Gut Microbiota in the Modulation of Outcomes after Liver Transplant

肝硬变是发病率和死亡率的主要原因，疾病进展与 肠道微生物组成和功能改变。治疗肝硬变的唯一可靠方法是肝脏。 移植(LT)。然而，有相当大比例的肝移植术后患者出现多药耐药 生物体(MDRO)、认知障碍和代谢综合征，这可能是生命- 并导致长期残疾或肝移植前功能的不完全恢复。 此外，利用目前可用的生物标志物，还不清楚哪些患者会患上这些疾病。 术后不良事件和一些证据表明，肠道微生物区系改变发挥了 重要的角色。这一提议代表了使用LT前微生物调制的第一步 用中心假说预防肝移植术后并发症：肠道微生物组成 和肝移植前的功能可以成功地预测移植后的结果。 我们将使用以下具体目标来研究这一假设： 目的1：确定移植前肠道微生物组成和功能在 通过MDRO定植预测移植后感染， 目的2：确定移植前肠道微生物组成和功能在 移植后代谢综合征的发展， 目的3：确定移植前肠道微生物组成和功能在 肝移植术后认知功能恢复 研究将分为两部分：第一部分将利用已经从150个LT收集的纵向样本 来自两个中心的收件人。第2部分将在每个站点再招募50名患者，以验证研究结果 第1部分：粪便微生物区系组成(16srRNA测序，多样性，相对丰度 潜在致病和有益的类群以及MDRO的特异性分子检测 将进行定植)和功能(代谢组学、胆汁酸)。认知功能 (经过验证的纸-笔和计算机化技术)和代谢综合征 肝移植术后确诊。移植前的微生物评估将用于预测这些结果。 独立于已经验证的使用生物信息学的临床预测因子。这将有助于指导 未来基于微生物群的精确医学研究在预测LT患者中的作用。 VCU和CUIMC的CTSA与具有长期记录的领先LT中心相关 在肝硬变、肝移植、微生物区系和认知方面的临床和转化性研究。两者都有 各中心将在招聘和分析方面平等协作。该提案符合PAR-19-100 通过专注于精准医学和人类微生物组的翻译研究。

Cirrhosis is a major cause of morbidity and mortality, and disease progression is associated with altered gut microbial composition and function. The only reliable cure for cirrhosis is liver transplant (LT). However, a sizable proportion of post-LT patients develop multi-drug resistant organisms (MDROs), cognitive impairment and metabolic syndrome, which can be life- threatening and result in long-term disability or incomplete recovery of pre-LT function. Moreover, using currently available biomarkers, it is unclear which patients will develop these post-LT adverse events and there is some evidence that altered gut microbiota plays an important role. This proposal represents the first step towards using pre-LT microbial modulation in preventing post-LT complications with the central hypothesis: Gut microbial composition and function before liver transplant can successfully predict post-transplant outcomes. We will study this hypothesis using the following specific aims: Aim 1: To determine the role of pre-transplant gut microbial composition and function in the prediction of post-transplant infections through MDRO colonization, Aim 2: To determine the role of pre-transplant gut microbial composition and function in the development of post-transplant metabolic syndrome, Aim 3: To determine the role of pre-transplant gut microbial composition and function in cognitive recovery after liver transplant The study will have 2 parts: Part 1 will utilize already collected longitudinal samples from 150 LT recipients from both centers. Part 2 will enroll 50 more patients per site to validate findings from part 1. Stool microbiota composition (16srRNA sequencing for diversity, relative abundance of potentially pathogenic and beneficial taxa, and specific molecular assays for MDRO colonization) and function (metabolomics, bile acids) will be performed. Cognitive function (validated paper-pencil and computerized techniques) and metabolic syndrome will be diagnosed post-LT. Pre-transplant microbial assessment will be used to predict these outcomes independent of already validated clinical predictors using bio-informatics. This will help guide future precision medicine based research on microbiota in prognosticating LT patients. The CTSAs at VCU and CUIMC are associated with leading LT centers with a long track record of clinical and translational research in cirrhosis, liver transplant, microbiota, and cognition. Both centers will collaborate equally in recruitment and analysis. This proposal fits with PAR-19-100 through the focus on Precision Medicine and Translational studies of the human microbiome.