Abstract 004: Plasma Zonulin, Along With a Unique Gut Microbiome Profile, Are Potential Predictors of Systolic Blood Pressure in Humans

Abstract

Objectives: We have previously shown that gut pathophysiology and dysbiosis are closely associated with hypertension (HTN) in animal models. However, whether this association also occurs in human HTN is unknown. To address this knowledge gap, we tested two hypotheses. 1. Hypertensive patients (HTN) have gut barrier dysfunction. 2. Prediction of blood pressure will be possible from circulating markers of gut health and gut microbiome composition. Design and Method: Plasma and fecal samples were collected from HTN (n=22, mean SBP 155.8±3.4mmHg) and reference subjects without HTN (REF) (n=18, mean SBP 121.1±1.5mmHg) (see ClinicalTrials.gov, NCT02188381 for protocol). Gut microbiomes were analyzed using shotgun metagenomic sequencing and Qiime. Plasma analytes were measured by ELISA. Results: Plasma intestinal fatty acid binding protein (REF;1.2 ± 0.1 ng/ml, HTN;1.9 ± 0.2 ng/ml, p=0.0097) and lipopolysaccharide (REF; 39.0 ± 9.5 pg/ml, HTN; 98.0 ± 26.2 pg/ml, p=0.0423) were increased in HTN, suggesting increased intestinal inflammation and permeability. Additionally, the soluble form of zonulin (regulator of gut tight junction proteins) was markedly elevated in the plasma of HTN (REF; 28.4 ± 2.0 ng/ml, HTN; 42.6 ± 2.7 ng/ml, P=0.0002) further supporting gut barrier dysfunction. Plasma zonulin was correlated with SBP (R 2 =0.5301, p<0.0001). Two models predicting SBP were built using stepwise linear regression analysis of microbiome shotgun metagenomics data and circulating markers of gut health. The first model used plasma zonulin as a single predictor, and the second zonulin plus butyrate producing bacteria (adjusted R 2 values of 0.506 and 0.554 respectively, p<0.001 for both). Our first model was validated by prediction of SBP in a separate validation cohort (n=36) from zonulin plasma levels (R 2 =0.4608, p<0.0001). Conclusions: Markers of increased gut permeability, particularly zonulin, and abundance of butyrate producing bacteria predicted SBP. These results support the hypothesis that gut barrier dysfunction and gut microbiome composition are directly linked with HTN in humans.