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: 9769125
• 负责人: Amanda M Brandow
• 金额: $ 75.68万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769125
• 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; Intestines; 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; Plasma; Play; Population; Quality of life; Race; Recombinant DNA; Recurrence; Reperfusion Injury; Reporter; Research; Rheumatoid Arthritis; Role; Severities; Siblings; Sickle Cell; Sickle Cell Anemia; TLR4 gene; Testing; Vertebral column; Work; base; care seeking; chemokine; chemotherapy; chronic pain; chronic pelvic pain; clinical phenotype; cytokine; daily pain; dysbiosis; effective therapy; gut microbiota; immunoregulation; improved; inflammatory milieu; 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.

项目总结/文摘