Recent evidence indicates a link between gut pathology and microbiome with hypertension (HTN) in animal models. However, whether this association exists in humans is unknown. Thus, our objectives in the present study were to test the hypotheses that high blood pressure (BP) patients have distinct gut microbiomes and that gut–epithelial barrier function markers and microbiome composition could predict systolic BP (SBP). Fecal samples, analyzed by shotgun metagenomics, displayed taxonomic and functional changes, including altered butyrate production between patients with high BP and reference subjects. Significant increases in plasma of intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), and augmented gut-targetting proinflammatory T helper 17 (Th17) cells in high BP patients demonstrated increased intestinal inflammation and permeability. Zonulin, a gut epithelial tight junction protein regulator, was markedly elevated, further supporting gut barrier dysfunction in high BP. Zonulin strongly correlated with SBP (R2 = 0.5301, P<0.0001). Two models predicting SBP were built using stepwise linear regression analysis of microbiome data and circulating markers of gut health, and validated in a separate cohort by prediction of SBP from zonulin in plasma (R2 = 0.4608, P<0.0001). The mouse model of HTN, chronic angiotensin II (Ang II) infusion, was used to confirm the effects of butyrate and gut barrier function on the cardiovascular system and BP. These results support our conclusion that intestinal barrier dysfunction and microbiome function are linked to HTN in humans. They suggest that manipulation of gut microbiome and its barrier functions could be the new therapeutic and diagnostic avenues for HTN.

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Introduction Increased gut permeability (“leaky gut”) has been proposed as a potential contributor to age-related inflammation and gut dysbiosis. However, information on the relationship between a leaky gut and inflammation and physical frailty during aging are limited. Objective To investigate the hypothesis that an aging-associated leaky gut is linked to the age-related inflammation and frailty. Methods Two cohorts of healthy adults were studied: young (18–30-years-old, n=19) and older (≥70-years-old, n=18). Serum concentrations of the TNF-α and IL6, zonulin (a marker for leaky gut) and high-mobility group box protein (HMGB1, a nuclear protein triggering inflammation) were measured. Correlations of serum levels of zonulin and HMGB1 with strength of plantar flexor muscles and number of steps taken per day were analyzed. Results Serum concentration of zonulin and HMGB1 were 22% (p = 0.005) and 16% (p = 0.010) higher in the older vs young adults. Serum zonulin was positively associated with the concentrations of the TNF-α (r=0.357, p=0.032) and IL6 (r=0.345, p=0.043). Importantly, both zonulin and HMGB1 were negatively correlated with skeletal muscle strength (zonulin: r=−0.332, p=0.048; HMGB1: r=−0.383, p=0.023) and habitual physical activity (zonulin: r=−0.410, p=0.016; HMGB1: r=−0.483, p=0.004). Conclusions Serum zonulin was associated with both systemic inflammation and two key indices of physical frailty. These data suggest that a leaky gut may play a critical role in the development of age-related inflammation and frailty.

Clinical studies demonstrated a positive correlation between hypertension and cognitive decline. Beneficial effects of angiotensin II receptor blockers on cognitive functions have also been reported earlier; however, its role in chronic neuroinflammation-induced memory impairment in the hypertensive state is not well understood. Therefore, in the present study, we investigated the effect of angiotensin II receptor blockers on memory impairment induced by lipopolysaccharide (LPS) in spontaneously hypertensive rats (SHRs). Our data provides the strong evidence that intracerebroventricular (ICV) administration of LPS (25 μg) on the 1st, 4th, 7th, and 10th days leads to sustained neuroinflammation (as indicated by increased TNF-α, GFAP, COX-2, and NF-κB) and oxidative stress (increased reactive oxygen species (ROS) and nitrite levels) resulting in amyloid beta (Aβ) deposition, apoptosis (increased Bax and decreased Bcl-2 expression as well as increased caspase-3 activity and TUNEL-positive cells), and memory impairment. Further, we found that exaggerated inflammatory response and oxidative stress were associated with RAS over-activation (as evident from the increased ACE expression, angiotensin II (Ang II) level, and angiotensin type 1 receptor (AT1R) expression) and decreased BDNF and p-CREB expression. Oral administration of candesartan (an AT1R blocker) at a non-anti-hypertensive dose (0.1 mg/kg) for 15 days attenuated LPS-induced (ICV) apoptosis, amyloidogenesis, and memory impairment. Candesartan shows neuroprotection by inhibiting TLR4/Ang II-induced NF-κB inflammatory signaling and by enhancing associated BDNF/CREB expression in SHRs. Our study also demonstrated that when both AT1R and angiotensin type 2 receptor (AT2R) were blocked by candesartan and PD123319 concomitantly, the protective effects of candesartan were blunted suggesting that functionally active AT2R is required for beneficial effects of AT1R blockade.