From here to eternity: gut microbial response to drug therapy and inflammation

摘要 基因组革命给我们带来了“财富的尴尬” 疾病中肠道微生物群落的组成，但我们仍然远未了解微生物如何 基因和途径影响宿主健康。虽然大量研究表明微生物组与 由于疾病状态，我们对响应疾病相关扰动的微生物基因知之甚少，例如 如炎症或药物治疗，以及这些微生物反应如何导致疾病和药物反应。 缺乏对微生物基因如何反应和对疾病相关扰动的贡献的了解限制了我们的研究 合理设计微生物组靶向疗法的能力，例如粪便微生物群移植、活体微生物组移植 生物治疗药物和小分子微生物抑制剂。我实验室的长期目标是了解如何 微生物组有助于解决全身炎症。 R35 NIGMS 的总体目标 MIRA 拨款用于支持我的研究项目，重点是破译微生物遗传 对炎症和药物治疗反应的决定因素以及它们如何影响宿主。有了支持 在 R35 MIRA 拨款中，我的目标是在未来 5 年内在十字路口建立一个独特且富有成效的利基市场 通过调查以下关键问题来研究微生物学、遗传学和全身炎症性疾病/ 主题：(1) 哪些微生物基因对于响应宿主炎症和药物治疗很重要，(2) 这些微生物基因随后如何导致宿主炎症，以及（3）靶向特定药物是否可以 微生物基因影响宿主炎症环境下肠道微生物生态和进化。拟议的 研究计划旨在通过利用尖端技术和我独特的技术来填补这些知识空白 计算机科学、基因组学、微生物学、临床免疫学和微生物学背景。人类 肠道微生物组“从现在到永恒”与我们同在，但我们才刚刚开始发现体内的强大力量 塑造微生物群落及其进化。这些转变的微生物遗传基础 炎症和药物治疗的研究并不普遍；填补这一基础知识空白将带来回报 未来，通过提高目前正在治疗的患者的治疗策略的功效 炎症性疾病。

ABSTRACT The genomic revolution has provided us with an “embarrassment of riches” with respect to our understanding of the composition of gut microbial communities in disease, but we are still far from understanding how microbial genes and pathways impact host health. While a wealth of studies show that the microbiome is associated with disease states, we know little about the microbial genes that respond to disease-associated perturbations, such as inflammation or drug therapy, and how these microbial responses contribute to disease and drug response. Lack of knowledge of how microbial genes respond and contribute to disease-associated perturbations limits our ability to rationally design microbiome-targeted therapies, such as fecal microbiota transplant, live biotherapeutics, and small molecule microbial inhibitors. My lab’s long-term goal is to understand how the microbiome contributes to the resolution of systemic inflammation. The overall objective of this R35 NIGMS MIRA grant is to support the aspect of my research program focused on deciphering the microbial genetic determinants of responses to inflammation and drug therapy and how these impact the host. With the support of the R35 MIRA grant, over the next 5 years, I aim to establish a unique and productive niche at the intersection of microbiology, genetics, and systemic inflammatory disease by investigating the following key questions / themes: (1) which microbial genes are important for responding to host inflammation and drug treatment, (2) how do these microbial genes subsequently contribute to host inflammation, and (3) can drugs targeting specific microbial genes impact gut microbial ecology and evolution in the setting of host inflammation. The proposed research program seeks to fill these knowledge gaps by harnessing cutting-edge technologies and my unique backgrounds in computer science, genomics, microbiology, clinical immunology, and gnotobiology. The human gut microbiome is with us “from here to eternity” but we are just beginning to uncover the powerful forces in vivo that shape the microbial community and its evolution. The microbial genetic basis of these shifts in the setting of inflammation and drug therapy is not commonly studied; filling this fundamental knowledge gap will pay dividends in the future by improving the efficacy of therapeutic strategies that are currently underway in patients with inflammatory disease.