Regulation of Viscerosensory Sympathetic Reflexes: The Role of Diet-Derived Lipid Mediators.

胃肠道和心血管健康密切相关，然而饮食来源的脂质代谢物和肠道微生物菌群影响传出交感神经活动的机制在很大程度上是未知的。我们实验室和其他人的工作提供了越来越多的证据，证明肠神经系统直接影响交感神经对全身血压的控制。内脏感觉交感神经网络是一个功能性的神经回路，连接肠的传入感觉纤维和脊髓水平的传出血管收缩神经元。虽然这种神经回路可能影响健全个体的全身血压，但它在脊髓损伤（SCI）患者发生严重高血压危象中的作用是无可辩驳的。自主神经反射障碍（AD）通常是脊髓损伤患者的临床急症，其特征是对其他无害的内脏刺激（如粪便嵌塞）的阵发性高血压反应。尽管其具有明显的意义，但涉及内脏感觉-交感反射（VSSRs）调节的机制尚不清楚。我们的初步研究表明，表达瞬时受体电位阳离子通道V1 （TRPV1）的c -纤维感觉神经元参与了内脏感觉交感神经回路的传入肢体。我们的建议旨在（目标1）提供对饮食来源的脂质介质在夸大AD表型中的作用的机制理解，（目标2）询问减轻脊髓损伤后交感神经高反射的新治疗策略，以及（目标3）定义与脊髓损伤相关的肠道生态失调在促进致病性饮食来源的脂质介质产生中的作用。我们的中心假设确定了新的致病因素（膳食脂肪酸含量和sci相关的生态失调）和生化机制（饮食来源的TRPV1脂质配体），它们可能是治疗干预的独立靶点。独特的是，我们合理设计的治疗策略针对AD的主要潜在原因（即内脏c纤维过敏），而不是症状结果（即急性高血压危象），因此构成了重大的范式转变。

Gastrointestinal and cardiovascular health are intimately linked, yet the mechanism by which diet-derived lipid metabolites and the gut microbial flora impact efferent sympathetic nerve activity is largely unknown. Work from our laboratory and others’ provides increasing evidence that the enteric nervous system directly influences the sympathetic control of systemic blood pressure. The viscerosensory-sympathetic network is a functional neural circuit connecting afferent sensory fibers of the gut and efferent vasoconstrictor neurons at the level of the spinal cord. While this neural circuitry likely influences systemic blood pressure in able-bodied individuals, its role in the development of severe hypertensive crises in patients living with spinal cord injury (SCI) is irrefutable. Autonomic dysreflexia (AD) is often a clinical emergency in SCI individuals and is characterized by paroxysmal hypertension in response to otherwise innocuous visceral stimuli (e.g. fecal impaction). Despite its obvious significance, mechanisms involved in the regulation of viscerosensory-sympathetic reflexes (VSSRs) are poorly understood. Our preliminary studies indicate that C-fiber sensory neurons expressing transient receptor potential cation channel V1 (TRPV1) are involved in the afferent limb of the viscerosensory-sympathetic circuitry. Our proposal seeks to (Aim 1) provide a mechanistic understanding of the role of diet-derived lipid mediators in exaggerating the AD phenotype, (Aim 2) interrogate novel therapeutic strategies for attenuating sympathetic hyperreflexia following SCI, and (Aim 3) define the role of SCI-associated gut dysbiosis in contributing to the production of pathogenic diet-derived lipid mediators. Our central hypotheses identify new pathogenic factors (dietary fatty-acid content and SCI-associated dysbiosis) and a biochemical mechanism (diet-derived TRPV1 lipid ligands) that may be independent targets for therapeutic intervention. Uniquely, our rationally designed therapeutic strategies target the major underlying cause of AD (i.e. visceral C-fiber hypersensitivity) rather than the symptomatic outcome (i.e. acute hypertensive crisis) and thus constitute a major paradigm shift.