Competing with pathogens and opportunistic pathogens for resources and adhesion sites within the gastrointestinal tract to promote a healthier microbial balance.
• Strengthening the integrity of the tight junctions between intestinal cells to enhance the function of the gut barrier.
• Mitigating the translocation of microbial components into systemic circulation to reduce systemic inflammation and oxidative stress.
• Modulating immune responses to regulate the balance between proinflammatory and anti-inflammatory cytokine levels.
• Boosting the production of beneficial microbial metabolites, such as SCFAs, that maintain gut health and offer immunomodulatory benefits.¹

More research is necessary to explore the precise impact of probiotics on the production of TMAO, which indirectly promotes CVD.² More research is also required to determine the optimal probiotic strains, dosages, and treatment durations for the prevention and management of CVD.¹

Improve Heart & Gut Health with Prebiotics

Prebiotics, such as inulin and fructooligosaccharides, play a crucial role in promoting a healthy gut microbiome. Prebiotics stimulate the growth of beneficial bacteria and generate SCFAs. Research shows SCFAs regulate glycemic levels, manage body weight, and maintain intestinal integrity.²

Prebiotic supplementation has demonstrated potential for the amelioration of CVD through multiple mechanisms, including rectifying intestinal dysbiosis and endotoxemia, exerting anti-inflammation effects, improving lipid profiles in CAD patients, and enhancing antioxidant capacity. Furthermore, prebiotics reduce serum cholesterol levels and have anti-obesogenic benefits. Prebiotic interventions in patients with T2DM have also been found to significantly improve fasting blood glucose levels, contributing to the prevention of cardiovascular disease.²

Future Research on the Gut Microbiome-Heart Axis: GLP-1 & Beyond

In 2013, researchers discovered a connection between the production of the gut hormone glucagon-like peptide-1 (GLP-1) and the heart hormone atrial natriuretic peptide. This indicates that GLP-1 receptor agonists play a functional role in overall cardiovascular homeostasis and could be a significant area of future research.²

Unfortunately, investigating the gut-heart axis to discover novel and clinically effective treatment strategies can be difficult. The gut microbiome differs widely amongst individuals and populations due to many variables, including diet, genetics, lifestyle, and environmental exposures. Due to this considerable interindividual variability, identifying gut microbiome biomarkers related to cardiovascular health can be challenging.²

Moreover, shifts in the composition of the gut microbiome in response to environmental or dietary changes might vary significantly across populations to confound the determination of clear causality. Researchers also question the bidirectional relationship between the gut microbiome and cardiovascular health. Research shows the gut microbiome affects cardiovascular health, but do cardiovascular diseases and risk factors also have an impact on the composition of the gut microbiome?²

While it could be difficult to disentangle these intricate nuances and bidirectional relationships to determine the beneficial effects of putting gut microbiome-heart axis research into therapeutic use, optimizing the health of your patient’s gut microbiome today might promote robust health for decades.^1,2

Gut Microbiome Test for Optimal Health

To assess the health of the gut microbiome, measure levels of inflammatory markers, and test for pathogens and opportunistic pathogens, order our comprehensive Expanded GI Health Panel™ with GP3x and Calprotectin today.

• The Expanded Bacterial Stool Culture (GP3x) is a complete aerobic culture that reports all bacterial colonies isolated on the culture plates rather than the two or three most dominant species as reported on our standard (GP3) culture results.
• According to the American College of Gastroenterology clinical guidelines for the management of suspected IBS, a fecal Calprotectin test should be ordered as part of a comprehensive workup in all patients with gastrointestinal symptoms to rule out inflammatory bowel disease.

To place a test order, click here. As a reminder, DiagnosTechs will drop ship test kits directly to your patients. You may select this option at the top of the order form.

Please visit our Provider Tools page for more information about choosing the right test, test result interpretation, and treatment options.

References:

1. Petruzziello C, Saviano A, Manetti LL, et al. The Role of Gut Microbiota and the Potential Effects of Probiotics in Heart Failure. Medicina (Kaunas). 2024;60(2):271. doi:10.3390/medicina60020271
2. Shariff S, Kwan Su Huey A, Parag Soni N, et al. Unlocking the gut-heart axis: exploring the role of gut microbiota in cardiovascular health and disease. Ann Med Surg (Lond). 2024;86(5):2752-2758. doi:10.1097/MS9.0000000000001744
3. Coutinho-Wolino KS, de F Cardozo LFM, de Oliveira Leal V, et al. Can diet modulate trimethylamine N-oxide (TMAO) production? What do we know so far?. Eur J Nutr. 2021;60(7):3567-3584. doi:10.1007/s00394-021-02491-6
4. Kurilshikov A, van den Munckhof ICL, Chen L, et al. Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk. Circ Res. 2019;124(12):1808-1820. doi:10.1161/CIRCRESAHA.118.314642
5. Li J, Gao Q, Ma Y, et al. Causality of Opportunistic Pathogen Klebsiella pneumoniae to Hypertension Development. Hypertension. 2022;79(12):2743-2754. doi:10.1161/HYPERTENSIONAHA.122.18878
6. Alvarenga L, Kemp JA, Baptista BG, et al. Production of Toxins by the Gut Microbiota: The Role of Dietary Protein. Curr Nutr Rep. 2024;13(2):340-350. doi:10.1007/s13668-024-00535-x
7. Mbaye B, Wasfy RM, Alou MT, et al. Limosilactobacillus fermentum, Lactococcus lactis and Thomasclavelia ramosa are enriched and Methanobrevibacter smithii is depleted in patients with non-alcoholic steatohepatitis. Microb Pathog. 2023;180:106160. doi:10.1016/j.micpath.2023.106160
8. Verhaar BJH, Prodan A, Nieuwdorp M, Muller M. Gut Microbiota in Hypertension and Atherosclerosis: A Review. Nutrients. 2020;12(10):2982. doi:10.3390/nu12102982
9. Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol. 2020;16(4):223-237. doi:10.1038/s41581-019-0244-2