Probiotics as a Potential Therapeutic Strategy for Hypertension: Unraveling the Gut Microbiome and Serum Metabolome

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Hypertension, often referred to as high blood pressure, stands as one of the most pervasive chronic diseases worldwide, exerting a profound influence on human health and longevity (1).

The global prevalence of hypertension is staggering, with an estimated 31.1% of adults, equating to 1.39 billion individuals, afflicted by this condition in 2010 (2). This alarming prevalence is driven by various factors, and one of the most prominent culprits has been identified as increased sugar consumption, particularly the intake of dietary fructose syrup (3).

Recent research has highlighted the detrimental impact of high fructose consumption on blood pressure, uncovering a multitude of underlying mechanisms, including heightened salt retention, insulin resistance, reduced renal nitric oxide production, and a novel discovery—alterations in gut microbial composition (4 – 6).

The Link Between Fructose and Hypertension

Multiple studies have unveiled the connection between high fructose intake and an elevated risk of hypertension. High fructose consumption can affect blood pressure through several mechanisms, creating a complex interplay of physiological processes. One of the pivotal factors contributing to hypertension is increased salt retention, leading to an augmentation of blood volume and consequently higher blood pressure.

Moreover, fructose consumption is linked to the development of insulin resistance, a condition characterized by the body’s inability to efficiently utilize insulin, which plays a crucial role in regulating blood sugar levels. Insulin resistance is closely associated with elevated blood pressure.

Another key factor is the reduction in renal nitric oxide production, which has a vasodilatory effect and promotes the relaxation of blood vessels. A decrease in nitric oxide production can lead to vasoconstriction and consequently higher blood pressure. More recently, research has unveiled that high fructose intake can disrupt the composition of gut microbiota, specifically by decreasing levels of Bacteroides and elevating Firmicutes (7). Bacteroides bacteria are known to produce short-chain fatty acids (SCFAs) that play a significant role in blood pressure regulation through G protein-coupled sensory receptors (6, 8).

Probiotics and Their Role in Human Health

In light of the detrimental effects of high fructose consumption on blood pressure and gut microbiota composition, the scientific community has turned to probiotics as a potential therapeutic strategy for mitigating hypertension. Probiotics, defined as live microorganisms with beneficial effects on human health, have been extensively studied and found to mediate the diversity and abundance of gut microbiota while bolstering the immune system response (9).

A myriad of probiotic strains have exhibited positive effects under various clinical conditions, including acute gastroenteritis, irritable bowel syndrome, and more (10, 11, 12).

The Protective Effect of Probiotics on Hypertension

Notably, research has explored the protective effects of probiotics against hypertension. Hsu et al. discovered that Lactobacillus casei could shield against hypertension by reducing plasma acetate levels and decreasing renal Olfr78 expression (13).

Other studies have shown that probiotics can ameliorate endothelial dysfunction by releasing converting enzyme inhibitory peptides and impairing lipopolysaccharide signaling, ultimately leading to a reduction in blood pressure (14, 15). Furthermore, probiotics can alleviate high blood pressure by modifying the gut microbiota, inhibiting the colonization of pathogenic bacteria, and modulating the abundance of metabolites (16).

A New Era of Research: Gut Microbiome, Serum Metabolome, and Probiotics

Recent advances in research methods have allowed for a deeper understanding of the complex relationship between probiotics, the gut microbiome, and blood pressure regulation. Integrative analyses using fecal metagenomics and serum metabolomics have provided a bridge between gut microbial composition and host metabolic activity in response to probiotic interventions. This innovative approach enables researchers to uncover the mechanisms behind probiotics’ antihypertensive effects.

In this study, we utilize shotgun metagenomic sequencing and untargeted mass spectrometry (MS)-based serum metabolomics to investigate the impact of two specific probiotics, Bifidobacterium lactis M8 and Lactobacillus rhamnosus M9, on alterations in the gut microbiome and serum metabolome. Moreover, we aim to correlate these changes with blood pressure regulation, shedding light on the intricate relationships between the gut microbiome, serum metabolites, and hypertension.

Discoveries in Microbial Taxa and Functional Units

Through our rigorous analysis, we have identified several microbial taxa and functional units that are statistically associated with blood pressure. These findings bring us closer to understanding the precise mechanisms through which probiotics influence hypertension. Furthermore, we have revealed intricate interactions between specific microbial genera and metabolic functions, providing insight into the potential mechanism by which probiotics alleviate high blood pressure.

Discussion

In the course of this study, we embarked on a comprehensive investigation into the potential of probiotics as a therapeutic strategy for hypertension. Through intervention experiments with the probiotics Bifidobacterium lactis M8 and Lactobacillus rhamnosus M9 on a hypertensive mouse model induced by high fructose consumption, we have unveiled compelling evidence that these probiotics can significantly reduce blood pressure (BP).

Furthermore, our study delves deep into the relationship between these clinical outcomes and the substantial alterations in the gut microbiota induced by the probiotics. This discussion will explore the key findings, their implications, and potential mechanisms underlying the observed effects.

Microbial Taxa Alterations and Blood Pressure Regulation

Our investigation revealed significant alterations in the gut microbiota composition associated with BP regulation. Of particular interest is the role of specific bacterial taxa in this process. One notable discovery was the decrease in the abundance of Alistipes, which was correlated with reduced BP. This finding is consistent with prior research that has suggested a positive correlation between Alistipes and BP (23, 24).

Moreover, Alistipes has been associated with bile acid levels, which have implications for portal hypertension through farnesoid-X receptor activity (25, 26). This prompts speculation that Alistipes may influence host hypertension via bile acid metabolism. Additionally, a negative correlation was observed between Alistipes and steroid hormone biosynthesis, indicating the potential role of Alistipes in regulating steroid hormone production, which in turn is linked to hypertension (27).

Another key bacterium, Alloprevotella, displayed increased abundance in the high-fructose treatment group but decreased when treated with M8 and M9. This aligns with previous findings that suggest higher levels of short-chain fatty acids (SCFAs) in the feces of hypertensive individuals (28). Furthermore, Alloprevotella has been implicated in the pathogenesis of hypertension through the promotion of epithelial inflammatory responses (29). Thus, Alloprevotella’s influence on SCFA production and inflammation underscores its potential role in BP regulation.

Likewise, SCFA-reducing bacteria, such as Coprobacillus and Butyricimonas, were more abundant in the M9 group compared to the fructose group, suggesting their involvement in BP regulation. Prior research has indicated that Coprobacillus can influence health through various means, such as inhibiting fat absorption (30) and reducing immune system reactivity and inflammation (31).

These findings underscore that SCFA production is not the sole determinant of these bacteria’s functional relevance, suggesting that other metabolic capacities of the gut microbiota may also contribute to BP regulation. Therefore, despite the absence of SCFA detection in our metabolomics data, the changes in SCFA-producing bacteria abundances offer insights into potential mechanisms through which the gut microbiota can influence BP.

We also identified significant alterations in the fructose group as compared to the control group, such as the high abundance of Allobaculum in the control group, which tended to increase in the M9 group. This supports the notion that Allobaculum could have a protective effect against high BP, which is in agreement with previous findings that demonstrated a strong negative correlation between Allobaculum abundance and elevated BP (32, 33).

Additionally, Allobaculum’s role in mucin degradation and its inverse correlation with circulating leptin levels, a known influencer of BP, suggests that changes in leptin concentration may impact mucin production and the gut microbiota’s composition, influenced by Allobaculum’s activity (34).

Taxonomic Profiling at Species Level

To gain a more detailed understanding of the specific bacterial species affected by probiotic treatment, we employed Kraken2 to assign metagenomic reads at the species level. This approach revealed six species that were more abundant in the M8 group, including Bacteroides dorei, Bacteroides vulgatus, and Bifidobacterium animalis.

Additionally, 10 species, such as Alistipes shahii, Alistipes dispar, and Alistipes megaguti, were less abundant in the M8 group, consistent with the significantly reduced levels of Alistipes identified at the genus level. Notably, in the M9 group, four of the species differentially abundant in comparison to the fructose group were also differentially abundant when compared to the M8 group. These species include more abundant Paenibacillus larvae and less abundant Lactobacillus reuteri and Lactobacillus johnsonii. This finding highlights the potential role of these probiotic-modulated species in BP regulation.

Metabolic Pathway Alterations and BP Regulation

Our study extended beyond taxonomic profiling to examine the functional implications of probiotic treatment. We found that the reduced BP in the M8 and M9 groups was associated with decreased levels of several gut microbial pathways. Among these, the DNA repair system pathways, including base excision repair (BER) and nucleotide excision repair (NER), were affected. Dysbiosis in the microbiota has been linked to the accumulation of unrepaired DNA breaks and BER intermediates, contributing to hypertension development (37).

Metabolic pathways such as D-glutamine and D-glutamate metabolism, which are correlated with hypertension, were also affected. Additionally, glycosphingolipid biosynthesis, a pathway associated with improving insulin sensitivity, was impacted. The extensive alterations in microbial pathways triggered by probiotic treatment align with previous findings and underline the potential mechanisms by which these alterations influence BP.

Microbiota-Metabolite Associations and Mechanistic Insights

We sought to gain deeper insights by analyzing the associations between microbes and metabolites. Notably, the metabolic pathway for steroid hormone biosynthesis (ko00140) displayed the most robust connections in the microbe-metabolite associations between the M8 and fructose groups.

Steroid hormones have diverse effects on BP, with different classes of steroid hormones demonstrating distinct impacts. For instance, testosterone supplementation and reduced levels of 17 beta-estradiol have been shown to activate the renin-angiotensin-aldosterone system, leading to increased BP (40, 41). Furthermore, cortisone promotes water and sodium reabsorption in the kidneys, increasing BP after transformation into the active hydrocortisone (42).

Some Clostridium species have been reported to produce enzymes that modify steroidal hormones (43, 44). These findings suggest that bacterial modification of steroidal hormones may play a significant role in BP regulation, and species showing strong correlations with steroid hormone biosynthesis, such as Alistipes, Clostridium IV, and Tannerella, warrant further investigation for their influence on BP.

Vitamin digestion and absorption pathways emerged as another key association with BP regulation, particularly in the M9 treatment group. Microbiota-derived vitamins, synthesized via enzymatic pathways in vitamin synthesis, including biotin and cobalamin, are primarily absorbed in the colon.

Thus, the microbes exhibiting strong positive correlations with vitamin digestion and absorption, such as Ruminococcus, could influence colon function through vitamin synthesis pathways, subsequently impacting disease states. These findings emphasize the importance of investigating the production of different vitamins by Ruminococcus.

The associations of bacteria with metabolic pathways further elucidated potential mechanisms. For example, Ruminococcus species, regulated by M9, were positively correlated with vitamin digestion and absorption. Notably, Ruminococcus has been associated with vitamin D biosynthesis (49).

Vitamin D deficiency is considered a risk factor for hypertension (50). It has been demonstrated that the gut microbiota can serve as essential suppliers or synthesizers of vitamins, with Lactobacillus reuteri, for instance, shown to increase serum vitamin D levels (51). Vitamin D plays a role in suppressing renin-angiotensin-aldosterone activity, improving vascular wall function, and reducing vascular oxidative stress, all of which contribute to hypertension regulation (52).

Circulatory and Nervous System Pathways

Importantly, the study unveiled alterations in metabolic pathways related to the circulatory and nervous systems, which are directly associated with hypertension. For instance, vascular smooth muscle contraction, a fundamental process in hypertension, was observed to decrease with fructose intake and partially recover with probiotic treatment, indicating an improvement in vascular reactivity and tone (18).

The serotonergic synapse pathway is another notable finding, with arachidonic acid being known to relax blood vessels and reduce hypertension (53). Cholinergic synapse regulation by probiotics was observed, which is linked to enhanced sympathetic outflow and BP elevation by the rostral ventrolateral medulla (54).

Distinct Modulation Effects of M8 and M9

One intriguing aspect of our findings is the distinctive modulation effects observed for M8 and M9. For instance, M8 seemed to prevent chronic inflammation, as indicated by F4/80, by increasing the abundance of Bacteroides, which was negatively associated with lipopolysaccharide biosynthesis.

In contrast, M9 appeared to regulate tryptophan metabolism to prevent inflammation. This suggests that probiotics may act through different mechanisms, even within the same taxonomic groups, and that these effects are often strain-specific. Prior research has identified varying probiotic efficacies across different taxonomic groups, with strain specificity playing a significant role (55). This underscores the complex and multifaceted nature of probiotic modulation.

Limitations and Future Directions

It is important to acknowledge several limitations of this study. The small sample size may have limited our statistical power to detect smaller differences. To further validate the efficacy of probiotics, future studies should consider factors such as treatment duration, probiotic form, and dosage. Investigating the interaction and synergistic effects of the two probiotics could also provide insights into developing combinatorial therapies to enhance their effectiveness. Dietary probiotic supplements, in contrast to drug therapy, offer a less invasive approach to alleviating hypertension and have the potential to be a valuable alternative treatment.

In conclusion, our study has unveiled the profound potential of probiotics in mitigating hypertension through their modulation of the gut microbiota and metabolic pathways. The intricate associations between specific bacteria, metabolites, and metabolic pathways highlight the multifaceted mechanisms through which probiotics exert their effects. As we move forward, the insights gained from this study may pave the way for more targeted and personalized approaches in the prevention and auxiliary treatment of hypertension, offering hope for individuals affected by this prevalent chronic condition. Further investigations with larger sample sizes and clinical studies will be crucial for substantiating these findings and facilitating the translation of probiotics into effective therapies for hypertension.


reference link : https://journals.asm.org/doi/10.1128/msystems.00331-23

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