The Gut Microbiome and Serum Metabolites as a Biological Mechanism Underlying Pain in Kidney Transplantation (Biome-KT)

肠道微生物组和血清代谢物作为肾移植疼痛的生物机制 (Biome-KT)

• 批准号: 10633444
• 负责人: Mark Lockwood
• 金额: $ 61.66万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633444
• 关键词: Address; Adult; Affect; Age; Anxiety; Bacteria; Biological; Biological Markers; Brain; Catabolism; Chemicals; Chronic Kidney Failure; Clinical; Cognitive; Communities; Consumption; Data; Diet; Dietary Practices; Disease; Emotional; End stage renal failure; Endocrine; Endotoxins; Enterococcus; Environmental Risk Factor; Fatigue; Fatty acid glycerol esters; Feces; Fiber; Foundations; Gastrointestinal tract structure; General Population; Genes; Goals; Growth; Hemodialysis; Human body; Immunologics; Immunosuppression; Impairment; Income; Indoles; Inflammation; Intervention; Intestines; Investigation; Kidney; Kidney Diseases; Kidney Transplantation; Kynurenic Acid; Kynurenine; Life; Link; Longitudinal Studies; Measures; Mediating; Mental Depression; Metabolic; Microbe; Modeling; Neuropathy; Nociception; Pain; Pain intensity; Pain interference; Pain management; Pathway interactions; Patient Self-Report; Persons; Phenotype; Play; Probiotics; Psychological Stress; Quinolinic Acid; Race; Recreation; Renal function; Reporting; Risk; Role; Serotonin; Serum; Signaling Molecule; Stress; Supplementation; Testing; Time; Toxin; Transplant Recipients; Transplantation; Treatment Protocols; Tryptophan; Urea; Volatile Fatty Acids; Withdrawal; beta diversity; chemical reduction; chronic pain; comorbidity; daily functioning; design; experience; food consumption; gut microbiome; gut microbiota; health related quality of life; host-microbe interactions; improved; indexing; indoleacetic acid; innovation; machine learning algorithm; machine learning model; microbial; microbial community; microbial composition; microbiome; microbiota; microorganism; mortality; multimodality; neurotoxic; novel; pain reduction; pain relief; pain score; painful neuropathy; patient oriented; patient population; perceived stress; post-transplant; prevent; prospective; restoration; social; stress reduction; sugar; systemic inflammatory response; transplant model; treatment adherence; treatment optimization

7. Abstract Nearly half (47%) of people with end-stage kidney disease (ESKD) whose kidney function is restored after kidney transplantation experience chronic pain compared to 19% of adults in the US general population. Pain is associated with comorbid fatigue, depression and anxiety, and withdrawal from usual physical and social activities; resulting in an inability to participate in and enjoy life. Severe pain can result in nonadherence to immunosuppression and treatment protocols and result in an increased risk of rejection, graft loss, and mortality. The role of symbiotic microbes (microbiota) in the gastrointestinal tract, and their functional genes (microbiome), is well established in diseases involving pain. Diet and stress play a major role in synthesis of signaling molecules critical to immunologic, metabolic, and endocrine pathways regulating chronic pain. Dietary patterns change dramatically after transplantation, as recipients move from a restricted “renal” diet to a regular diet, often resulting in increased consumption of foods high in sugars and fat. Moreover, psychological stress significantly impairs the function of the microbiome, initiating biological pathways involved in pain, leading to a disproportionate pain burden. Because the microbiome, serum metabolites, and pain are dynamic, our novel investigation will employ a prospective repeated measures design to interrogate the dynamic temporal relationships between the microbiome, metabolites associated with pathways regulating pain, transplantation factors (e.g. immunosuppression, kidney function), changing dietary patterns, and perceived stress, on pain scores before and after kidney transplantation. We posit the gut microbiome, and its byproducts, may partially explain the underlying biological mechanisms of pain Interference in kidney disease. We will address three aims: 1) To determine differential dynamic temporal relationships between microbial composition/functional genes and circulating serum metabolites in KTRs with pain vs no pain, 2) To determine the moderation effects of diet and perceived stress on dynamic temporal relationships between microbiome features, serum metabolites, and pain scores among KTRs, and 3) To use machine learning algorithms to identify host-microbial interactions that are causally linked to pain interference among KTRs. Because kidney function is restored, the kidney transplant model is powerful to study the longitudinal relationships between the microbiome, circulating metabolites and chronic pain in people with ESKD to develop patient-centered interventions to treat pain across the spectrum of CKD.

7. 摘要 近一半 (47%) 的终末期肾病 (ESKD) 患者在肾病治疗后肾功能得到恢复 相比之下，美国普通人群中 19% 的成年人会经历慢性疼痛。疼痛是 与共病疲劳、抑郁和焦虑以及退出平常的身体和社交活动有关 活动;导致无法参与和享受生活。剧烈疼痛可能导致不遵守 免疫抑制和治疗方案会导致排斥反应、移植物丢失和死亡的风险增加。 共生微生物（微生物群）在胃肠道中的作用及其功能基因（微生物组）， 在涉及疼痛的疾病中已得到充分证实。饮食和压力在信号分子的合成中起着重要作用 对调节慢性疼痛的免疫、代谢和内分泌途径至关重要。饮食模式改变 移植后，随着受者从限制性“肾脏”饮食转向常规饮食，通常会导致 增加高糖和高脂肪食物的摄入。此外，心理压力也会严重影响 微生物组的功能，启动与疼痛有关的生物途径，导致不成比例的疼痛 负担。由于微生物组、血清代谢物和疼痛是动态的，我们的新研究将采用 前瞻性重复测量设计来询问之间的动态时间关系 微生物组、与调节疼痛途径相关的代谢物、移植因子（例如 免疫抑制、肾功能）、改变饮食模式和感知压力，对之前的疼痛评分 以及肾移植后。我们认为肠道微生物组及其副产物可以部分解释 疼痛的潜在生物学机制 干扰肾脏疾病。我们将实现三个目标：1） 确定微生物组成/功能基因之间的差异动态时间关系 疼痛与无痛 KTR 中的循环血清代谢物，2) 确定饮食和饮食的调节作用 微生物组特征、血清代谢物和疼痛之间动态时间关系的感知压力 KTR 之间的分数，以及 3) 使用机器学习算法来识别宿主-微生物相互作用 与 KTR 之间的疼痛干扰有因果关系。由于肾功能已经恢复，所以需要进行肾移植 模型对于研究微生物组、循环代谢物和微生物之间的纵向关系非常有用。 ESKD 患者的慢性疼痛制定以患者为中心的干预措施来治疗各种疼痛 慢性肾病。