PDF(Pubmed)
Abstract：
Chronic abdominal pain in the absence of ongoing disease is the hallmark of disorders of gut-brain interaction (DGBIs), including irritable bowel syndrome (IBS). While the etiology of DGBIs remains poorly understood, there is evidence that both genetic and environmental factors play a role. In this study, we report the identification and validation of Avpr1a as a novel candidate gene for visceral hypersensitivity (VH), a primary peripheral mechanism underlying abdominal pain in DGBI/IBS. Comparing two C57BL/6 (BL/6) substrains (C57BL/6NTac and C57BL/6J) revealed differential susceptibility to the development of chronic VH following intrarectal zymosan (ZYM) instillation, a validated preclinical model for post-inflammatory IBS. Using whole genome sequencing, we identified a SNP differentiating the two strains in the 5\' intergenic region upstream of Avpr1a, encoding the protein arginine-vasopressin receptor 1A (AVPR1A). We used behavioral, histological, and molecular approaches to identify distal colon-specific gene expression differences and neuronal hyperresponsiveness covarying with Avpr1a genotype and VH susceptibility. While the two BL/6 substrains did not differ across other gastrointestinal (GI) phenotypes (e.g., GI motility), VH-susceptible BL/6NTac mice had higher colonic Avpr1a mRNA and protein expression. Moreover, neurons of the enteric nervous system were hyperresponsive to the AVPR1A agonist AVP, suggesting a role for enteric neurons in the pathology underlying VH. These results parallel our findings that patients\' colonic Avpr1a mRNA expression was higher in patients with higher pain ratings. Taken together, these findings implicate differential regulation of Avpr1a as a novel mechanism of VH-susceptibility as well as a potential therapeutic target specific to VH.
摘要：
在没有持续疾病的情况下，慢性腹痛是肠-脑相互作用（DGBIs）障碍的标志，包括肠易激综合征（IBS）。虽然DGBIs的病因仍然知之甚少，有证据表明遗传和环境因素都起作用。在这项研究中,我们报告了Avpr1a作为内脏高敏感性（VH）的新候选基因的鉴定和验证，DGBI/IBS腹痛的主要外周机制。比较两个C57BL/6（BL/6）底物（C57BL/6NTac和C57BL/6J）揭示了直肠内酵母聚糖（ZYM）滴注后对慢性VH发展的不同易感性，一种经过验证的炎症后IBS临床前模型。使用全基因组测序，我们确定了在Avpr1a上游的5'基因间区域中区分两个菌株的SNP，编码蛋白质精氨酸加压素受体1A（AVPR1A）。我们用行为，组织学,和分子方法来确定远端结肠特异性基因表达差异和神经元高反应性与Avpr1a基因型和VH易感性的共变。虽然这两个BL/6亚型在其他胃肠道(GI)表型之间没有差异(例如，GI运动性)，VH敏感BL/6NTac小鼠结肠Avpr1amRNA和蛋白表达较高。此外，肠神经系统的神经元对AVPR1A激动剂AVP反应过度，提示肠神经元在VH病理中的作用。这些结果与我们的发现相似，即疼痛评分较高的患者结肠Avpr1amRNA表达较高。一起来看,这些发现暗示Avpr1a的差异调节是VH易感性的新机制，也是VH特异性的潜在治疗靶点。
■方法的组合，从基因组分析到功能分析，确认Avpr1a为内脏痛的高优先级候选基因。
■方法的组合，从基因组分析到功能分析，确认Avpr1a为内脏痛的高优先级候选基因。
