Introduction
Hypertension is one of the most important and controllable risk factors for all-cause morbidity and mortality worldwide and is strongly associated with an increased risk of cardiovascular disease [
1]. Although reductions in blood pressure can significantly reduce the occurrence of a wide range of acute events, long-term blood pressure control is required to reduce the global burden of disease and mortality [
2]. Long-term substandard blood pressure control [
3] or unstable control [
4] can damage vital organs, such as the heart, brain, and kidneys, and it can lead to serious adverse events. The number of people with hypertension in China has reached 244.5 million [
5]. However, the treatment rate of hypertension is less than 30%, and the average rate of achieving the standard is only 5.7% [
6]. Therefore, the incidence of cardiovascular diseases caused by long-term substandard blood pressure control will remain high in China for many years.
It is well-known that hypertension is associated with genetics [
7]. However, the human genome includes not only the deoxyribonucleic acid (DNA) inherited from parents but also the various flora (formed by interactions with the external physical environment after birth) that stably and harmoniously live within the body, accounting for up to 90% or more genome. Together, inherited parental DNA and intestinal flora form the human genome [
8].
The abundance and number of intestinal flora vary according to human diseases, such as obesity, type-2 diabetes, non-alcoholic liver disease, malnutrition and hypertension [
9]. Studies have shown that dietary modification can reduce the prevalence of hypertension in the population [
10], and the absorption and metabolism of food are inevitably affected by intestinal flora and its metabolites. Current research confirms that the composition of intestinal flora and its metabolites, such as short-chain fatty acids, lipopolysaccharides and oxidized trimethylamine, influence the progression of cardiovascular disease [
11]. Compared with healthy subjects, patients with hypertension have lower intestinal flora diversity, fewer short-chain fatty acid-producing microflora and more Gram-negative bacteria (which are sources of lipopolysaccharides) [
12]. Furthermore, some animal studies have indicated that short-chain fatty acids directly regulate blood pressure, and lipopolysaccharides have significant pro-inflammatory effects [
13]. This suggests that intestinal flora plays an important role in blood pressure regulation.
Most clinical studies have focused on investigating the relationship between intestinal flora and its related metabolites on the occurrence [
14], development [
15], treatment [
16] and complications [
17] of hypertension, and animal studies have focused on elucidating the mechanisms by which intestinal flora intervene in blood pressure [
18,
19]; however, research on whether long-term blood pressure control in patients with hypertension is related to intestinal flora has not been reported.
Given the current situation of the long-term survival of patients being seriously affected by whether blood pressure standards are met or not, this study aimed to analyse the intestinal flora of patients with hypertension with and without standard blood pressure control; the aims were to explore the method of predicting late blood pressure control by the intestinal flora of patients with hypertension and to provide a basis for the achievement of blood pressure standards in patients with diagnosed hypertension.
Discussion
A comparative analysis of the differential indicators between the two groups of patients and a multivariate regression analysis were performed to statistically identify indicators that may affect blood pressure attainment. The results revealed that intestinal flora F/B (OR: 0.559, 95% CI 0.336–0.930), the genus Streptococcus (OR: 0.994, 95% CI 0.990–0.998) and the genus Paraprevotella (OR: 0.978, 95% CI 0.964–0.993) were negatively associated with blood pressure attainment, and ACE (OR: 1.273, 95% CI 1.042–1.556) and the genus Akkermansia (OR: 1.022, 95% CI 1.003–1.043) were positively associated with blood pressure attainment. The differences persisted after correction for age, sex and BMI. The ROC curves for the genus level of differential bacteria were plotted to assess the predictive value of gut flora on blood pressure attainment, and the results revealed that ACE (AUC = 85.282), Streptococcus (AUC = 82.705) and Akkermansia (AUC = 77.333) had fair predictive specificity and sensitivity.
The general clinical data of the two groups of patients did not differ significantly in terms of age, BMI, exercise and diet, which may have interfered with the study outcome, but there were differences in yoghurt intake. Some studies have shown that probiotic supplementation can reduce blood pressure in patients with hypertension [
24]. However, after a multifactorial analysis, the present study found no effect of yoghurt intake on blood pressure attainment, which may have been related to the small number of patients and the yoghurt intake classification. Patients differed in the comparison of phyla levels in terms of Actinobacteria, Verrucomicrobia, Bacteria (unclassified) and F/B indices. Only one F/B was finally included in the regression analysis, which is because during the analysis of this bacteriophage assay, under the detected phylum-level classification of Actinobacteria, other detected bacteria (e.g.,
Senegalimassilia,
Collinsella and
Adlercreutzia) were excluded from the genus-level comparison because of their low detection rates. Considering the actual clinical situation and to avoid the duplication of statistics, only the genus-level
Bifidobacterium was included in the regression analysis without the phylum-level Actinobacteria; only one genus-level bacteria,
Akkermansia, was analysed under the phylum level of Verrucomicrobia; this bacterium was different in the subsequent genus-level comparison, so a regression analysis was performed by genus level, and thus, it was not included. The phylum Bacteria (unclassified) was not included in the statistics, because it did not have any clinical application.
The F/B is an important indicator of intestinal flora balance: the larger the F/B value, the worse the flora balance and the more serious the flora disorder. Studies showed that the feeding of minocycline to pregnant and lactating rats resulted in an increased intestinal flora–F/B ratio and increased blood pressure in the offspring, accompanied by decreased levels of plasma acetate and butyric acid [
25]. In another study, the exogenous supplementation of butyric acid or acetic acid in spontaneously hypertensive rats prevented an increase in blood pressure and an increase in the F/B ratio [
26]. Furthermore, short-chain fatty acids are metabolites of intestinal flora, mainly butyric acid, acetic acid and propionic acid, with hypotensive, immunomodulatory and cardioprotective functions [
27,
28]. These studies suggest that F/B is closely related to blood pressure, indicating that the intestinal flora of patients in the blood pressure attainment group in this study may provide more short-chain fatty acids to enhance the antihypertensive effect.
For the comparison of flora diversity, α diversity reflected the diversity, homogeneity and abundance of the distribution of the intestinal flora in the two groups of patients, and as previous studies in humans [
29] and rats [
30] had confirmed it to be correlated with blood pressure, it was included in the statistics. However, the β-diversity analysis only aimed to identify a significant difference between the two groups of flora and did not clearly propose the index of difference; it was used to describe the general difference in flora and to guide the subsequent analysis of the specific differences in the flora of the two groups of patients. The NMDS analysis was not included in the regression analysis, because the stress value was too high and might not have reflected the true situations of the two groups.
During the initial comparison of genus levels, a large number of differential bacteria were found, but from a practical point of view, the bacteria that were not identified at the genus level and those that were too small in number (the mean value of the genus level OUT in the two groups was < 10) were excluded. The bacteria that accounted for more than one-third of the blanks in both groups were also excluded. Finally, the four genus-level bacteria with differences were counted for the regression analysis. Comparing the differences in genus levels,
Streptococcus and
Paraprevotella were higher in the gut, and
Akkermansia and
Bifidobacterium were lower in the uncontrolled group compared with the controlled group. An increase in
Paraprevotella and a decrease in
Akkermansia have been observed in hypertensive rats during the progression from compensated cardiac hypertrophy to heart failure [
31]. Chang et al. [
32] found a lower abundance of
Bifidobacterium in the intestinal flora of women with pre-eclampsia. Jin et al. [
33] discovered that
Akkermansia, propionic acid or butyric acid significantly reduced symptoms in rats with pre-eclampsia. Zhang et al. [
34] found higher pharyngeal
Streptococcus levels in patients with pulmonary hypertension compared with those of healthy subjects. Liu et al. [
35] reported fewer genera of short-chain fatty acid-producing bacteria and more genera of
Streptococcus associated with inflammation in the intestinal flora of patients with primary aldosteronism compared with the flora of a healthy group. It has also been reported that
Paraprevotella is involved in the pathogenesis of hypertension in salt-sensitive rats [
36]. The results of all these studies support those of the present research in one way or another.
The regression statistics of the indicators analysed for differences between the groups showed that intestinal flora F/B (OR: 0.559, 95% CI 0.336–0.930) and the genera levels of Streptococcus (OR: 0.994, 95% CI 0.990–0.998) and Paraprevotella (OR: 0.978, 95% CI 0.964–0.993) were negatively associated with blood pressure attainment, while ACE (OR: 1.273, 95% CI 1.042–1.556) and Akkermansia (OR: 1.022, 95% CI 1.003–1.043) were positively associated with blood pressure; this association persisted after correction for age, sex and BMI. The ROC curves for the predictive value of blood pressure compliance were plotted, with ACE (AUC = 85.282), Streptococcus (AUC = 82.705) and Akkermansia (AUC = 77.333) having the highest predictive values, providing some basis for later blood pressure compliance in patients attending clinics.
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