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 改变肠道微生物组成和功能。肝硬化的唯一可靠治愈方法是肝脏 移植（LT）。但是，很大一部分LT患者会发展出多药耐药性 生物体（MDRO），认知障碍和代谢综合征，可以是生命 威胁并导致长期残疾或前LT功能不完整的恢复。 此外，使用当前可用的生物标志物，尚不清楚哪些患者会开发这些 LT后不良事件，并且有一些证据表明肠道菌群的作用 重要角色。该提案代表了使用Pre-LT微生物调制的第一步 在以中心假设为预防LT后并发症时：肠道微生物组成 肝移植之前的功能可以成功预测移植后结局。 我们将使用以下特定目的研究这一假设： 目标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， 目标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， 目标3：确定移植前肠道微生物组成和功能在 肝移植后认知恢复 该研究将有2个部分：第1部分将利用已经收集的150 lt的纵向样品 两个中心的接收者。第2部分将为每个站点再注册50名患者，以验证从 第1部分。粪便菌群组成（16sRRNA测序多样性，相对丰度 潜在的病原和有益分类单元，以及MDRO的特定分子测定 将进行定殖）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）和代谢综合征将是 诊断后LT。移植前微生物评估将用于预测这些结果 独立于使用生物信息学的已经验证的临床预测指标。这将有助于指导 对预测LT患者的未来精确医学研究。 VCU和CUIMC的CTSA与远程记录的领先LT中心有关 肝硬化，肝移植，微生物群和认知的临床和转化研究。两个都 中心将在招聘和分析方面同样合作。该提案与Par-19-100符合 通过关注人类微生物组的精确医学和翻译研究。