Neural mechanisms of host-microbiota interaction in hypertension: a potential for bio-electronic medicine

摘要 高血压（HTN）是一种常见的心血管疾病，也是其他心血管疾病的主要危险因素。 疾病如果不治疗，HTN会导致许多并发症，如中风、痴呆、糖尿病， 肾脏疾病、阻塞性睡眠呼吸暂停和神经系统疾病。尽管在预防和多方面取得了进展， 在药物治疗中，很大一部分患者对目前的治疗仍然有抗性或难治性。在大多数 例，难治性HTN是强烈的神经源性，其特征是自主神经功能障碍 系统（ANS）最近与肠道生态失调有关。然而，HTN中宿主-微生物群相互作用的机制 并没有很好的定义。我们新的初步数据表明，神经肠-脑通信的中断 可能是由迷走神经传入纤维上的多巴胺能受体信号减少介导的 从肠道到孤束核的投射。在本申请中，我们建议使用现有技术 在转基因和人源化大鼠中的体内成像、电生理学和神经刺激方法， 询问健康和HTN中宿主-微生物群相互作用的特定分子和神经机制， 评估生物电子医学中迷走神经刺激的潜力，以减轻 HTN中肠道生态失调的症状。

Abstract Hypertension (HTN) is a prevalent cardiovascular condition and a leading risk factor for other cardiovascular diseases. If it remains untreated, HTN can lead to numerous comorbidities such as stroke, dementia, diabetes, kidney disease, obstructive sleep apnea, and neurological disorders. Despite advances in prevention and multi- drug therapy, a significant proportion of patients remain resistant or refractory to current treatments. In most cases, treatment-resistant HTN is strongly neurogenic, characterized by a dysfunctional autonomic nervous system (ANS) most recently linked to gut dysbiosis. However, mechanisms of host-microbiota interaction in HTN are not well defined. Our new preliminary data suggests that a breakdown in the neural gut-brain communication resulting from gut dysbiosis may be mediated by reduced serotonergic receptor signaling on the vagal afferent projections from the gut to the nucleus of the solitary tract. In this application, we propose to use state of the art in vivo imaging, electrophysiology and neural stimulation approaches in transgenic and humanized rats in order to interrogate specific molecular and neural mechanisms of host-microbiota interaction in health and HTN, while evaluating the potential of sub-diaphragmatic vagal stimulation for bio-electronic medicine to alleviate the symptoms of gut dysbiosis in HTN.