Microbes have the capacity to manipulate behavior and mood through altering the neural signals in the vagus nerve as well as changing taste receptors, toxins that produce bad feelings, and chemicals that release good feelings. Dysbiosis of the gut microbiota (GM) has been linked to obesity, insulin resistance, cancer, hypertension and changes in mental health. Many researchers are producing research on this work; some of which have demonstrated the link between gut microbes and hypertension (HTN) in rats. New research supported by the National Natural Science Foundation of China has demonstrated associations between gut microbiota and hypertension in human.

The research conducted by Baylor College of Medicine tested the hypothesis that GM transplantations from a hypertensive rat to a healthy rat would give that animal HTN. In addition, GM transplantations from the healthy rat to a hypertensive rat would attenuate the HTN.Researchers studied two sets of rats, one group with high blood pressure and one with normalblood pressure (BP). They used samples of pooled cecal contents from wild type rats (WKY) and spontaneously hypertensive stroke prone rats (SHRSP). The recipient WKY and SHR rats were given antibiotics for about four week to reduce their natural microbiota.

After the course of antibiotics, the researchers transplanted hypertensive GM to normal BPrats and normal GM to the hypertensive group, resulting in four groups; WKY with WKY microbiota (WKY g-WKY), WKY with SHRSP microbiota (WKY g-SHRSP), SHR with SHRSP microbiota (SHR g-SHRSP), and SHR with WKY microbiota (SHR g-WKY). Sure enough, BPincreased in healthy rats when they were given GMfrom hypertensive animals. When the rats had reached 11.5 weeks of age Systolic BPincreased 26mmHg in WKY g-SHRSP compared to that in WKY g-WKY (182±8 versus 156±8 mmHg, p=0.02). It is worth noting that while the Systolic BP of WKY g-SHRSP is significantly greater than WKY g-WKY, it is still lower than SHR g-SHRSP. This suggests that numerous mechanisms, one of which appears to be gut dysbiosis, are influencing the hypertensive phenotype of SHR and SHRSP.

In addition to BP, the researchers also used 16S ribosomal RNA gene sequencing for identification of types of bacteria predominated in each animal. They observed a significant increase in the ratio of Firmicutes to Bacteroidetes (F:B ratio) in hypertensive animals WKY g-SHRSP, as compared to the normotensive WKY g-WKY (p=0.042, caused by an increase in the relative abundance of Firmicutes and a decrease of Bacteroidetes).

On the WKY background a number of taxa were found to be characteristic of either g-WKY or g-SHRSP.The genera Bacteroides and Bifidobacterium, which are generally considered beneficial taxa, were associated with the normotensive WKY microbiota.The genus Adlercreutzia, showed an increased abundance in the WKY microbiota. Adlercreutzia metabolizes epigallocate chin gallate (EGCG) to metabolites that inhibit angiotensin-I converting enzyme (ACE), increasing endothelial nitric oxide production, and decreasingBP. Additionally, the genus Desulfovibrio, which reduces sulfate to hydrogen sulfide (H2S), was present in both groups receiving the SHRSP microbiota and absent in groups receiving WKY microbiota. Notably, H2S inhibits epithelial oxidation of butyrate, the primary energy source for colonic epithelium, which has been shown to lead to impaired gut barrier function and inflammation. The researchers observed a strong positive correlation between BP and the lactate producing genus Lactobacillus. While a potential link between lactate and BPregulation is not fully understood, plasma lactate levels have been shown to be associated with an increase in BP. They also observed negative correlations between Systolic BPand the abundance of the SCFA (Short chain fatty acids) producing Clostrideaceae (butyrate producers), Holdemania, and Coprobacillus (acetate producers).Similar shifts in SCFA and lactate producing bacteria have been reported in the SHR, AngII infusion, and OSA-induced HTN models. Given the importance of SCFA production in maintaining gut barrier function and reducing gut wall inflammation, they measured SCFA concentrations in feces from WKY and SHR rats ravaged with WKY or SHRSP microbiota.

This study provides “further evidence for the continued study of the microbiota in the development of HTN in humans and supports a potential role for probiotics as treatment for HTN”.

The findings from the study onrats was used by Chinese researchers to conduct new research in humans. The research published in National Institute of Health, demonstrated that they carried out a strategy based on metagenomic and metabolomic analyses, coupled with GM transplantation. They sequenced the total bacteria DNA of stool samples from a cohort of 41 healthy controls, 56 subjects with pre-HTN, 99 individuals with primary HTN, and performed fecal GM transplantation from patients to germ-free mice. 

All the individuals in the present study are from a cohort study among employees of the Kailuan Group Corporation. All the subjects in the HTN group were newly diagnosed hypertensive patients prior to antihypertensive treatment. Patients suffering from cancer, heart failure, renal failure, smoking, stroke, peripheral artery disease, and chronic inflammatory disease were all excluded. Drugs including statins, aspirin, insulin, metformin, nifedipine, and metoprolol were not used on the patients, and other drug consumption was not compared because the sample size was quite small. Hence, it is not likely that the medication ingested directly influenced the gut metagenome and metabolites, as there was no significant difference in the drugs consumed by these subjects.

The results demonstrate that decreased diversity altered enterotype distribution and variation in bacteria populations were associated with both pre-HTN and HTN. The bacterial metabolic functions and GM-related metabolites in pre-hypertensive and hypertensive adults were closely linked to inflammatory state. Compared to the healthy controls, they found dramatically decreased microbial richness and diversity, Prevotella-dominated gut enterotype, distinct metagenomic composition with reduced bacteria associated with healthy status and overgrowth of bacteria such as Prevotella and Klebsiella, and disease-linked GM function in both pre-HTN and HTN populations.  Prevotella may play an essential role in HTN, probably by triggering the inflammatory response.

Unexpectedly, the GM characteristic in pre-HTN group was quite similar to that in HTN. The metabolism changes of host with pre-HTN or HTN were identified to be closely linked to GM dysbiosis. A disease classifier based on GM and metabolites was constructed to discriminate pre-hypertensive and hypertensive individuals from controls accurately. Furthermore, fecal transplantation from hypertensive human donors to germ-free mice observed elevated BP to be transferrable through GM, and the direct influence of GM on BPof the host was demonstrated.

The tail-cuff measurement indicated a tendency for higher BP in recipient mice inoculated with stool samples from hypertensive donors as compared to controls. Such results were not obtained by fecal microbiota transplantation in conventionally raised mice.Researchers said “we speculate that the immune inflammatory system might play a crucial role in the pathogenesis of HTN”. Further mechanism research to make clear whether gut bacterial metabolites show a contribution to the immune inflammatory system during the development of HTN is being performed.

In HTN studies, most work focused on patients with a clinical definition of HTN, who display a Systolic BP higher than 140 mmHg or DBP ≥90 mmHg. However, population studies suggest that there is an intermediate stage of BP between control and HTN defined as pre-HTN, which should not be ignored.

Surprisingly, the bacterial diversity, enterotype, composition, and metabolic functions, as well as classified characteristics in pre-HTN highly coincided with those in HTN. There was a little difference in the structure of GM between pre-HTN and HTN, indicating that pre-HTN is not simply a transition stage between normotensive and hypertensive status based upon BP levels, but rather a state in which gut dysbiosis has already occurred.

Moreover, they revealed indiscriminate metabolic profiling between pre-HTN and HTN, consistent with a previous report that the serum spectral profiles of the hosts were similar at a stage of Systolic BP ≥130 mmHg and at Systolic BP ≥150 mmHg. The close correlation of metabolic products and GM further strengthened and highlighted the importance of pre-HTN.

These studies support the updated conclusion by the Systolic BP Intervention Trial (SPRINT) research group, that controlling one’s Systolic BP to an optimal level lower than 120 mmHg rather than a pre-HTN level below 140 mmHg leads to significantly decreased occurrence of cardiovascular events and death.

Studies like these point towards a new strategy aimed at preventing the development of hypertension and reducing cardiovascular risks through restoring the homeostasis of gut microbiota by improving either diet andlifestyle, early intervening with drugs or probiotics.

 

COPYRIGHT: This article is property of We Speak Science, a non profit institution co-fonded by Dr. Detina Zalli (Harvard University) and Dr. Argita Zalli (Imperial College London). The article is written by MSc. Gjena Dura (Molecular biologist, University of Tirana).

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