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Hypertension (HTN) is associated with gut dysbiosis and the depletion of butyrate-producing bacteria in animal models and people. Furthermore, fecal material transfer from donor hypertensive patients increases blood pressure in normotensive recipient animals and ameliorates HTN-associated pathophysiology. These observations have implications in the impaired interactions between the gut and gut microbiota in HTN. Although this concept is supported in animal models, little is known about human HTN. Therefore, our objective for this study was to compare gene expression with transcriptomics and its potential to influence microbiota in subjects with normal and high blood pressure (HBP). Colon samples from reference subjects with normal blood pressure (REF) and HBP were used for RNA-seq to analyze their transcriptomes. We observed the significant downregulation of gene sets governing immune responses (e.g., <i>SGK1</i> and <i>OASL</i>), gut epithelial function (e.g., <i>KRT20</i> and <i>SLC9A3R1</i>), gut microbiota (e.g., <i>PPARG</i> and <i>CIDEC</i>) and genes associated with cardiovascular and gut diseases (e.g., <i>PLAUR</i> and <i>NLN</i>) in HBP subjects; the expression of genes within these pathways correlated with blood pressure. Potential drug targets in the gut epithelium were identified using the Drug Gene International Database for possible use in HTN. They include peroxisome proliferator-activated receptor gamma (<i>PPRG),</i> active serum/glucocorticoid regulated kinase 1 <i>(SGK1)</i> and 3 beta-hydroxysteroid isomerase type II inhibitor <i>(HSD3B).</i> Finally, butyrate, a microbiota-derived short-chain fatty acid, restored the disrupted expression of certain functional genes in colonic organoids from HBP subjects. Patients with HBP exhibit a unique transcriptome that could underlie impaired gut–microbiota interactions. Targeting these interactions could provide a promising new therapeutic intervention for hypertension management.