High-Density Lipoprotein Cholesterol as a Potential Medium between Depletion of Lachnospiraceae Genera and Hypertension under a High-Calorie Diet

Abstract

Gut microbial dysbiosis has been associated with hypertension. An extremely high incidence of essential hypertension was found in the Han and the Yugur people who resided in Sunan County in China's nomadic steppes, with little population movement. To investigate gut microbial contributions to this high incidence of hypertension, we recruited a total of 1, 242 Yugur and Han people, who had resided in Sunan County for more than 15 years and accounted for 3% of the local population. The epidemiological survey of 1,089 individuals indicated their nearly 1.8-times-higher prevalence of hypertension (38.2 to 43.3%) than the average in China (23.2%), under a special high-calorie diet based on wheat, cattle, mutton, and animal offal. Investigations of the fecal microbiota of another cohort of 153 individuals revealed that certain Lachnospiraceae genera were positively correlated with high-density lipoprotein cholesterol (HDL-C) but negatively correlated with systolic blood pressure (SBP) and diastolic blood pressure (DBP). HDL-C was negatively correlated with SBP and DBP. We further observed that the serum butyrate content was lower in both Han and Yugur people with hypertension than in those without hypertension. This study gives novel insight into the role of gut microbial dysbiosis in hypertension modulation under a high-calorie diet, where the notable depletion of Lachnospiraceae genera might lead to less production of butyrate, contributing to the lower level of HDL-C and elevating blood pressure in hypertension. IMPORTANCE Dietary nutrients can be converted by the gut microbiota into metabolites such as short-chain fatty acids, which may serve as disease-preventing agents in hypertension. Due to the limited population mobility and unique high-calorie dietary habits, the cohort of this study can serve as a representative cohort for elucidating the associations between the gut microbiota and hypertension under a high-calorie diet. Moreover, low levels of HDL-C have previously been associated with an increased risk of various cardiovascular diseases (CVDs). Our findings provide new insight showing that low levels of HDL-C may be a potential medium between the depletion of Lachnospiraceae genera and hypertension under a high-calorie diet, which might also be a potential candidate for other CVDs.

Keywords: Lachnospiraceae; butyrate; ethnic group; gut microbiota; high-calorie diet; high-density lipoprotein cholesterol; hypertension; systolic blood pressure.

FIG 1

The recruited cohort and potential link between the gut microbiota and hypertension. (A) Members of the recruited cohort resided in Sunan County, Gansu Province, China. The local populational proportions are shown in the pie chart. (B) Yugur people (n = 450) and Han people (n = 639) who had been living in Sunan County for more than 15 years were investigated for the epidemic survey of hypertension prevalence and dietary customs in this study. (C) The potential ethnicity-specific mechanism proposed in this study, that the gut microbiota might promote hypertension pathogenesis by reducing intestinal butyrate and lowering HDL-C levels.

FIG 2

Differences in microbiota compositions between Han and Yugur individuals with and without hypertension. (A and B) Individual gut microbiota compositions of 81 hypertension patients and 72 nonhypertension individuals plotted on an unweighted UniFrac PCoA plot (A) and a weighted UniFrac PCoA plot (B), with the box plots below each one showing sample distributions. (C) Box plot showing the microbiota Shannon diversity of 17 Yugur without hypertension, 55 Han without hypertension, 23 Yugur with hypertension, and 58 Han with hypertension. (D, left) Box plots showing the relative abundances of 31 specific genera that had significantly different distributions between the hypertension and nonhypertension groups (P < 0.05; q < 0.05 [by a Mann-Whitney-Wilcoxon test]). Hierarchical Ward linkage clustering was based on the Euclidean distance of the abundances of these genera among all the 153 samples. (Right) Heat map showing the scaled mean abundances of these genera in four subgroups as described above for panel C. Significance between subgroups is annotated in the heat map. The classified genera are annotated with the family and genus names, and the unclassified genera are designated with a higher rank with an asterisk. In all of the panels, statistical significance was tested using the Mann-Whitney-Wilcoxon test (*, P < 0.05; **, P < 0.01; n.s., not significant). The boxes represent the 25th to 75th percentiles, the black lines indicate the medians, and the whiskers extend to the maximum and minimum values within 1.5 times the interquartile range.

FIG 3

Microbial biomarkers for discriminating hypertension from nonhypertension. (A and B) The random-forest algorithm with 10 randomized 10-fold cross-validations was performed on 31 hypertension-related genera identified in Fig. 2, using all samples (n = 153), Han samples (n = 113), and Yugur samples (n = 40), to calculate the area under the receiver operating characteristic curve (AUROC) (A) and the Gini importance of each genus feature (B). The top five features are displayed and colored to show the group in which they are more significantly abundant (P < 0.05; q < 0.05 [by a Mann-Whitney-Wilcoxon test]). (C–E) Box plots of the abundances of the most discriminant genus features and their family among hypertension and nonhypertension groups of Han and Yugur. Statistical significance was calculated by a Mann-Whitney-Wilcoxon test. The boxes represent the interquartile ranges between the first and third quartiles, and the lines inside represent the medians. Whiskers denote the lowest and highest values within 1.5 times the interquartile range from the first and third quartiles, respectively.

FIG 4

Correlations of Lachnospiraceae members with high-density lipoprotein cholesterol. (A to C) Scatterplots of the concentration of log₁₀-transformed relative abundances of gut microbes (x axis) and high-density lipoprotein cholesterol (HDL-C) (y axis). The blue line is plotted using linear regression, with the 95% pointwise confidence interval band shaded gray. The correlation and statistical significance were calculated using Spearman correlation analysis. (D) Box plots showing the differences in concentrations of HDL-C between the hypertension group and the nonhypertension group. Statistical significance was calculated by a Mann-Whitney-Wilcoxon test (***, P < 0.001). The boxes represent the interquartile ranges between the first and third quartiles, and the lines inside represent the medians. Whiskers denote the lowest and highest values within 1.5 times the interquartile range from the first and third quartiles, respectively.