Pressure from the bugs within: Gut microbiota and human arterial hypertension

The human body houses a large number of diverse bacteria outnumbering other organisms such as archaea and fungi by orders of magnitude. The whole community of organisms is commonly referred to as human microbiota, while microbiome is defined as the collective genomes of these organisms. While earlier estimates suggested that the number of bacteria colonizing the human body may exceed the number of human cells 10-fold, more recent estimates suggest that the ratio between bacteria and human cells may be closer to one.¹ In any case, the microbial colonization is vast, and it may be no surprise that these microorganisms interact with and affect the human body. The study by Sun et al² in this issue illustrates the importance of this interaction for human arterial hypertension (Figure). The gut appears to be particularly important in that regard given its colonization with ≈ 100 trillion microbial cells comprising > 1,000 bacterial species, the large surface area, contact to food, and its involvement in local and systemic immune responses. The composition of the gut microbiota is highly variable between subjects because each subject harbors a unique set of microbial species.

Figure.

Schematic of data reported by Sun et al. on the association of gut bacteria (at the genus level) with human hypertension. to Figure. Schematic of data reported by Sun et al on the association of gut bacteria (at the genus level) with human hypertension. CARDIA indicates Coronary Artery Risk Development in Young Adults.

Animal research testing microbiota influences on blood pressure yielded exciting, new concepts regarding the pathogenesis of arterial hypertension. For example, gut microbiota-derived short-chain fatty acids appear to regulate blood pressure through differential actions on G-protein-coupled receptors. ^{3, 4} Mice with genetic deletion of the Toll-like receptor 5, which is expressed in the gut mucosa and serves as defense mechanism against infections, feature all components of the metabolic syndrome including an increase in blood pressure.⁵ Changes in dietary salt intake affect gut microbiome and metabolite compositions, which in turn regulates blood pressure through immune-mediated responses.^{6, 7} Antibiotics of different classes showed disparate, individualized effects on blood pressure of hypertensive rat models⁸ through hitherto unknown mechanisms. Gut microorganisms may also modulate the risk of hypertension-related organ damage. In hypertensive mice receiving cerebrospinal elastase injections, gut microbiota depletion through antibiotics markedly reduced the risk for intracranial aneurysm formation.⁹ In another study, supplementation with the short-chain fatty acid propionate, which is also produced from dietary fibers by bacteria in the gut, attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in mouse models.¹⁰ Thus, from a mechanistic point of view, current data, albeit limited, point to the microbiome influencing blood pressure through interactions with the immune system or through biologically active metabolites. However, translating these findings from highly controlled animal experiments to patients with arterial hypertension is by no means trivial.

The study by Sun et al² is the first largerscale study testing the hypothesis that gut microbial diversity and composition relates to blood pressure in human beings. The study comprised 529 middle-aged participants of the prospective CARDIA study (Coronary Artery Risk Development in Young Adults). to The authors conducted a cross-sectional fecal microbiotal substudy at the year-30 follow-up visit. The 16S ribosomal RNA sequencing approach was applied to determine microbial diversity and to identify specific genera in fecal samples. After grouping sequences into operational taxonomic units and measuring their relative abundances, the authors applied multivariate statistics to test their hypotheses. Microbiotal sequencing data were correlated to hypertension status and other sociodemographic and clinical characteristics. The main finding of the study was that arterial hypertension and microbial diversity were inversely correlated to each other. Furthermore, several bacteria genera such as Sporobacter sp. or Anaerovorax sp. were significantly associated with blood pressure and with hypertension status. However, when a statistical model that included adiposity determined by either body mass index or waist circumference was applied, none of the microbiota associated with hypertension or blood pressure.

Previous associations between hypertension and microbiota in humans are mined in small cohorts.¹¹ The study by Sun et al is notable for rigor as it is conducted in a large cohort. Although the clever use of incorporating a microbiome substudy of a longstanding study is appreciable, confirmation in an independent is required. Indeed, the large number of statistical tests applied coupled with the variability of microbiota does not reliably exclude false-positive findings. The complexities of identifying and translating microbial metabolite signatures as potential clinical biomarkers with regard to the composition and dynamics of gut microbiome remains to be addressed. Yet, such studies are based on correlations and are, therefore, not sufficient to prove causality.

Beyond mere associations in humans, more in-depth mechanistic studies assessing the complex interaction of gut microbiota, diet, exercise, genetic predisposition, and environment on blood pressure are warranted. Cutting-edge animal model systems including germ-free models should be a strong focus area of further research. In addition, there is a need for carefully conducted mechanism-oriented human investigations. For example, the finding that increased salt ingestion alters gut microbiotal composition in the context of hypertension deserves to be confirmed in humans.⁶

The ultimate goal of hypertension research is to develop diagnostic tools and new preventive and therapeutic measures. Perhaps, unhealthy gut microbiota could be identified early on to gauge cardiovascular and metabolic risk. Moreover, interventions altering microbial diversity could have a bearing on blood pressure. Unhealthy gut microbiota may be amenable to interventions such as probiotics or stool transplantations. Perhaps, metagenome engineering could be utilized to target specific bacterial genes involved in formation of bioactive metabolites that lower blood pressure. Introduction of such genetically engineered bacteria into patients with arterial hypertension could be a novel means to manage hypertension in the clinic. Finally, the gut is not the only site to be targeted as far as hypertension is concerned. Dietary nitrate can be converted by different microorganisms in the oral cavity to nitrite, which can increase NO bioavailability thereby lowering blood pressure. In a randomized controlled crossover clinical trial in 15 patients with treated arterial hypertension, antibacterial mouthwash use for 3 days reduced salivary nitrite, tended to decrease plasma nitrite, and slightly reduced systolic blood pressure.¹²

While we await further research, a turn back to look at the history of human health is poignant. In the 19^th Century, people ate good food and had healthy lifestyles but succumbed to pathogenic microbes causing fatal infectious diseases. Research and scientific advances of modern medicine dramatically decreased deaths from infectious diseases. Meanwhile, antibiotic-resistant microorganisms, increased number of immune-compromised patients, and lack of new antimicrobial medications pose new medical challenges. However, recent research highlights the fact that bacteria colonizing the human body also affect human physiology and the risk for common diseases including arterial hypertension. Thus, in the modern era, researchers are still waging a war on microbes. The notable difference is that the microbes are not exogenous pathogens but residents inside the human body as part of an ecosystem we now refer to as the holobiont. The true impact of correcting microbiotal dysbiosis in hypertensives should not be underestimated because, when combined with the practices of our ancestors to each a healthy diet and exercise, effective preventive or therapeutic strategies to curb microbiotal dysbiosis may lower the incidence of hypertension, which remains the single biggest risk factor for the top killer of our kind in the modern era, namely cardiovascular diseases.