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

研究微生物组和炎症在镰状细胞病患者急性和慢性疼痛中的作用

• 批准号: 10462603
• 负责人: Amanda M Brandow
• 金额: $ 68.33万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462603
• 关键词: Absence of pain sensation; Accident and Emergency department; Acute; Acute Pain; Adolescent; Adult; Affect; Age; Bacterial Translocation; Biological Assay; Biological Factors; Biology; Blood; Cells; Chronic; Chronic Fatigue Syndrome; Clinical Research; Complex Regional Pain Syndromes; Complication; Data; Development; Disease; Emergency department visit; Feces; Frequencies; Gender; Genes; Genetic Transcription; Goals; Health; Health Care Costs; Hemolysis; Hospitalization; Immune system; Immunologic Receptors; Impairment; Incidence; Inflammation; Inflammatory; Inflammatory Response; Inherited; Inpatients; Irritable Bowel Syndrome; Knowledge; Lead; Ligation; Lipopolysaccharides; Measures; Migraine; Modeling; Nervous system structure; Nociceptors; Opioid; Outcome; Pain; Pain management; Patient Outcomes Assessments; Patients; Pattern recognition receptor; Peripheral; Persons; Plasma; Play; Population; Quality of life; Race; Recurrence; Reperfusion Injury; Reporter; Research; Rheumatoid Arthritis; Ribosomal DNA; Role; Severities; Siblings; Sickle Cell; Sickle Cell Anemia; TLR4 gene; Testing; Vertebral column; Work; base; care seeking; chemokine; chemotherapy; chronic inflammatory disease; chronic pain; chronic pelvic pain; clinical phenotype; cytokine; daily pain; debilitating pain; dysbiosis; effective therapy; gut microbiota; immunoregulation; improved; inflammatory milieu; intestinal barrier; microbial; microbiome; microbiota; microorganism antigen; multidisciplinary; novel; opioid sparing; peripheral pain; response; sickling; side effect; social stigma; targeted treatment

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.

项目摘要/摘要 拟议工作的总体目标是研究微生物组和注射急性的作用 镰状细胞病（SCD）患者的慢性疼痛。间歇性，令人痛苦的急性疼痛 SCD患者的大多数急诊科和住院 这些发作随着年龄的增长而增加。慢性，使人衰弱的每日疼痛也发生在约40％的青少年和 患有SCD的成年人以及慢性疼痛的事件和严重程度也随着年龄的增长而增加。批判知识 差距存在于鉴定出慢性病以外的其他原因，这导致了不可预测的临床 经常急性和慢性疼痛的表型。阿片类药物是急性和 慢性SCD疼痛；但是，它们通常提供无效的镇痛，并可能导致重大副作用，并且 柱头。为了使急性和慢性SCD疼痛的生物学有更多的了解 开发具有阿片类药物的目标疗法，以改善SCD患者的生活质量。改变 肠道菌群或营养不良是慢性感染的已知驱动力，尚未在SCD中探索 在其他慢性炎症性疾病和与疼痛有关的疾病中发挥作用。营养不良一直关联 类风湿关节炎，偏头痛，慢性骨盆疼痛和化学疗法引起的疼痛的疼痛。营养不良可以 导致“泄漏”的肠道屏障，导致细菌转移到血液中。细菌易位（即 全身微生物抗原暴露）会触发慢性炎症，这可能会感觉到周围疼痛 伤害感受器，导致复发性急性和慢性疼痛。免疫调节这种炎症反应 可以调节对疼痛的炎症影响。 SCD患者发生神经系统敏感性。 但是，导致SCD神经系统敏感性的生物学因素尚不清楚。那， 研究微生物组，注射和SCD疼痛之间的联系很重要。在这个 提案，我们将调查肠道微生物改变的微生物抗原是否驱动 SCD患者的炎症和疼痛。提出了以下目的：1）检查关系 在全身微生物抗原水平，肠道微生物群组成和多样性之间 SCD和健康匹配对照患者的炎症状态，2）研究是否急性 SCD患者的慢性疼痛与全身微生物抗原暴露的增加有关 炎症状态升高。我们的合作和多学科团队具有临床和研究专业知识 SCD疼痛生物学，感染，微生物组和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表达的方法 SCD疼痛。我们的工作有可能确定新型阿片类药物疼痛治疗的目标 减少患者的痛苦。

项目成果

Preliminary construct validity of patient-reported outcomes to assess chronic pain in adults with sickle cell disease.

• DOI: 10.1182/bloodadvances.2023009707
• 发表时间: 2023-07-25
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Mucalo, Lana;Field, Joshua J.;Highland, Janelle;Khan, Hamda;Hankins, Jane S.;Singh, Ashima;Brandow, Amanda M.
• 通讯作者: Brandow, Amanda M.