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

项目总结/摘要 拟议工作的总体目标是研究微生物组和炎症在急性炎症中的作用。 以及镰状细胞病（SCD）患者的慢性疼痛。间歇性的剧烈疼痛 SCD患者的大多数急诊室就诊和住院以及 这些发作随着年龄的增长而增加。慢性、使人衰弱的日常疼痛也发生在约40%的青少年中， 成年SCD患者的发病率和慢性疼痛的严重程度也随着年龄的增长而增加。批判性的知识 在确定慢性镰状化以外的原因方面存在差距，这些原因导致不可预测的临床 频繁的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SCD疼痛;然而，它们通常提供无效的镇痛，并可能导致显著的副作用， 耻辱需要增加对急性和慢性SCD疼痛生物学的理解， 开发阿片类药物保留的靶向治疗，以改善SCD患者的生活质量。的改变 肠道微生物群或微生态失调，一种已知的慢性炎症驱动因素，尚未在SCD中进行研究， 在其他慢性炎症性疾病和疼痛相关疾病中发挥作用。生态失调与 与类风湿性关节炎疼痛、偏头痛、慢性盆腔痛和化疗引起的疼痛有关。生态失调可以 导致肠道屏障“渗漏”，导致细菌移位进入血液。细菌易位（即， 全身性微生物抗原暴露）可引发慢性炎症， 伤害感受器，并导致复发性急性和慢性疼痛。这种炎症反应的免疫调节 可以调节炎症对疼痛的影响。神经系统致敏发生在SCD患者中。 然而，导致SCD神经系统致敏的生物学因素尚不清楚。因此，在本发明中， 研究微生物组、炎症和SCD疼痛之间的联系是重要的。在这 建议，我们将调查是否来自肠道微生物群改变的微生物抗原驱动 SCD患者的炎症和疼痛。提出了以下目标：1）检查关系 系统性微生物抗原水平、肠道微生物群组成和多样性与 SCD患者和健康人种匹配对照的炎症状态和2）调查是否急性 SCD患者的慢性疼痛与全身性微生物抗原暴露的增加有关， 炎症状态升高。我们的协作和多学科团队拥有临床和研究专业知识， SCD疼痛生物学、炎症、微生物组和SCD患者报告的结局。我们将利用多方面的 研究微生物暴露和宿主炎症反应如何影响 SCD疼痛。我们的工作有可能确定新的阿片类药物保留疼痛治疗的目标， 减少患者痛苦。

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.