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

• 批准号: 9508042
• 负责人: Gail Ann Cresci
• 金额: $ 24.9万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9508042
• 关键词: Acetaldehyde; Acetates; Actinobacteria class; Acute; Adverse effects; Alcohol abuse; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholism; Alpha Cell; 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; Impairment; 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; Pathogenicity; Patients; Permeability; Positioning Attribute; Probiotics; Process; Production; Productivity; Propionates; Proteobacteria; Recruitment Activity; 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; molecular targeted therapies; mortality; mouse model; novel; novel therapeutics; prebiotics; problem drinker; professor; programs; public health relevance; receptor; skills training; soluble fiber; stem

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师和年轻的研究者，致力于发展学术研究事业，重点是识别和表征乙醇诱导的肠道生态失调导致乙醇诱导的器官损伤的分子机制。凭借在临床营养和肠道微生物群的兴趣强大的背景下，候选人已经开发了特殊的专业知识，在使用不同的小鼠模型，代表肠道生态失调，如临床实践中所见，以测试特定的 肠和肝损伤的发展中涉及的假说。这些模型系统的使用揭示了发酵副产物丁酸在保护肠道健康中的重要作用。候选人最近和目前的工作为她提供了发展自己的研究计划并开始向独立过渡的机会。本建议书中描述的职业发展计划概述了2年的辅导培训，其中包括技术技能培训以及旨在促进 成功过渡到独立。还概述了在成功受聘为医学中心附属的竞争性学术研究机构的助理教授职位后，为期3年的独立科学和职业发展计划。候选人的导师具有出色的科学生产力和成功的指导的良好记录，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）与显著的发病率和死亡率以及随后的经济负担相关。虽然在理解ALD诱导、进展和消退的机制方面取得了很大进展，但这些发现尚未导致针对ALD原因而不是症状的改进的治疗策略。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ALD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诱导的肠道和肝脏损伤方面的重要性。先前针对乙醇诱导的肠道生态失调的研究工作是有希望的，但并不持久，可能是因为他们没有针对已知会被乙醇消耗耗尽的丁酸盐产生细菌。由于丁酸盐在维持肠道健康方面的重要作用，我们假设操纵宿主的肠道微生物群以提高丁酸盐产量将促进肠道生态失调的持久纠正，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，旨在增强丁酸生产细菌和交叉饲料发酵副产物转化为丁酸盐，在小鼠和人类中挽救乙醇诱导的肠和肝损伤，并确定乙醇暴露期间丁酸盐保护肠细胞健康的机制。我们期望这些目标的结果将提供未来的分子靶点和新的治疗方法来治疗乙醇诱导的肠道生态失调和随后的器官损伤。