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

7.摘要 近一半(47%)的终末期肾病(ESKD)患者的肾功能在肾功能恢复后恢复 与美国总人口中19%的成年人相比，移植经历了慢性疼痛。痛苦就是 与共病的疲劳、抑郁和焦虑，以及从日常的身体和社交活动中退缩有关 活动；导致无法参与和享受生活。剧烈疼痛可能会导致不坚持 免疫抑制和治疗方案，并导致排斥、移植物丢失和死亡的风险增加。 共生微生物(微生物区系)在胃肠道中的作用及其功能基因(微生物组)， 在与疼痛有关的疾病中得到了很好的应用。饮食和压力在信号分子的合成中起主要作用 对调节慢性疼痛的免疫、代谢和内分泌途径至关重要。饮食模式发生变化 移植后，当受者从受限的“肾脏”饮食转变为常规饮食时，通常会导致 增加对高糖和高脂肪食物的消费。此外，心理压力显著地损害了 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，我们的新调查将使用 一种前瞻性重复测量设计，用于询问动态时间关系 微生物组、与调节疼痛的途径相关的代谢物、移植因子(例如 免疫抑制、肾功能)、饮食结构的改变以及感知到的压力对疼痛评分的影响 以及肾移植后。我们假设肠道微生物组及其副产品可以部分解释 肾脏疾病疼痛干预的潜在生物学机制。我们将实现三个目标：1) 确定微生物组成/功能基因和 有疼痛和无疼痛KTRs的循环血清代谢产物，2)确定饮食和 微生物组特征、血清代谢物和疼痛之间的动态时间关系的感知应激 KMR中的分数，以及3)使用机器学习算法来识别 与KDR之间的疼痛干扰有因果关系。因为肾功能恢复了，所以肾移植 模型有力地研究了微生物群、循环代谢产物和 ESKD患者的慢性疼痛将开发以患者为中心的干预措施，以治疗各种类型的疼痛 CKD。

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.