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

描述（由申请人提供）：该候选人是一名临床营养学家和年轻的研究者，致力于发展学术研究事业，专注于乙醇诱导的肠道生态失调的分子机制的鉴定和表征，这有助于乙醇诱导的器官损伤。凭借在临床营养学方面的强大背景和对肠道微生物群的兴趣，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生态失调，如在临床实践中所见，以测试特异性

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.