Hypertension-Mediated Gut Microbiota Changed Exacerbate Oxidative Phosphorylation and Fatty Acid Metabolism in the Colon

Background: Hypertension is one of the most common chronic diseases worldwide, with primary causes including genetic factors, age, and unhealthy lifestyles. Approximately 70-80% of hypertension cases are associated with unhealthy lifestyles. Among these factors, high-salt diet, as a trigger for hypertension, is becoming increasingly prevalent in modern dietary patterns. As a direct influencer of diet, gut microbiota affects the human body by adjusting the balance of beneficial and harmful bacteria, and by metabolizing dietary components such as fiber and cholesterol, producing a range of metabolites that are absorbed into the bloodstream and exert their effects. Previous studies have shown that dysbiosis of the gut microbiota exacerbates the progression of hypertension. However, research on the relationship between high-salt diet-induced hypertension and the gut microbiota is limited. This study aims to elucidate the causal relationship between high-salt diet-induced hypertension and the gut microbiota, investigating the role of gut microbiota in hypertension, exploring the mechanisms by which high-salt diet-induced hypertension affects the blood pressure through alterations in gut microbiota. Method: This study employed a high-salt diet-induced hypertension mouse model, with blood pressure measured using the tail-cuff method. Fecal samples were collected in sterile containers and stored at -80°C. The gut microbiota in the mouse fecal was analyzed using 16S rRNA sequencing. Sequencing data underwent quality control and denoising using Quantitative Insights Into Microbial Ecology 2 (QIIME2). Sequences were clustered into operational taxonomic units (OTUs). Linear discriminant analysis Effect Size (LEfSe) analysis was used to identify gut bacterial genera with significant differences between the hypertension (HTN) group and the control (Ctrl) group. A fecal microbiota transplantation experiment was conducted to validate the impact of the gut microbiota on mouse blood pressure. RNA-Seq was performed to explore the mechanisms by which high-salt diet-induced changes in gut microbiota regulate gene expression in the colon. Result: After the induction of high-salt diet, the systolic blood pressure (SBP) of the hypertensive mice significantly increased (SBP of Ctrl group=121.41±4.90mmHg, SBP of HTN group=133.09±8.91mmHg, p value＜0.001). In the HTN group, the gut microbiota exhibited a decreased Shannon index and an increased Simpson index, with principal coordinate analysis (PCoA) revealing significant separation. At the genus level, the HTN group showed a decrease in the abundance of Lachnospiraceae, Lactobacillus, and Oscillospiraceae , and an increase in the abundance of Alloprevotella, Clostridia_UCG-01, Prevotellaceae_NK3B31_group and Dubosiella. LEfSe analysis indicated an increased abundance of Butyrivibrio and Aerococcus, and a decreased abundance of Allobaculum and Oscillospiraceae in the HTN group. After the bedding exchange, Ctrl group that received bedding from HTN group exhibited increased SBP, whereas HTN group that received bedding from Ctrl group showed decreased SBP(SBP of Ctrl group that received bedding from HTN group=129.68±1.27mmHg, SBP of HTN group that received bedding from Ctrl group=127.38±3.56mmHg). RNA-Seq indicated that high-salt diet caused differential expression of 4,218 genes in colon, with 942 genes upregulated and 3,276 genes downregulated. The differentially expressed genes between the HTN and Ctrl groups were enriched in pathways such as ECM-receptor interaction, calcium signaling pathway, and focal adhesion. Gene Set Enrichment Analysis (GSEA) revealed that high-salt diet-mediated changes in gut microbiota exacerbate oxidative phosphorylation and promote fatty acid metabolism in the colon. Conclusion: In summary, high-salt diet-induced hypertension alters the gut microbiota in mice, and the gut microbiota is also a contributing factor to blood pressure regulation. High-salt diet-mediated changes in gut microbiota promote oxidative phosphorylation and fatty acid metabolism in colon.