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

基本信息

批准号：
10231248
负责人：
Jasmohan S Bajaj
金额：
$ 23.62万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-07 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231248
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

项目摘要

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.

肝硬化是发病和死亡的主要原因，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，相当一部分 LT 后患者出现多重耐药性有机体（MDRO）、认知障碍和代谢综合征，这些可能会影响生命威胁并导致长期残疾或 LT 前功能恢复不完全。此外，使用目前可用的生物标志物，尚不清楚哪些患者会出现这些症状 LT 后不良事件，并且有一些证据表明肠道微生物群的改变起着重要作用重要作用。该提案代表了使用 LT 前微生物调节的第一步预防 LT 后并发症的中心假设是：肠道微生物组成肝移植前的功能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：目标 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移植过程中的作用肝移植后认知恢复该研究将分为 2 部分：第 1 部分将利用已从 150 LT 中收集的纵向样本来自两个中心的接收者。第 2 部分将在每个中心再招募 50 名患者来验证研究结果第 1 部分. 粪便微生物群组成（16srRNA 测序，了解多样性、相对丰度潜在致病和有益类群，以及 MDRO 的特定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技术）和代谢综合征将 LT 后诊断。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基于微生物群的精准医学研究可预测 LT 患者。 VCU 和 CUIMC 的 CTSA 与拥有长期记录的领先 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。两个都中心将在招募和分析方面平等合作。该提案符合 PAR-19-100 通过关注人类微生物组的精准医学和转化研究。

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Three Villages of Hepatic Encephalopathy.

肝性脑病三村。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Bajaj; Jasmohan S
通讯作者：
Jasmohan S

Bowel Movement Frequency Is Not Linked With Cognitive Function in Cirrhosis.

肝硬化患者的排便频率与认知功能无关。

DOI：
发表时间：
2022-04
期刊：
影响因子：
0
作者：
Duong, Nikki;Reuter, Bradley;Saraireh, Hamzeh;Nadhem, Omar;Acharya, Chathur;Fagan, Andrew;Hassouneh, Ramzi;Bajaj, Jasmohan S
通讯作者：
Bajaj, Jasmohan S

Multiple bacterial virulence factors focused on adherence and biofilm formation associate with outcomes in cirrhosis.

多种细菌毒力因素集中于粘附和生物膜形成，与肝硬化的结果相关。

DOI：
发表时间：
2021-01
期刊：
影响因子：
12.2
作者：
Bajaj, Jasmohan S;Shamsaddini, Amirhossein;Acharya, Chathur;Fagan, Andrew;Sikaroodi, Masoumeh;Gavis, Edith;McGeorge, Sara;Khoruts, Alexander;Fuchs, Michael;Sterling, Richard K;Lee, Hannah;Gillevet, Patrick M
通讯作者：
Gillevet, Patrick M

Impact of bacterial infections and spontaneous bacterial peritonitis prophylaxis on phage-bacterial dynamics in cirrhosis.

细菌感染和自发性细菌性腹膜炎预防对肝硬化噬菌体-细菌动态的影响。

DOI：
发表时间：
2022-12
期刊：
影响因子：
0
作者：
Bajaj, Jasmohan S;Rodriguez, Marcela Peňa;Fagan, Andrew;McGeorge, Sara;Sterling, Richard K;Lee, Hannah;Luketic, Velimir;Fuchs, Michael;Davis, Brian C;Sikaroodi, Masoumeh;Gillevet, Patrick M
通讯作者：
Gillevet, Patrick M

Chronic Liver Diseases and the Microbiome-Translating Our Knowledge of Gut Microbiota to Management of Chronic Liver Disease.

慢性肝病和微生物群——将我们对肠道微生物群的知识转化为慢性肝病的管理。