Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure

Abstract

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.

Probiotics Prevent Dysbiosis and the Rise in Blood Pressure in Genetic Hypertension: Role of Short‐Chain Fatty Acids

“…SCFAs have been demonstrated to exert many beneficial effects on intestinal epithelium, including inhibition of inflammation, and modulation of oxidative stress . Furthermore, an improved barrier function by SCFAs has been reported in vitro, ex vivo, and in animal studies . In agreement with these data, we also found that probiotics, and acetate and butyrate consumption increased mRNA levels of tight junction protein occludin and ZO‐1 in the colon.…”

The gut microbiota and its interactions with cardiovascular disease

“…Therefore, the ratio of the levels of faecal Firmicutes to Bacteroidetes (the F/B ratio) is a useful proxy for classifying the metabolic composition of the microbiome of an individual. Changes in bacteria composition associated with hypertension are followed by alterations in the levels of bacterial metabolic products (Kim, et al , ). This concept is corroborated by data from several studies in hypertensive models that demonstrated higher F/B ratio in affected hosts (Yang, et al , ; Marques, et al , ; Toral, et al , ).…”

“…Furthermore, targeted inhibition of this inflammatory pathway reduces the risk of incident adverse cardiovascular events (Ridker, et al , ). SCFAs, such as butyrate, have received increasing interest in relation to hypertension, and their main effects are modulation of the microbial composition and inflammation reduction (Wang, et al , ; Kim, et al , ). Propionate also exhibits hypotensive effects, possibly via expansion of the splenic Treg cell population (Bartolomaeus, et al , ).…”

Gut metagenomic and short chain fatty acids signature in hypertension: a cross-sectional study

“…Other recent studies may reinforce this hypothesis, reporting a strong relation between hypertension, gut mucosal permeability and altered inflammatory status in rats 11 and humans 41 with hypertension. Kim et al reported significant increases in plasma of intestinal fatty acid binding protein, lipopolysaccharide, and augmented gut-targeting proinflammatory T helper 17 cells in high BP patients, which demonstrated increased intestinal inflammation and permeability in HT subjects 41 . Together with these results, they also observed significant lower levels of plasma butyrate in HT subjects.…”