Abstract
Increasing evidences suggest that the gut microbiota have their contributions to the hypertension, but the metagenomic characteristics and potential regulating mechanisms in primary hypertension patients taking antihypertension drugs are not clear yet. We carried out a metagenomic analysis in 30 primary hypertension patients taking antihypertension medications and eight healthy adults without any medication. We found that bacterial strains from species, such as Bacteroides fragilis, Bacteroides vulgatus, Escherichia coli, Klebsiella pneumoniae, and Streptococcus vestibularis, were highly increased in patients; and these strains were reported to generate glycan, short-chain fatty acid (SCFA) and trimethylamine (TMA) or be opportunistic pathogens. Meanwhile, Dorea longicatena, Eubacterium hallii, Clostridium leptum, Faecalibacterium prausnitzii, and some other strains were greatly decreased in the patient group. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that ortholog groups and pathways related to glycan biosynthesis and multidrug resistance were significantly increased in the patient group, and some of the hub genes related to N-glycan biosynthesis were increased in the patient group, while those related to TMA precursor metabolism and amino acid metabolism both increased and decreased in the patient group. Metabolites tested by untargeted liquid chromatography–mass spectrometry (LC-MS) proved the decrease of acetic acid, choline, betaine, and several amino acids in patients’ fecal samples. Moreover, meta-analysis of recent studies found that almost all patients were taking at least one kind of drugs that were reported to regulate adenosine monophosphate-activated protein kinase (AMPK) pathway, so we further investigated if AMPK regulated the metagenomic changes by using angiotensin II-induced mouse hypertensive model on wild-type and macrophage-specific AMPK-knockout mice. We found that the changes in E. coli and Dorea and glycan biosynthesis-related orthologs and pathways were similar in our cohort and hypertensive wild-type mice but reversed after AMPK knockout. These results suggest that the gut microbiota-derived glycan, SCFA, TMA, and some other metabolites change in medication-taking primary hypertension patients and that medications might promote gut microbiota glycan biosynthesis through activating macrophage-AMPK.
Highlights
Hypertension is an increasing epidemic disease worldwide
K18457), as shown in Figure 2C, right side. These results suggested that the gut microbiota in the high blood pressure group (HBP) group adapted to the medication stimulation and had increased capabilities on generating short-chain fatty acid (SCFA) and LPS and metabolizing TMA precursors/glucose/fatty acids/amino acids, while the gut microbiota in control group (Ctrl) were more capable of metabolizing arginine and proline
For the third-level Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found six pathways significantly enriched in the HBP group, and four of them were around glycan biosynthesis and metabolism; the other two pathways were around lipid and steroid metabolism (Figure 2D, left side)
Summary
Hypertension is an increasing epidemic disease worldwide. In China, about 23% of the adult population had hypertension (Wang et al, 2018). Studies on animal models demonstrated that gut microbiota dysbiosis caused by antibiotics could upregulate BP (Pluznick et al, 2013), and angiotensin II (AngII) needed gut microbiota existence to induce hypertension (Karbach et al, 2016). Gut microbiota showed different enterotypes in healthy adults and hypertension patients (Li et al, 2017), and participants with lower BP had higher abundances of several SCFAproducing microbes (Verhaar et al, 2020), while circulating TMAO showed a dose–response relationship with increased odds of hypertension (Abbasalizad Farhangi and Vajdi, 2020). Gut microbiota and its metabolites participate in other hypertension-related cardiovascular diseases, such as coronary artery disease (Kazemian et al, 2020). Considering the complicated functions of gut microbiota, it is important to make comprehensive cognition of gut microbiota characteristics under hypertension, so as to better understand the pathological mechanisms of hypertension development and adopt better clinical interventions for treating hypertension and related cardiovascular diseases
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