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

应聘者描述(申请人提供)：应聘者是一名临床营养学家和年轻的研究人员，致力于发展学术研究生涯，专注于识别和表征乙醇引起的肠道生物失调的分子机制，这是导致乙醇引起的器官损伤的原因。在临床营养学方面有很强的背景，对肠道微生物区系感兴趣，候选人在使用不同的小鼠模型方面发展了特殊的专业知识，这些模型代表了肠道微生物失调，在临床实践中看到，以测试特定的 肠和肝损伤的发展过程中涉及的假说。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方面的重要作用。这位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。本提案中描述的职业发展计划概述了为期两年的指导性培训，其中包括技术技能培训以及旨在促进 向独立的成功过渡。还概述了一个3年期的自主科学和职业发展计划，该计划是在一个医学中心下属的竞争性学术研究机构成功招聘助理教授职位后进行的。候选人的导师拥有卓越的科学生产力和成功的指导记录，可以为候选人在克利夫兰诊所勒纳研究所的实验室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之而来的经济负担有关。尽管在了解ALD的诱发、进展和解决机制方面取得了长足的进步，但这些发现尚未导致针对ALD的病因而不是症状的治疗策略的改进。肠道微生物区系受到慢性酒精摄入的干扰，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。之前针对乙醇诱导的肠道生物失调的研究工作是有希望的，但不是持久的，可能是因为他们没有针对已知的因乙醇消费而枯竭的丁酸盐产生细菌。由于丁酸盐在维持肠道健康中的重要作用，我们推测，操纵宿主的肠道微生物区系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。在三个特定的目标中，我们将测试一种旨在增强丁酸产生菌并将发酵副产物交叉喂养到丁酸中的合生元在拯救乙醇引起的小鼠和人类的肠道和肝脏损伤方面的效果，并确定丁酸盐在乙醇暴露期间对肠道细胞健康的保护机制。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引起的肠道代谢失调和随后的器官损伤。

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.