Investigating the role of the microbiome and inflammation in acute and chronic pain in patients with sickle cell disease

项目摘要/摘要 这项拟议工作的总体目标是调查微生物群和炎症在急性胰腺炎中的作用。 镰状细胞病(SCD)患者的慢性疼痛。间歇性、极度剧烈的疼痛是 大多数SCD患者的急诊科就诊和住院次数以及 这些发作随着年龄的增长而增加。约40%的青少年也会出现慢性、衰弱的日常疼痛， 成人SCD和慢性疼痛的发生率和严重程度也随着年龄的增长而增加。批判性知识 除了慢性疾病之外，在确定导致不可预测的临床疾病的原因方面存在差距 经常出现急性和慢性日常疼痛的表型。阿片类药物是治疗急性和慢性前列腺癌的主干药物 慢性SCD疼痛；然而，它们往往提供无效的止痛，并可能导致显著的副作用和 耻辱。需要对急性和慢性SCD疼痛的生物学有更多的了解，以便 开发节省阿片类药物的靶向治疗，以提高SCD患者的生活质量。建筑的改动 肠道微生物区系或微生物失调是慢性炎症的已知驱动因素，尚未在SCD中得到探索，但 在其他慢性炎症性疾病和疼痛相关疾病中发挥作用。生物失调已被认为 伴有类风湿性关节炎、偏头痛、慢性盆腔疼痛和化疗引起的疼痛。生物失调可以 导致肠道屏障“泄漏”，导致细菌移位到血液中。细菌易位(即， 全身微生物抗原暴露)会引发慢性炎症，从而使周围疼痛变得敏感 痛觉感受器，并导致反复的急性和慢性疼痛。这种炎症反应的免疫调节 可以调节炎症对疼痛的影响。神经系统敏感化发生在SCD患者身上。 然而，导致SCD神经系统敏感化的生物学因素尚不清楚。因此， 研究微生物群、炎症和SCD疼痛之间的联系是重要的。在这 提议，我们将调查肠道微生物区系改变是否会驱动微生物抗原 SCD患者的炎症和疼痛。提出了以下目标：1)考察二者的关系 全身微生物抗原水平、肠道微生物区系组成和多样性与全身 SCD患者和健康种族匹配的对照组的炎症状态，2)调查急性 SCD患者的慢性疼痛与全身微生物抗原暴露增加和 炎症状态升高。我们的协作和多学科团队在临床和研究方面拥有专业知识 SCD疼痛生物学、炎症、微生物群和SCD患者-报告的结果。我们将利用一个多方面的 研究微生物暴露和宿主炎症反应如何影响其表达的方法 SCD疼痛。我们的工作有可能确定新的阿片类药物节省疼痛治疗的靶点，这将 减少病人的痛苦。

PROJECT SUMMARY/ABSTRACT The overall goals of the proposed work are to investigate the role of the microbiome and inflammation in acute and chronic pain in patients with sickle cell disease (SCD). Intermittent, excruciating acute pain accounts for the majority of emergency department visits and hospitalizations for patients with SCD and the frequency of these episodes increase with age. Chronic, debilitating, daily pain also occurs in ~40% of adolescents and adults with SCD and the incidence and severity of chronic pain also increases with age. A critical knowledge gap exists in the identification of reasons other than chronic sickling that contribute to the unpredictable clinical phenotype of frequent acute and chronic daily pain. Opioids are the backbone treatment for both acute and chronic SCD pain; however they often provide ineffective analgesia and can lead to significant side effects and stigma. An increased understanding of the biology of acute and chronic SCD pain is needed in order to develop opioid-sparing, targeted therapies to improve the quality of life of patients with SCD. Alterations in the intestinal microbiota or dysbiosis, a known driver of chronic inflammation, have not been explored in SCD but play a role in other chronic inflammatory diseases and pain-related disorders. Dysbiosis has been associated with pain in rheumatoid arthritis, migraines, chronic pelvic pain and chemotherapy-induced pain. Dysbiosis can lead to a “leaky” intestinal barrier resulting in bacterial translocation into the blood. Bacterial translocation (i.e., systemic microbial antigen exposure) can trigger chronic inflammation which can sensitize peripheral pain nociceptors and result in recurrent acute and chronic pain. Immune regulation of this inflammatory response can modulate the inflammatory impact on pain. Nervous system sensitization occurs in SCD patients. However, the biologic factors that lead to nervous system sensitization in SCD are unknown. Thus, investigating the connection between the microbiome, inflammation and SCD pain is important. In this proposal, we will investigate whether microbial antigens from intestinal microbiota alterations drive inflammation and pain in patients with SCD. The following aims are proposed: 1) Examine the relationship between systemic microbial antigen levels, intestinal microbiota composition and diversity and the systemic inflammatory state in patients with SCD and healthy race-matched controls and 2) Investigate whether acute and chronic pain in SCD patients is associated with increases in systemic microbial antigen exposure and an elevated inflammatory state. Our collaborative and multidisciplinary team has clinical and research expertise in SCD pain biology, inflammation, microbiome and SCD patient-reported outcomes. We will utilize a multifaceted approach to investigate how microbial exposure and host inflammatory response impacts the expression of SCD pain. Our work has the potential to identify targets for novel opioid-sparing pain treatments that will decrease patient suffering.