Targeting ethanol-induced gut dysbiosis with synbiotics to treat alcoholic liver

用合生元治疗乙醇引起的肠道菌群失调来治疗酒精肝

基本信息

批准号：
9069670
负责人：
Gail Ann Cresci
金额：
$ 13.56万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9069670
关键词：
Acetaldehyde Acetates Actinobacteria class Acute Adverse effects Alcohol abuse Alcohol consumption Alcohol-Induced Disorders Alcoholic Hepatitis Alcoholic Liver Diseases Alcoholism Antibiotics Bacteria Bacteroides Bacteroidetes Biological Models Biological Process Butyrates Cell Culture System Cells Chronic Clinic Clinical Clinical Nutrition Clostridium Clostridium difficile Cytoprotection Development Development Plans Economic Burden Electrolytes Endotoxemia Environment Epithelium Ethanol Extrahepatic Fermentation Fiber Future Gene Expression Gene Expression Regulation Gram-Negative Bacteria Health Homeostasis Human Immune Inflammatory Injury Institution Intestines Laboratories Lead Liver Mediator of activation protein Medical Medical center Mentors Mentorship Methods Molecular Molecular Target Morbidity - disease rate Mus Nutritional Support Nutritionist Organ Pathogenesis Patients Permeability Positioning Attribute Probiotics Process Production Productivity Propionates Proteobacteria Research Research Institute Research Personnel Role Solid Source Structure Supplementation Symptoms Technical Expertise Testing Therapeutic Therapeutic Effect Tight Junctions Tissues Training United States Volatile Fatty Acids Water Work absorption alcohol exposure career career development chronic alcohol ingestion clinical practice design efficacy testing energy balance fecal transplantation feeding gut microbiota improved in vivo Model interest liver injury microbial mortality mouse model novel novel therapeutics prebiotics problem drinker professor programs receptor skills training soluble fiber stem

项目摘要

DESCRIPTION (provided by applicant): The Candidate is a clinical nutritionist and young investigator dedicated to developing an academic research career focused on the identification and characterization of molecular mechanisms stemming from ethanol induced gut dysbiosis which contribute to ethanol-induced organ injury. With a strong background in clinical nutrition and interest in the gut microbiota, the candidate has developed particular expertise in the use of different mouse models that represent gut dysbiosis, as seen in clinical practice, to test specific hypotheses involved in development of intestinal and liver injury. Use of these model systems has revealed an important role for the fermentation byproduct butyrate in protecting intestinal health. The Candidate's recent and current work has provided her with the opportunity to develop her own research program and begin her transition to independence. The Career Development plan described in this proposal outlines 2-years of mentored training which includes technical skills training in addition to career development activities designed to promote the successful transition to independence. A 3-year program of independent scientific and career development after successful recruitment as an Assistant Professor position to a competitive academic research institution affiliated with a medical center is also outlined. The Candidate's Mentor has a proven track-record of excellent scientific productivity and successful mentorship and can provide the Candidate with a solid research environment in her lab at the Lerner Research Institute at the Cleveland Clinic. Research plan: Alcoholic liver disease (ALD) is associated with significant morbidity and mortality and subsequent economic burden. Although great strides have been made in understanding the mechanisms by which ALD is induced, progresses, and resolves, these discoveries have not yet led to improved therapeutic strategies which target the cause rather than symptoms of ALD. The gut microbiota is disturbed by chronic ethanol consumption, which is associated with altered gut permeability, endotoxemia and ALD. Our studies demonstrate the importance of butyrate in protecting gut health and dampening ethanol induced intestine and liver injury. Prior research efforts targeting ethanol induced gut dysbiosis are promising, but not lasting, likely because they did not target the butyrate-producing bacteria known to be depleted by ethanol consumption. Due to the vital role of butyrate in maintaining gut health, we hypothesize that manipulating the host's gut microbiota to enhance butyrate yield will promote lasting correction of gut dysbiosis and normalize intestinal and liver abnormalities caused by chronic ethanol exposure. In three specific aims, we will test the efficacy of a synbiotic, designed to enhance butyrate-producing bacteria and cross-feed fermentation byproducts into butyrate, in rescuing ethanol induced intestine and liver injury in both mice and humans, and determine the mechanisms of butyrate protection in intestinal cell health during ethanol exposure. We expect the results of these aims will provide future molecular targets and novel therapies to treat ethanol induced gut dysbiosis and subsequent organ injury.

描述（由申请人提供）：候选人是一名临床营养学家和年轻研究者，致力于发展学术研究生涯，重点是识别和表征乙醇引起的肠道菌群失调所产生的分子机制，从而导致乙醇引起的器官损伤。凭借在临床营养方面的深厚背景和对肠道微生物群的兴趣，该候选人在使用代表肠道菌群失调的不同小鼠模型（如临床实践中所见）来测试特定的肠道菌群方面积累了特殊的专业知识。涉及肠道和肝脏损伤发展的假设。这些模型系统的使用揭示了发酵副产物丁酸盐在保护肠道健康方面的重要作用。候选人最近和当前的工作为她提供了开发自己的研究计划并开始向独立过渡的机会。本提案中描述的职业发展计划概述了为期 2 年的指导培训，其中包括技术技能培训以及旨在促进成功过渡到独立。还概述了在成功招聘到附属于医疗中心的竞争性学术研究机构担任助理教授职位后的 3 年独立科学和职业发展计划。候选人的导师拥有卓越的科学生产力和成功指导的良好记录，可以在克利夫兰诊所勒纳研究所的实验室为候选人提供坚实的研究环境。研究计划：酒精性肝病（ALD）与显着的发病率和死亡率以及随后的经济负担相关。尽管在了解 ALD 的诱发、进展和消退机制方面已经取得了长足的进步，但这些发现尚未带来针对 ALD 病因而非症状的改进治疗策略。肠道微生物群受到慢性乙醇消耗的干扰，这与肠道通透性改变、内毒素血症和酒精性肝病有关。我们的研究证明了丁酸盐在保护肠道健康和抑制乙醇引起的肠道和肝脏损伤方面的重要性。先前针对乙醇引起的肠道菌群失调的研究工作很有希望，但并不持久，可能是因为它们没有针对已知会因乙醇消耗而消耗的丁酸产生细菌。由于丁酸盐在维持肠道健康中的重要作用，我们假设，操纵宿主肠道微生物群以提高丁酸盐产量将促进肠道菌群失调的持久纠正，并使慢性乙醇暴露引起的肠道和肝脏异常正常化。在三个具体目标中，我们将测试合生元的功效，该合生元旨在增强丁酸产生细菌并将发酵副产物交叉供给丁酸，以挽救乙醇引起的小鼠和人类肠道和肝脏损伤，并确定丁酸的机制在乙醇暴露期间保护肠道细胞健康。我们预计这些目标的结果将为治疗乙醇引起的肠道菌群失调和随后的器官损伤提供未来的分子靶点和新疗法。