Introduction

High blood pressure (BP; hypertension) is a leading global health risk. In an international survey, the prevalence of persons who had systolic BP ≥140 mm Hg increased substantially from 1990 to 2015, and losses of disability-adjusted life-years and deaths associated with high BP also increased [1]. The drivers of these trends include urbanization in developing countries, increased dietary salt intake, low consumption of fruits and vegetables, overweight and obesity, low physical activity, and ecosystem disruption (e.g., pollution and natural disasters). Advanced technologies, including omics technology, data science, and mobile health, provide new insights into the mechanisms underlying high BP and could identify therapeutic targets for maintaining optimal BP and cardiovascular health over a lifetime. This review highlights three scientific focus areas that are emerging opportunities for future research in BP: (1) social and residential environmental determinants of high BP, (2) the role of internal and external microbiota in BP regulation, and (3) the effect of climate change on BP. Collectively, this review article emphasizes that the “ecosystem” is a key determinant of BP regulation in humans and discusses how the ecosystem concept can be integrated into healthcare systems and applied to improve human health.

What is an ecosystem?

An ecosystem is defined as the complex of a community of organisms and its environment functioning as an ecological unit [2]. Ecosystem disruptions can affect BP regulation in humans in a variety of ways and through complex pathways (Fig. 1).

Fig. 1
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The “ecosystem” is a key determinant of BP regulation in humans

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The impacts of social and residential environmental factors on BP

Social factors, including education, income, occupation, housing, neighborhood, and social support, are crucial determinants of hypertension, racial health disparities in hypertension, compliance with treatment, and BP control among patients taking antihypertensive medication [3, 4]. The limited successes in achieving and sustaining BP control in the clinical setting must be overcome by improving the social determinants of health through a holistic health management approach tailored to each individual. We and other investigators have reported that regional differences are present within communities with regard to the prevalence and awareness of hypertension and hypertension-related target organ damage [5,6,7]. These regional differences may be attributable to the differences in access to services within the ecosystem (e.g., healthcare and education systems, safe places to engage in physical activity, ways to obtain healthy food) and in family system dynamics (e.g., early childhood experiences and development, such as nurturing by family members) across regions. Therefore, in the clinical setting, social and residential environmental factors should be assessed for each individual, and multilevel and multicomponent strategies, along with patient-level interventions, are required to achieve and sustain BP control. For example, maintaining continuity in attending medical appointments and medication adherence is challenging if patients have poor access to health services. In such cases, appropriate services, such as secured transportation systems, patient–healthcare provider communication facilitation using eHealth (e.g., remote telemonitoring) [8, 9], and community health worker engagement [10], may be required to improve productivity, retention, and quality of care. These interventions must involve multidisciplinary team-based care from a team that includes primary care providers, nurses, pharmacists, social workers, policy-makers, and community organizations [10, 11]. In the United States, states that have allocated more resources to social services than to medical expenditures have had better health outcomes than states that did not take such actions [12]. Early childhood programs (i.e., cognitive and social stimulation that develops language, emotional regulation, and cognitive skills from birth through 5 years of age) have led to reductions in BP during young adulthood [13]. Further investigations are required to determine how to incorporate social determinant data into clinical decision-making to improve BP management, including individualized risk assessments, the physician’s performance in conducting an appropriately thorough and comprehensive assessment of the factors affecting the patient’s BP, and person- and population-focused interventions. The widespread availability of digital technologies, electronic health records, mobile health apps, and machine learning analytic techniques offer opportunities to elucidate and validate the novel social and residential environmental factors associated with high BP, which in turn may lead to the identification of novel therapeutic targets for hypertension.

Role of microorganisms in BP

Microorganisms living within an ecosystem create microbial communities and play key roles in ecosystem functioning. During their lifespan, humans share their bodies with a variety of microorganisms. More than 10–100 trillion symbiotic microorganisms live on and within human beings, and the majority of these microorganisms populate the distal ileum and colon (referred to as the gut microbiota) [14]. For each individual, the taxonomic and functional composition of the gut microbiome is stable over time in the absence of stress or intervention [15]. While this may be true under highly controlled conditions, it is not the case for most human beings; we all experience stress, and most of us have been prescribed antibiotics at some point that have affected our microbiome.

Gut dysbiosis—an imbalance in the composition and function of the intestinal microbiome—has been shown to be associated with hypertension [16,17,18]. Furthermore, microbiome-encoded enzymes directly affect the intestinal and systemic metabolism of antihypertensive drugs [19]. In addition to the microbiota inside of the living body, external microbiota (e.g., the soil microbiome) may also affect BP in humans. For example, microorganisms in the foods we eat and the quality of these foods can affect micronutrient levels in humans and modulate our gut microbiota [20].

Biodiversity is fundamental for productivity, functioning, and stability within ecosystems [21, 22]. Biodiversity can maintain the stability and resilience of a healthy microbial ecosystem, e.g., even if a single species is lost, other species may reconstitute the missing biological function [23]. Emerging evidence suggests that decreased richness and diversity in the gut microbiota are associated with an increased risk for hypertension in humans [16, 17]. Loss of biodiversity in the gut microbiota occurs through aging, circadian rhythm disruption, and lifestyle choices, including poor diet and low physical activity [24, 25]. A loss of biodiversity in the gut microbiota renders people vulnerable to the stresses that elevate BP, including salt intake, socioeconomic factors, poor social environments, and sympathovagal imbalance [26].

Improvements in sanitation and personal hygiene and the increasing use of agrochemicals have reduced biodiversity in external microbiotas (e.g., the soil microbiome) [27]. These changes may affect human health. For example, an environment with low microbiotic diversity may cause allergies and autoimmune diseases (hygiene hypothesis) [28]. A loss of diversity in the soil microbiome causes forest degradation, which potentially affects BP in humans because of reduced opportunities to spend time relaxing in nature (e.g., shinrin-yoku) [29, 30]. Therefore, restoring biodiversity in our internal and external microbiotas may facilitate BP management in humans. Healthy diets (e.g., whole grains and vegetables), exercise, and adequate sleep quality help to restore biodiversity in the gut microbiota [31,32,33,34]. Increasing green spaces and vegetation and improving habitats to support a wide variety of plant and animal species within an environment can restore external biodiversity [35].

The gut microbiota in healthy adults is dominated by Bacteroidetes and Firmicutes, followed by Actinobacteria, Proteobacteria, Archaea, Eucarya (predominantly yeasts), and multiple phages [36]. Microbial species and their relative proportions vary across individuals, and this variation has been shown to be correlated with hypertension. The Firmicutes to Bacteroidetes ratio, which is increased by a Western diet [37], is a signature of gut dysbiosis, and a higher ratio is associated with hypertension [38]. Specific bacterial genera, including Streptococcus, Bifidobacterium, and Clostridium, may regulate BP by producing small molecules and metabolites generated from interactions with the host and its diet [16, 39,40,41]. For example, short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are metabolites generated by the fermentation of food polysaccharides (e.g., vegetables and fruits). SCFAs absorbed across the epithelium into the circulation regulate renin secretion, vascular tone, and sympathetic nerve activity by binding to G-protein-coupled receptors in the kidney, vasculature, and brain [42, 43]. Reduced SCFA-producing gut bacteria and circulating SCFA levels are found in hypertensive rodents and human patients [43, 44]. Supplementation with SCFAs and with probiotics that increase the production of SCFAs has been shown to reduce BP in mice and humans [42, 44, 45]. Therefore, modulating the composition and function of the gut microbiota using probiotics, antibiotics, and fecal transplant may be a novel preventive and treatment strategy for hypertension. However, there are some concerns, including safety (e.g., infectious risk in fecal transplant recipients) and poor standardization for interventional approaches because of a lack of understanding regarding which specific species, strains, or metabolites reduce BP. Furthermore, microbiome associations are complex and partly dependent on host genetics, diet, and lifestyle. Microbiome engineering that increases or decreases specific bacteria as well as bacteriocins [46] and bacteriophages [47] may elucidate the individual contributions of microbiotic components to BP regulation and drug metabolism, which may inform the development of targeted therapies and personized treatments for hypertension.

The effect of climate change on BP

The global mean surface temperature has increased by 1 °C since preindustrial times due to increasing greenhouse gas emissions [48]. According to climate models, a further increase of 2–6 °C by the end of the 21st century is estimated if we continue to burn fossil fuels and accumulate greenhouse gases [49]. Greenhouse gas emissions add energy to the climate system, which can increase the prevalence of extreme weather and climate events (e.g., heat waves, floods, wildfires, and droughts) that disrupt ecosystems [50]. Increased mean surface temperatures reduce soil moisture and increase the respiration rate of the soil microbiome, stimulating carbon loss from soils and accelerating global warming [51]. Furthermore, increased temperatures alter plant phenology, weed and crop growth, and populations of insects and pests. These changes can adversely affect human health, contributing to malnutrition (i.e., obesity and undernutrition), heat-related morbidity, cardiovascular diseases, kidney diseases, water and foodborne illnesses, and mental health disorders [50, 52,53,54]. For example, in July 2019, 57 persons died due to heat-related medical issues during 1 week in Japan, and an additional 18,000 persons were hospitalized [55].

The human body maintains an average core body temperature of 37 °C to optimize its physiological function. In a warm environment, heat loss occurs via vasodilation and sweating in the skin. A recent study suggested that human body temperature has been reduced over the past century and a half [56]. However, little is known regarding how this change in chronic body temperature may alter physiological functions in humans. Heat exposure may affect pharmacokinetics in humans, and medications can affect the body’s response to heat. For example, diuretics cause dehydration, and some psychiatric medications reduce thirst. Diuretic and psychiatric medication use is associated with an increased risk for heat-related diseases, and the risk is particularly evident among older adults, persons with chronic diseases, persons who perform heavy physical labor, and underserved communities [57, 58]. Therefore, adjusting medication types and doses among high-risk populations during periods of hot weather may be required for BP management.

Climate change also threatens the achievement of effective universal healthcare. Extreme weather events due to climate can disrupt as shown in (Table 1).

Table 1 Healthcare systems potentially disrupted by the extremely weather events due to climate
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Consequently, people may have difficulty achieving and sustaining BP control [60]. To avoid these outcomes, we can act now to mitigate climate change by developing and utilizing clean energy sources, producing and consuming sustainably produced food, and recycling nonhazardous waste. Implementing these strategies may be difficult given political, economic, and social challenges. However, as individuals, we can make a difference in mitigating climate change by changing our diets (reducing meat consumption and increasing fruit and vegetable intake) and transportation patterns. The healthcare sector should develop strategies for adapting to climate change (Table 2).

Table 2 Strategies for adapting to climate changes
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Conclusion

Hypertension is a complex and heterogeneous pathophenotype. A reductionist approach that assumes that all patients who have the same signs of a disease share a common disease mechanism and thus should be treated similarly is insufficient for optimal BP management. Herein, we have highlighted the contribution of the ecosystem to BP regulation in humans. In future studies, advanced analytic approaches and big data analyses that include information about the social determinants of health, panomics (i.e., transcriptomics, epigenomics, proteomics, metabolomics, and microbiomics), and climate will provide opportunities to elucidate the hidden and novel mechanisms underlying high BP, providing new strategies for improving BP management and human health.