Dietary Supplements and Inflammation Phase-2: Isoxanthohumol as a treatment for estrogen-deficient-induced visceral hyperalgesia.

项目总结 慢性内脏疼痛是应激性疾病最常见的临床表现之一。 肠道综合征、慢性盆腔疼痛、胰腺炎和间质性膀胱炎。这种情况使人虚弱， 大大降低了生活质量。女性在服用低雌激素时更容易表现出内脏疼痛 月经周期阶段和雌激素缺乏的更年期状态。本次临床观察为 在动物模型中概括为内脏高敏感性在低雌激素阶段加剧 发情周期5。此外，卵巢切除、雌激素缺乏的小鼠表现出更多的内脏、机械和 热痛觉过敏比做性腺完整、雌激素充足的小鼠。这加剧了痛觉过敏 卵巢切除的小鼠在补充雌激素后表现为无效。然而，确切的分子 雌激素治疗对痛觉调制的保护作用机制(S)尚不清楚。 此外，雌激素替代疗法对于许多女性来说并不是一个可行的选择，因为 如果它是在绝经后开始使用的，与使用它相关的负面健康风险。因此，理解 雌激素抵抗内脏疼痛的机制(S)及开发新的治疗方法 衰弱状态具有重要的临床意义。研究表明，服用雌激素 动物和人类体内的植物雌激素化合物增加了微生物的多样性，这是一个关键成分 一个健康而有弹性的肠道微生物群。临床前研究表明，性别差异存在于 肠道-微生物组轴的寿命和最近发现的雌激素缺乏诱导内脏 超敏反应依赖于微生物区系。然而，对微生物组成和/或 目前还缺乏调节这一效应的微生物代谢物。为了研究雌激素和雌激素的作用机制 植物雌激素介导其抗伤害效应，我们建议使用天然的异黄腐酚(IXO)。 啤酒花(Humulus lupulus L.)中发现的植物雌激素丙烯基黄酮类化合物与内脏过敏 评估、肠道微生物测序和粪便移植以验证IXO和雌激素的假设 通过改变肠道微生物群组成来减轻过敏反应。本研究将为下一步的研究奠定基础 为了了解雌激素和一种新的自然疗法IXO减少内脏的机制 雌激素缺乏引起的过敏症。此外，拟议的研究属于以下范围 父母资助，因为它调查使用一种饮食化合物来治疗虚弱的疾病。另外， 这一建议符合NCCIH通过补充治疗疼痛管理危机的使命 以及疼痛的综合管理。

PROJECT SUMMARY Chronic visceral pain is one of the most common clinical manifestations in such conditions as irritable bowel syndrome, chronic pelvic pain, pancreatitis, and interstitial cystitis. This condition is debilitating and dramatically decreases quality of life. Women are more likely to exhibit visceral pain during the low estrogen phase of the menstrual cycle and the estrogen-deficient menopause state. This clinical observation is recapitulated in animal models as visceral hypersensitivity is exacerbated during the low estrogen phase of the estrous cycle5. Furthermore, ovariectomized, estrogen-deficient mice present more visceral, mechanical, and thermal hyperalgesia than do gonadally intact, estrogen-sufficient, mice. This exacerbation of hyperalgesia exhibited by ovariectomized mice is nullified upon estrogen supplementation. However, the exact molecular mechanism(s) responsible for the protective effect of estrogen therapy on pain modulation remains unresolved. Additionally, estrogen replacement therapy is not a viable option for a number of women due to the potential negative health risks associated with its use if it is initiated after menopause. Therefore, understanding the mechanism(s) by which estrogen protects against visceral pain and developing new therapies to combat this debilitating condition is of significant clinical importance. Studies have revealed that administration of estrogen and phytoestrogen compounds in animals and humans augments microbial diversity which is a key component of a healthy and resilient gut microbiome. Pre-clinical studies have shown that sex differences exist across the lifespan in the gut-microbiome axis and it was recently revealed that estrogen-deficient-induced visceral hypersensitivity is microbiota-dependent. However, a greater understanding of the microbial composition and/or microbial metabolites that regulate this effect is lacking. To investigate the mechanisms by which estrogen and phytoestrogens mediate their anti-nociceptive effects, we propose to use isoxanthohumol (IXO), a natural phytoestrogen prenylflavonoid found in hops (Humulus lupulus L.), in conjunction with visceral hypersensitivity assessment, gut microbial sequencing, and fecal transplants to test the hypothesis that IXO and estrogen mitigate hypersensitivity via changes in the gut microbiome composition. This research will lay the foundation for understanding the mechanism by which estrogen and a new, natural therapy, IXO, reduces visceral hypersensitivity resulting from estrogen deficiency. Furthermore, the proposed research is within the scope of the parent grant as it investigates the use of a dietary compound to treat a debilitating condition. Additionally, this proposal falls in line with the mission of NCCIH to treat the pain management crisis through complementary and integrative management of pain.