Link between microbiota and hypertension: Focus on LPS/TLR4 pathway in endothelial dysfunction and vascular inflammation, and therapeutic implication of probiotics

1. Introduction

Hypertension is a widespread disorder affecting a heterogenous patient population. It is defined as sustained BP value of 140/90 mmHg or higher [1]. Aetiology is unknown in 95 % of cases (primary hypertension) whereas the cause is clearly identifiable in only 5 % of hypertensive patients (secondary hypertension) [2]. Globally, one-fifth of the adult population is hypertensive and the prevalence in those over 60 years old reaches 50 % [3]. It is estimated that 1.56 billion people will be hypertensive by 2025 [4]. Despite new treatments and lifestyle changes, a third of hypertensive patients has “treatment-resistant” hypertension, indicating that even with >3 prescribed medications normal BP is unattained [5]. Persistent hypertension is a key risk factor in cardiovascular disease, chronic kidney disease, cognitive dysfunction and dementia, remaining the biggest single contributor to the burden of mortality and disease globally [1]. In light of these statistics, understanding underlying pathophysiological mechanisms is of utmost importance. As a result, clinicians may be able to assess relevant points of failure in a given individual, thus enabling a more effective, robust and personalised intervention.

The mechanisms underlying hypertension are complex and include interactions between environmental, genetic, behavioural and endocrine factors [6]. A growing body of research has implicated microbiota in the pathophysiology of hypertension [7,8]. Indeed, gastrointestinal microbiota has been shown to regulate numerous physiological processes including immune system development and control, maintenance of intestinal barrier integrity and pathogen suppression [9,10]. A healthy microbiome is generally characterised by a high microbial diversity and richness [8,11]. However, exogenous and endogenous factors can alter the composition of this community at both taxonomical and functional levels leading to dysbiosis [12,13]. Notably, risk factors for hypertension such as age, high fat diet, sedentary lifestyle and obesity have also been shown to promote dysbiosis [14].

It has been demonstrated that microbial diversity and richness in spontaneously hypertensive rats (SHR) – a classical model of primary hypertension, is reduced compared to normotensive Wistar-Kyoto (WKY) rats [6]. Similarly, the microbiota composition in hypertensive patients differs greatly from normotensive samples, while it is similar in prehypertensive cohorts suggesting a causal relationship [5]. Supporting this hypothesis, faecal transplants from hypertensive patients to germfree mice resulted in a significant BP increase while dysbiosis-reducing minocycline treatment had the opposite effect [5,6,11].

Potential mechanisms contributing to hypertension development linked to dysbiosis involve: 1) metabolism-independent pathways: LPS and peptidoglycan translocation; and 2) metabolism-dependent pathways: mainly a decrease in short-chain fatty acids and secondary bile acids, as well as generation of trimethylamine-N-Oxidase. [14,15].

LPS, a component of gram-negative bacteria such as E. coli, is the most well-studied, prototypical class of pathogen associated molecular patterns [14]. In animal studies, LPS challenge has been commonly used to induce vascular dysfunction [14]. In human samples, endotoxemia levels characterised by increased presence of LPS in circulation, have been shown to increase with the burden of vascular disorders [3]. Furthermore, even subclinical endotoxemia has been correlated with cardiovascular disease and mortality [9].

Dysbiosis-induced impairment of intestinal barrier integrity and tight junction protein expression allows LPS to freely enter the bloodstream [3]. This has been evidenced in targeted sampling studies which found higher LPS levels in blood samples taken directly from hepatic veins as opposed to ventricle samples representing systemic circulation [16]. Furthermore, LPS can advance the dysregulation of intestinal barrier function creating a feed-forward cycle [16].

In epidemiological studies, intake of probiotic supplements and functional foods containing probiotics such as yogurt, has been associated with lower prevalence of hypertension [1]. The 2 most common bacterial genera used in probiotics, Lactobacilli and Bifidobacteria, naturally inhabit the healthy gastrointestinal tract and supplementation has been shown to exert beneficial effects on the host [15]. Animal studies to date have shown promising results whilst focusing on elucidating potential physiological actions involved [6,14]. It has been indicated that probiotics exert their effect on multiple points along the pathophysiological mechanisms linking LPS and hypertension.

This paper aims to examine the pathophysiological link between dysbiosis and hypertension with a specific interest in the direct effect of LPS translocation on endothelial dysfunction and vascular inflammation through NADPH/ROS/eNOS and MAPK/NF-κB pathways as identified by the systematic search of the literature. It further examines the potential of probiotics to exert positive effects on these mechanisms. Nutritional interventions targeting specific pathophysiological mechanisms may present an opportunity to support personalised nutrition practice [17]. Findings from this review could therefore further contribute to the understanding of the role of gut microbiota in hypertension and the role of probiotics to support personalised nutrition practice in the prevention and management of hypertension.