Gut Microbiota in the Modulation of Outcomes after Liver Transplant

肠道微生物群对肝移植后结果的调节

• 批准号: 10054215
• 负责人: Jasmohan S Bajaj
• 金额: $ 21.14万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-07 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054215
• 关键词: Acute; Adverse event; Ammonia; Animals; Anti-Infective Agents; Ascites; Bile Acids; Bioinformatics; Biological Assay; Biological Markers; Brain; Cardiovascular Diseases; Cessation of life; Chronic; Cirrhosis; Clinical; Clinical Research; Cognition; Cognitive; Derivation procedure; Development; Diagnosis; Disease Progression; Enrollment; Failure; Feces; Functional disorder; Future; Hepatic Encephalopathy; Human Microbiome; Impaired cognition; Infection; Intervention; Knowledge; Life; Liver Cirrhosis; Liver Failure; Measures; Medical center; Metabolic syndrome; Metabolism; Microbiology; Molecular; Morbidity - disease rate; Obesity; Outcome; Paper; Pathogenicity; Patients; Pharmaceutical Preparations; Phenotype; Play; Recovery; Research; Role; Sampling; Serum; Site; Syndrome; Techniques; Time; Translational Research; Transplant Recipients; Transplantation; Transplanted Liver Complication; United States; Universities; Validation; Virginia; bacterial resistance; brain dysfunction; chronic liver disease; clinical predictors; cognitive function; cognitive recovery; cohort; computerized; disability; gut microbes; gut microbiota; gut-liver axis; health related quality of life; improved outcome; insight; liver transplantation; metabolomics; microbial; microbiome; microbiome research; microbiota; mortality; multi-drug resistant pathogen; outcome prediction; post-transplant; precision medicine; predictive modeling; prevent; programs; prospective; recruit; therapy design; translational study; transplant centers; trimethylamine

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.

肝硬化是发病率和死亡率的主要原因，疾病进展与 改变肠道微生物的组成和功能。肝硬化唯一可靠的治疗方法是肝脏 移植（LT）。然而，相当大比例的LT后患者发展为多药耐药， 微生物（MDRO），认知障碍和代谢综合征，这可能是生命- 威胁并导致长期残疾或LT前功能的不完全恢复。 此外，使用目前可用的生物标志物，尚不清楚哪些患者会发生这些 LT后的不良事件，有一些证据表明，改变肠道微生物群发挥作用， 重要的作用这一提议代表了使用LT前微生物调节的第一步 在预防LT后并发症方面的中心假设：肠道微生物组成 和功能可以成功预测移植后的结果。 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定殖预测移植后感染， 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 肝移植后认知功能恢复 本研究将分为2部分：第1部分将使用已从150 LT中收集的纵向样本 两个中心的接收者。第2部分将在每个研究中心再入组50例患者，以验证 部分1.粪便微生物群组成（16 srRNA测序的多样性，相对丰度， 潜在的致病和有益分类群，以及MDRO的特异性分子测定 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技术）和代谢综合征将在 移植前微生物评估将用于预测这些结果 独立于已经使用生物信息学验证的临床预测因子。这将有助于指导 未来的精准医学基于微生物群的研究，在辅助LT患者中进行。 VCU和CUIMC的CTSA与具有长期跟踪记录的领先LT中心相关 肝硬化、肝移植、微生物群和认知方面的临床和转化研究。两 各中心将在招募和分析方面平等合作。本方案符合PAR-19-100 通过专注于精准医学和人类微生物组的转化研究。