Brain-Gut Microbiome-Immune Axis in Hypertension

 描述（由申请人提供）：高血压（HTN）是心血管疾病（CVD）和直接影响CVD的疾病（即糖尿病、慢性肾脏疾病、阻塞性睡眠呼吸暂停等）的最常见可改变风险。尽管生活方式改变和药物治疗进展，约20%的HTN患者对（或需要≥3种）抗高血压药物耐药（R-HTN）通常起源于神经源性，并与自主神经系统功能障碍有关。最近经皮肾动脉交感神经去神经术失败后，几乎没有治疗选择（SYMPLICITY HTN-3，PRAUGE-15）。因此，基于机制的突破对于开发控制和潜在地治愈R-HTN的新策略是必要的。我们相信，我们在R-HTN中的肠道生态失调和功能失调的脑-肠-骨髓（BM）相互作用的证据代表了这一突破。 我们提出了一个脑-肠-BM功能障碍相互作用假说：HTN风险因素通过影响自主脑区增加交感神经驱动，启动一系列关键信号事件，这些事件是建立神经源性R-HTN的关键。这包括增加的肠道硬度、渗透性和炎症，导致肠道微生物生态失调。生态失调相关的变化增加骨髓祖细胞和其他促炎细胞的BM产生。这有助于增加外周炎症和神经炎症，因为一些BM衍生的髓样祖细胞迁移到室旁核（PVN），并分化成小胶质细胞。因此，我们假设R-HTN的建立是由SNA介导的肠道生态失调、BM促炎细胞活性和神经炎症增加引起的。 提出了三个具体目标来支持/反驳R-HTN中这种功能失调的脑-肠-BM相关神经炎症假说：目标1将研究以下假说：增加的肠道SNA在HTN中增强的肠道通透性、促炎性条件和微生物生态失调中至关重要。目的2将定义肠道生态失调如何增加HTN中促炎祖细胞和神经炎症的产生。目的3将评估人类R-HTN与严重的肠道微生物生态失调有关的假设，以及米诺环素治疗将逆转生态失调并降低血压的假设。这些研究将利用最先进的综合生理基因组技术，并将由一个特殊的研究团队进行。 因此，从小鼠到人类的这种基于机制的转化研究的结果将为R-HTN的范式改变治疗方法的开发提供基础，而不涉及更多的抗高血压药物。

 DESCRIPTION (provided by applicant): Hypertension (HTN) is the most prevalent modifiable risk for cardiovascular disease (CVD) and disorders directly influencing CVD (i.e. diabetes, chronic kidney disease, obstructive sleep apnea, etc.). Despite lifestyle changes and advances in drug therapy, ~20% of all HTN patients are resistant to (or require ≥3) antihypertensive drugs Resistant HTN (R-HTN) is generally neurogenic in origin and associated with a dysfunctional autonomic nervous system. Few treatment options remain available following the recent failure of percutaneous renal artery sympathetic denervation (SYMPLICITY HTN-3, PRAUGE-15). Thus, a mechanism- based breakthrough is imperative to develop novel strategies to control and potentially cure R-HTN. We believe that our evidence of gut dysbiosis and dysfunctional brain-gut-bone marrow (BM) interaction in R-HTN represents this breakthrough. We propose a brain-gut-BM dysfunctional interaction hypothesis: HTN risk factors increase sympathetic drive by influencing autonomic brain regions, setting in motion a sequence of critical signaling events key to establishing neurogenic R-HTN. This includes increased gut stiffness, permeability and inflammation leading to gut microbial dysbiosis. Dysbiosis-associated changes increase BM production of myeloid progenitors and other proinflammatory cells. This contributes to increased peripheral inflammation, and neuroinflammation, as some BM-derived myeloid progenitors migrate to the paraventricular nucleus (PVN), and differentiate into microglia. Therefore, we hypothesize that establishment of R-HTN is caused by an increased SNA-mediated gut dysbiosis, activity of BM proinflammatory cells, and neuroinflammation. Three specific aims are proposed to support/refute this dysfunctional brain-gut-BM linked neuroinflammation hypothesis in R-HTN: Aim 1 will investigate the hypothesis that increased gut SNA is critical in enhanced intestinal permeability, proinflammatory conditions, and microbial dysbiosis in HTN. Aim 2 will define how gut dysbiosis increases production of proinflammatory progenitors and neuroinflammation in HTN. Aim 3 will evaluate the hypothesis that human R-HTN is linked to profound gut microbial dysbiosis and that treatment with minocycline will reverse the dysbiosis and lower BP. These studies will utilize state-of-the-art integrative physiological genomic techniques and will be conducted by an exceptional team of investigators. Thus, the outcome of this mechanism-based translational study spanning from mice to humans will provide the basis for development of paradigm-changing therapeutic approaches for R-HTN without involving more anti-hypertensive drugs.