Year: 2019
Type: editorial
Abstract: In the current issue of Acta Physiologica, Duarte and colleagues present the intriguing results of their studies aimed to investigate whether changes in the gut microbiota alter the gut-immune system interactions inducing changes in vascular function and blood pressure (BP).1 These findings extend our understanding of the mechanisms linking alterations of the gut microbiota to hypertension. Hypertension is a major risk factor for cardiovascular disease and stroke. The majority of hypertensive patients suffer from essential hypertension, for which the causes are still not fully understood. As such, therapeutic approaches for essential hypertension primarily focus on lowering BP rather than correcting the causes. Essential hypertension is a complex disease that can involve dysfunction in multiple body systems including the kidneys, vasculature, and central nervous system. Exciting findings in the last decade have demonstrated the GI tract, and more specifically the microorganisms residing within, can also play an important role in BP regulation.2-7 As individuals, we serve as hosts to trillions of microorganisms, collectively termed the microbiota, including bacteria, fungi, protists, and viruses. Bacteria make up a major component of the microbiota, and the largest population of these bacteria reside in the gut. While these bacteria have historically been ascribed to aiding in digestion, it is now recognized that their roles are much more far-reaching and these bacteria influence multiple aspects of host physiology. To name only a few, the gut microbiota has been shown to influence host metabolism, immune system maturation and activation, and behavior. Considering the breadth of influence the gut microbiota has on host physiology, it is not surprising that disruption of the gut microbiota community structure has been observed in numerous disease states. Disruption to this community, termed gut dysbiosis, has been identified in several metabolic, cardiovascular, and neurological diseases. However, it has proven difficult to discern when gut dysbiosis is a consequence or causal in a disease state. In the case of hypertension, gut dysbiosis has now been observed in multiple patient populations and various animal models.2-7 While the makeup of the microbiota community varies greatly between models and study location, for the most part, the microbiota associated with hypertension is characterized by increased Firmicutes:Bacteroidetes ratio, reduced diversity and richness, and reduced short chain fatty acid producers, as compared to normotensive controls.2, 4, 5, 7 To examine a potential cause and effect relationship between gut dysbiosis and hypertension, our lab and others have transplanted the microbiota from various rodent models of hypertension into normotensive recipients and examined the effect on BP.2, 3, 7 In the first study of this kind, we observed that transplanting the gut microbiota from hypertensive obstructive sleep apnea rats into normotensive rats induced a significant elevation in BP, comparable to that observed in the hypertensive donors.2 Similar results have now been observed when transplanting normotensive recipients with the gut microbiota from the spontaneously hypertensive rat (SHR).3, 7 Furthermore, when the gut microbiota from hypertensive patients was transplanted into germ-free mice (ie, lacking any microbiota), there was a significant elevation in BP as compared to germ-free mice that received the microbiota from a normotensive patient.6 Interestingly, this study also compared the gut microbiota of pre-hypertensive and hypertensive patients. While the gut microbiota of normotensives and hypertensives was statistically distinct from one another, there was no distinguishable difference between pre- and hypertensive patients.6 Collectively, these studies indicate that gut dysbiosis precedes and contributes to the development of hypertension in various animal models and patients. Research in the field has now turned to understanding the mechanisms through which gut dysbiosis may induce hypertension. Several hypotheses have been put forth. First, the gut microbiota generates, or is responsible for signaling the release of, a plethora of bioactive compounds that can pass the epithelial-blood barrier and have systemic effects on the host. These include short-chain fatty acids, catecholamines, and neurotransmitters that may affect various sites involved in BP regulation. Second, the gut epithelial barrier serves as a site of constant interaction between microbes and the immune system. Dysbiosis is often associated with breakdown of the epithelial barrier and inflammation, which is tightly linked to hypertension. Third, bidirectional communications exist between the microbiota and host via the nervous system. Therefore, it may be possible for gut dysbiosis to be sensed by the host via nerve endings in the gut. In a model of hypertension, neural pathways from gut to brain regions involved in BP regulation were shown to be altered. With the growing evidence that gut dysbiosis contributes to hypertension, further understanding of the mechanisms involved are greatly needed. Studies by Toral et al examined the hypothesis that dysbiosis in SHRs elicits an inflammatory response resulting in vascular dysfunction and hypertension.1 The authors confirm previous observations that the gut microbiota of SHRs is distinct from WKY and exhibits increased Firmicutes:Bacteroidetes ratio, decreased acetate-producing bacteria, and increased lactate producers.1 To demonstrate the causal role of the gut microbiota in hypertension, fecal microbiota transfers were performed with WKYs receiving WKY (W-W) or SHR (W-S) microbiota, and SHRs receiving SHR (S-S) or WKY (S-W) microbiota. W-S exhibited a significant elevation in BP as compared to W-W. Conversely, S-W had a significantly lower BP as compared to S-S.1 In line with the BP observations, aortic endothelium-dependent relaxation to acetylcholine was found to be impaired in S-S and W-S as compared to W-W. This was associated with increased reactive oxygen species and NAPDH oxidase activity measured in aortas from groups receiving SHR microbiota. Elevated ROS may impair vascular function not only by reducing NO bioavailability, but also by promoting vascular inflammation. Accordingly, aortas from rats receiving the SHR microbiota had elevated markers of proinflammatory Th17 cells and reduced markers of anti-inflammatory Treg cells, as compared to W-W aortas. Treatment of hypertensive W-S rats with an IL-17 neutralizing antibody improved aortic vascular function and reduced BP, further suggesting a role for Th17 cells in SHR hypertension.1 With the observation that the SHR microbiota increased proinflammatory T-cells in the aorta, the authors examined the effects of WKY and SHR microbiota on immune cell activation. Dendritic cells are constantly surveying the contents of the gut lumen, including the makeup of the gut microbiota. Dendritic cells can phagocytize bacteria, or be activated by bacterial signals, and migrate to mesenteric lymph nodes (MLNs) where they play a role in activation of naïve T cells. MLNs of rats receiving the SHR microbiota had elevated markers of activated dendritic cells and T cells as compared to rats transplanted with the WKY microbiota.1 Additionally, there was a shift in MLN T-cell polarization following microbiota transplantation, with rats receiving SHR microbiota having greater Th17 and reduced Treg percentages as compared to rats receiving WKY microbiota. To examine the importance of the antigen presenting cell - T cell interaction, an inhibitor of T cell costimulation was administered to W-S rats to impair T cell activation. In response to this inhibitor, W-S rats exhibited lower Th17 cell activation in MLN, decreased T cells in aorta, improved vascular function and lower BP.1 Altogether these studies shed new light on a microbiota–immune-vascular interaction. In the model put forth by the authors, the SHR microbiota leads to increased migration of activated dendritic cells to the MLN and T cell activation. Accumulation of T cells in the aorta then leads to increased oxidative stress and vascular dysfunction contributing to hypertension. A gap in our understanding of this pathway lies in identifying the bacteria and/or bacterial metabolites that initiate this inflammatory response. Given that interrupting this pathway abolished hypertension in rats with an SHR microbiota, these additional studies are highly warranted. Furthermore, the benefits of understanding this pathway may extend beyond hypertension and be applicable to other disease states associated with gut dysbiosis and vascular dysfunction, such as diabetes, obesity, and cognitive disorders. None.
Source: Acta Physiologica
DOI: 10.1111/apha.13338
Author: David J. Durgan
Institution: Baylor College of Medicine
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2953547963