Hypertension is a major global health issue affecting 1.13 billion people worldwide, according to the World Health Organization. It increases the risk of cardiovascular diseases, including heart disease and stroke, and represents a tremendous public health burden. Its high prevalence is also an issue in Korea, with the number of patients with hypertension exceeding 12 million in 2018 (Kim et al., 2021) and continuously increasing, owing to the rapid aging of the population and westernized lifestyles.

Hypertension is a complex multifactorial disease, with genetic, environmental, and demographic factors contributing to its prevalence. Recently, animal studies have indicated that the gut microbiota play an important role in the regulation of blood pressure (Yang et al., 2015; Adnan et al., 2017; Santisteban et al., 2017). Numerous clinical studies have attempted to elucidate the relationship between the gut microbiota and hypertension, as well as to identify microbial markers of hypertension (Li et al., 2017; Yan et al., 2017; Sun et al., 2019; Nagase et al., 2020; Verhaar et al., 2020; Maifeld et al., 2021; Nakai et al., 2021). Metabolites produced by the gut microbiota, such as short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and lipopolysaccharides (LPS), are suggested to directly affect endothelial, kidney, and heart tissues, amongst others (Al Khodor et al., 2017; Kang and Cai, 2018; Marques et al., 2018; Oyama and Node, 2019; Yang et al., 2020). However, even large-cohort studies have not identified consistent microbial markers and occasionally produce slightly conflicting results. Therefore, the relationship between hypertension and the gut microbiota still needs to be elucidated (Sun et al., 2019; Palmu et al., 2020; Verhaar et al., 2020).

The gut microbiome exhibits large individual differences and is affected by various factors. Among them, diet has a significant influence on the human gut microbiota. Variations in the gut microbiota exist regardless of age, sex, ethnicity, and geography, and are mainly determined by habitual diet. These recurrent patterns of microbial composition in the gut microbiome can be separated into several clusters termed the “enterotype.” These enterotypes are functionally and ecologically different. Therefore, it can be assumed that different enterotypes and their microbial architectures influence the development of hypertension in different ways and to varying degrees.

To elucidate these interactions and investigate the microbial markers associated with hypertension, in this study, we analyzed the association between the gut microbiota and hypertension across different enterotypes using 16S rRNA amplicon sequencing data.

In the overall comparison of gut microbial features between the normotension and hypertension groups, the latter was associated with low gut microbial diversity and some distinctive taxa, depleted SCFA-producing bacteria, such as Ruminococcacea and Faecalibacterium, and enriched LPS-producing gram-negative bacteria, such as Bacteroidales, Negativiticus, and Megamonas, although there were no significant differences in gut microbial composition. SCFAs are the products of indigestible dietary fiber fermentation by colonic microbes and may alter blood pressure (Marques et al., 2018; Yang et al., 2020). They can directly regulate blood pressure by binding to the SCFA receptor on vascular smooth muscle and endothelial cells. Several animal studies have demonstrated a relationship between hypotensive effects and increased SCFA levels due to high-fiber diet intake, as well as acetate and propionate supplementation (Pluznick et al., 2013; Marques et al., 2017). Bacterial LPS is a representative pathogen-associated molecular pattern that allows human cells to detect bacterial invasion and initiate innate immune response (Matsuura, 2013). Colonic-derived LPS can pass into the circulatory system, thereby increasing the plasma LPS level (termed metabolic endotoxemia) and promoting systemic inflammation involved in various metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (Mohammad and Thiemermann, 2020).

In this study, we attempted to analyze the association between gut microbiota and hypertension in terms of enterotype, beyond simply comparing the gut microbiota of normotensive and hypertensive groups, because the microbial architecture is functionally and ecologically different between enterotypes. Enterotypes have generally been defined by the dominance of either Bacteroides, Prevotella, or Ruminococcacea (Arumugam et al., 2011) and are strongly associated with long-term diets. Individuals consuming carbohydrate-rich diets, including dietary fiber and simple sugars, belong to the Prevotella enterotype, whereas those consuming protein-and animal fat-rich diets belong to the Bacteroides enterotype (Wu et al., 2011). Ruminococcaceae is associated with the long-term consumption of fruits and vegetables (Tomova et al., 2019). Considering Korean diets, the Ruminococcaceae enterotype has been linked to adults on a Korean-style balanced diet (Wu X. et al., 2021). Recently, the splitting of the Bacteroides group into two subgroups, Bacteroides 1 and Bacteroides 2, showed that the latter could be linked to lower gut microbial gene richness and clinical characteristics, including severe obesity and systemic inflammation (Aron-Wisnewsky et al., 2019; Vieira-Silva et al., 2020). Our analysis also produced four enterotype clusters, in line with previous reports on gut microbiome community variation (Ding and Schloss, 2014; Vandeputte et al., 2017; Vieira-Silva et al., 2019).

Considering the clinical characteristics among the four enterotypes, the Bac2 enterotype was associated with significantly higher levels of obesity or metabolic syndrome-defining variables, including BMI, waist circumference, triglyceride level, and blood pressure. In addition, the Bac2 enterotype was characterized by lower gut microbial diversity and decreased levels of Faecalibacterium, a potent butyrate-producing bacterium. These findings are consistent with those of most investigators, who suggested that the Bacteroides2 enterotype is a dysbiotic gut microbiome with pro-inflammatory properties and is associated with obesity and inflammation-related diseases. In contrast, the Rum enterotype in our study had the lowest values for these hypertension-related clinical characteristics, as well as the highest gut microbial diversity. The Ruminococcaceae enterotype has been considered abundant for the gut microbe producing anti-inflammatory compounds, causing a lower inflammatory response (Tomova et al., 2019; Alili et al., 2021; Brial et al., 2021; Wu X. et al., 2021; Geng et al., 2022).

Therefore, the gut microbial features identified as being related to blood pressure in the entire cohort, such as gut microbial diversity and relative abundance of SCFA- or LPS-producing bacteria, seemed to be the features associated with the Bac2 or Rum enterotypes rather than those directly related to blood pressure.

We tested the association between gut microbiota and blood pressure for each enterotype to clarify the presence of an enterotype-mediated gut microbial risk pattern determined by the local microenvironment. The results revealed that, with the exception of the Bac2 enterotype, there were no associations between hypertension status and gut microbiota in the Pre, Bac1, and Rum enterotypes. However, the clinical characteristics significantly associated with hypertension in the entire cohort showed significant differences among these three enterotypes. Therefore, the development of hypertension in these enterotypes could be attributed to typical clinical features related to hypertension, such as aging, sex, obesity, or lipid value, rather than the gut microbiota. Interestingly, HDL and TG levels only showed a significant association with hypertension in the Bac1 enterotype. Despite the lack of a precise understanding of the underlying mechanism, it is believed to be related to the animal food-based dietary habits of the Bacteroides enterotype.

Interestingly, only in the Bac2 enterotype, there were differences in the gut microbial features such as the microbial diversity and relative abundance of taxa including Faecalibacterium, Blautia, Anaerostipes, and Megamonas, as well as in the clinical characteristics related to hypertension between the two blood pressure groups. However, among those distinctive taxa, only Faecalibacterium, but not Blautia, Anaerostipes, or Megamonas, was significantly lower in the hypertension group of the Bac2 enterotype than those in the other enterotypes. Although the Bac2 enterotype inherently possesses dysbiotic traits, the observation that the Faecalibacterium proportion of the gut microbiome in the Bac2 enterotype hypertension group was significantly lower than that in the hypertension groups of the other enterotypes implies that hypertension in this particular enterotype is additionally linked to gut microbiome dysbiosis, as well as clinical manifestations.

In particular, butyrate can enter the bloodstream and exert a potent hypotensive effect by preventing vascular inflammation. It can also act on vagal afferent neurons and the central nervous system to affect blood pressure (Onyszkiewicz et al., 2019; Wu Y. et al., 2021). Consistent with previous results, Faecalibacterium which is considered the most potent butyrate-producing bacteria and the biomarker most closely associated with hypertension prevention also revealed to had the strongest association with decreased blood pressure in our study.

We discovered that the clinical phenotypes associated with obesity or metabolic syndrome, including hypertension, showed an unfavorable association with the Bac2 enterotype and a protective relationship with the Rum enterotype. Considering this result, the increasing number of people with hypertension in Korea (Kim et al., 2021) may be related to the increasing prevalence of the Bacteroides enterotype, as well as the loss of microbial diversity and SCFA-producing bacteria in the gut, due to the westernization of diet in the Korean population. Therefore, our findings are consistent with previous reports of lowered cardiometabolic risk profiles in participants consuming diets rich in fruits and vegetables (Borgi et al., 2016).

Furthermore, we found that among the four enterotypes the pro-inflammatory features of depleted SCFA-producing bacteria were associated with hypertension in the dysbiotic Bac2 enterotype, and that the effect of gut microbiota-mediated risk for hypertension might be modulated according to the local microbial environment. Many human intervention studies aimed at reducing blood pressure through the modulation of the gut microbiome using dietary fiber, prebiotics, or postbiotics are ongoing. However, considering our study’s results, it seems that the impact of these interventions may differ depending on the enterotype. Clinical trials with stratification of the target population according to enterotype, and those comparing the effectiveness of SCFAs in reducing blood pressure across different enterotypes, may provide a reference for creating treatment guidelines that screen and select the population in line with microbial modulation as the primary treatment, thus opening up the possibility of a tailored approach in the treatment of hypertension.

To our knowledge, this is the first study to evaluate the association between the gut microbiota and hypertension in a large Korean cohort. This study assessed the enterotype-based relationship between the gut microbiome and hypertension and showed that low-diversity Bacteroides2-enterotype-like composition is associated with hypertension, while the reverse is true for high-diversity Ruminococcus-enterotype-like composition. As well as, the depletion of SCFA-producing bacteria and increase in LPS-producing bacteria as dysbiosis associated with hypertension were significant only in the Bac2 enterotype. Further prospective studies with larger sample sizes or other ethnicities could provide more definitive and significant evidence for assessing the involvement of enterotypes in the association between the gut microbiome and hypertension.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://www.ebi.ac.uk/ena, PRJEB56540.

The studies involving human participants were reviewed and approved by Ethics Committee of Gangbuk Samsung Hospital. The patients/participants provided their written informed consent to participate in this study.

JS conceived of the presented idea, planned the experiments and wrote the manuscript. JK and SY developed the theory and performed the computations. M-JK contributed to sample preparation. C-SK supervised the project. All authors contributed to the article and approved the submitted version.