Hypertension is an independent and preventable risk factor for the development of cardiovascular diseases, however, little is known about the impact of gut microbiota composition in its development. We carried out comprehensive gut microbiota analysis and targeted metabolomics in a cross-sectional study of 29 non-treated hypertensive (HT) and 32 normotensive (NT) subjects. We determined fecal microbiota composition by 16S rRNA gene sequencing and bacterial functions by metagenomic analysis. The microbial metabolites analysed were short chain fatty acids (SCFA) both in plasma and feces, and trimethylamine N-oxide (TMAO) in plasma. The overall bacterial composition and diversity of bacterial community in the two groups were not significantly different. However, Ruminococcaceae NK4A214, Ruminococcaceae_UCG-010, Christensenellaceae_R-7, Faecalibacterium prausnitzii and Roseburia hominis were found to be significantly enriched in NT group, whereas, Bacteroides coprocola, Bacteroides plebeius and genera of Lachnospiraceae were increased in HT patients. We found a positive correlation between the HT-associated species and systolic and diastolic blood pressure after adjusted for measured confounders. SCFA showed antagonistic results in plasma and feces, detecting in HT subjects significant higher levels in feces and lower levels in plasma, which could indicate a less efficient SCFA absorption. Overall, our results present a disease classifier based on microbiota and bacterial metabolites to discriminate HT individuals from NT controls in a first disease grade prior to drug treatment.Hypertension is one of the leading risk factors for the development of cardiovascular diseases (CVD) globally, and lifestyle measures are effective as a preventive strategies 1 . In 2015, hypertension based on office blood pressure (BP) reported the highest rates with a global prevalence of 1.13 billion cases, and 150 million in central and eastern Europe regardless of the income countries status 2-4 .The identification of the determinants of hypertension is still challenging although it is well recognized its multifactorial etiology 5 . It has been elucidated the interplay of genetic and environmental factors related with risk-conferring behaviors, such as, smoking, lack of physical activity, alcohol consumption and unhealthy diet 6,7 .Recently, it has been evidenced the role of gut microbiota dysbiosis on the modulation of high BP, both in animal and human hypertension 8 . Mell et al. (2015) were the first to demonstrate the differential fecal microbial composition of Dahl salt-sensitive and Dahl salt-resistant rats 9 . In the same period, Yang et al. (2015) also found a clear gut dysbiosis in spontaneously hypertensive rats (SHR) mediated by a decrease in microbial richness and open Scientific RepoRtS | (2020) 10:6436 | https://doi.org/10.1038/s41598-020-63475-w www.nature.com/scientificreports www.nature.com/scientificreports/ Scientific RepoRtS | (2020) 10:6436 | https://doi.org/10.1038/s41598-020-63475-w www.nature.com/scientificreports...

Purpose To assess the sustained and acute effects, as well as the influence of sustained consumption on the acute effects, of orange juice (OJ) with a natural hesperidin content and hesperidin-enriched OJ (EOJ) on blood (BP) and pulse (PP) pressures in pre- and stage-1 hypertensive individuals. Methods In a randomized, parallel, double-blind, placebo-controlled trial, participants (n = 159) received 500 mL/day of control drink, OJ, or EOJ for 12 weeks. Two dose–response studies were performed at baseline and after 12 weeks. Results A single EOJ dose (500 mL) reduced systolic BP (SBP) and PP, with greater changes after sustained treatment where a decrease in diastolic BP (DBP) also occurred (P < 0.05). SBP and PP decreased in a dose-dependent manner relative to the hesperidin content of the beverages throughout the 12 weeks (P < 0.05). OJ and EOJ decreased homocysteine levels at 12 weeks versus the control drink (P < 0.05). After 12 weeks of EOJ consumption, four genes related to hypertension (PTX3, NLRP3, NPSR1 and NAMPT) were differentially expressed in peripheral blood mononuclear cells (P < 0.05). Conclusion Hesperidin in OJ reduces SBP and PP after sustained consumption, and after a single dose, the chronic consumption of EOJ enhances its postprandial effect. Decreases in systemic and transcriptomic biomarkers were concomitant with BP and PP changes. EOJ could be a useful co-adjuvant tool for BP and PP management in pre- and stage-1 hypertensive individuals.