Collaborative Research: Identification of Immunomodulatory Microbiota Metabolites

Lee/Jayaraman 1264502/1264526本研究的总体目标是鉴定由肠道微生物群产生的影响肥胖症脂肪组织炎症的生物活性代谢物。人类胃肠道（GI）由数百万亿种细菌定殖，这些细菌属于约1，000个物种，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（包括肥胖）相关。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生的基础。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产物是宿主脂肪组织炎症的重要调节剂。鉴定这些微生物群代谢物是非常困难的，因为肠道中的大多数肠道细菌的特征很差，而且这些细菌中的许多不能在培养物中生长。由于微生物能够进行宿主不可用的代谢反应，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，该项目研究了一种新的生物信息学-代谢组学方法，能够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关于微生物群代谢物影响肥胖症中脂肪组织炎症的机制的体外实验建立生理学基础。该项目的预期成果是确定可以明确来源于肠道微生物群并存在于宿主脂肪组织中的特定代谢物，并确定其在肥胖症脂肪组织炎症背景下的免疫调节特性。更广泛的影响这项研究是新颖的，因为很少有研究探讨了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发生变化并影响炎症状态。这项研究具有变革的潜力，无论是在方法上还是在发现方面。拟议的实验可以为测量生物活性化学物质的一般方法铺平道路，这些化学物质天然存在于体内，但由细菌而不是身体产生。天然细菌代谢产物的抗炎特性的发现可能会导致新的，安全的治疗肥胖作为一种炎症性疾病的方式。拟议的项目是高度跨学科的，并提供了一个独特的机会，培养学生在尖端研究在工程和生命科学的几个不同领域的接口。为了为代表性不足的少数民族创造研究机会，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克萨斯州A M的少数民族学生在塔夫茨大学的首席研究员实验室实习。此外，研究人员将通过招募本科生参加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，将拟议的研究纳入各自机构正在进行的教育和推广工作。由于该项目的跨学科性质，生物技术，生物化学，CBET部门的生物质工程项目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.