Collaborative Research: Identification of Immunomodulatory Microbiota Metabolites

本研究的总体目标是确定肠道微生物群产生的影响肥胖脂肪组织炎症的生物活性代谢物。人类胃肠道（GI）是由数以万亿计的细菌定植的，这些细菌属于约1000种，统称为微生物群。微生物群组成和/或功能的改变（生态失调）与越来越多的代谢紊乱有关，包括肥胖。脂肪组织的慢性、低度炎症与肥胖密切相关，也是胰岛素抵抗和代谢综合征发展的基础。越来越多的证据表明，肠道生态失调导致肠系膜脂肪组织炎症。然而，分子介质及其作用机制仍然知之甚少。这项工作假设微生物衍生的代谢物是宿主脂肪组织炎症的重要调节剂。鉴定这些微生物群的代谢物非常困难，因为肠道中的大多数共生细菌特征不明显，其中许多细菌不能在培养物中生长。由于微生物能够进行宿主无法进行的代谢反应，并且一个物种合成的代谢物可以被另一个物种进一步修饰，因此微生物群可获得的生物转化空间是巨大的。为了克服这些挑战，本项目研究了一种新的生物信息学-代谢组学方法，可以集中和定量地探索肠道微生物群代谢物。生物信息学和代谢组学分析的结果将用于为微生物代谢产物影响肥胖脂肪组织炎症机制的体外实验建立生理学基础。该项目的预期结果是确定特定的代谢物，这些代谢物可以明确地来源于肠道微生物群，并存在于宿主脂肪组织中，并确定它们在肥胖脂肪组织炎症背景下的免疫调节特性。本研究的新颖之处在于，很少有研究探索微生物群代谢物在肥胖症慢性体脂炎症发展中的作用。拟议的工作将确定和量化细菌代谢物，其水平可能在肥胖条件下改变并影响炎症状态。这项研究在方法论和发现方面都具有变革潜力。拟议的实验可能为一种通用的方法铺平道路，用于测量自然存在于体内的生物活性化学物质，但这些化学物质是由细菌而不是人体产生的。具有抗炎特性的天然细菌代谢物的发现可能会为作为炎症性疾病的肥胖带来新的、安全的治疗方式。拟议的项目是高度跨学科的，并提供了一个独特的机会，培养学生在工程和生命科学的几个不同领域的接口前沿研究。为了给代表性不足的少数族裔创造研究机会，该提案包括一项联合暑期实习计划。每年将招募两名来自德州农工大学的少数族裔学生到塔夫茨大学首席研究员的实验室实习。此外，研究人员将通过招募本科生参与拟议工作的开放式项目，并将方法和发现纳入代谢工程和系统生物学的现有课程，将拟议的研究整合到各自机构的持续教育和推广工作中。由于该项目的跨学科性质，该奖项由CBET部门的生物技术、生化和生物质工程项目获得，由分子和细胞生物学部门的系统和合成生物学项目共同资助。

Lee/Jayaraman1264502/1264526 The overall goal of this research is to identify bioactive metabolites generated by the gut microbiota that impact the inflammation of adipose tissue in obesity. The human gastrointestinal (GI) tract is colonized by hundreds of trillions bacteria belonging to ~1,000 species that are collectively termed the microbiota. Alterations in the microbiota composition and/or function (dysbiosis) are correlated to a growing number of metabolic disorders, including obesity. Chronic, low-grade inflammation of adipose tissue is robustly associated with obesity, and also underlies the development of insulin resistance and the metabolic syndrome. There is growing evidence that gut dysbiosis leads to inflammation in mesenteric adipose tissue. However, the molecular mediators and mechanisms of their actions remain poorly understood. This work hypothesizes that microbiota-derived metabolites are important modulators of host adipose tissue inflammation. Identifying these microbiota metabolites has been extremely difficult, because a majority of the commensal bacteria in the gut are poorly characterized and many of these bacteria cannot be grown in culture. As microbes are capable of performing metabolic reactions not available to the host, and metabolites synthesized by one species can be further modified by another species, the biotransformation space accessible to the microbiota is vast. To overcome these challenges, this project investigates a novel bioinformatics-metabolomics approach enabling focused and quantitative exploration of gut microbiota metabolites. The results of the bioinformatics and metabolomics analyses will be used to establish a physiological basis for in vitro experiments on the mechanisms whereby microbiota metabolites influence adipose tissue inflammation in obesity. The expected outcome of this project is to identify specific metabolites that can be unequivocally sourced to the gut microbiota and are present in host adipose tissue, and to determine their immunomodulatory properties in the context of adipose tissue inflammation in obesity. Broader Impact This research is novel in that few studies have explored the role for microbiota metabolites in the development of chronic body fat inflammation in obesity. The proposed work will identify and quantify bacterial metabolites whose levels may be altered under conditions of obesity and influence the state of inflammation. This research has transformative potential, both methodologically as well as discovery-wise. The proposed experiments could pave the way for a general methodology for measuring bioactive chemicals that are naturally present in the body, but are produced by bacteria, rather than the body. The discovery of naturally resident bacterial metabolites with anti-inflammatory properties could lead to new, safe treatment modalities for obesity as an inflammatory disease.The proposed project is highly interdisciplinary, and provides a unique opportunity to train students in cutting-edge research at the interface of several different fields in engineering and life science. To create research opportunities for underrepresented minorities, the proposal includes a plan for a joint summer internship program. Two minority students from Texas A&M will be recruited each year to intern in the lead investigator's laboratory at Tufts. In addition, the investigators will integrate the proposed research into ongoing educational and outreach efforts at their respective institutions by recruiting undergraduate students to participate in open-ended projects from the proposed work and incorporating the methodologies and findings into existing courses in Metabolic Engineering and Systems Biology.Due to the interdisciplinary nature of the project, this award by the Biotechnology, Biochemical, and Biomass Engineering Program of the CBET Division is co-funded by the Systems and Synthetic Biology Program of the Division of Molecular and Cellular Biology.