Probing Microbe-Material Interactions towards In situ Gut Microbiome Engineering

第1部分：非技术概述人体有数万亿细菌、真菌、原生动物和病毒定植；统称为微生物组。细菌微生物群，特别是在人类胃肠道中，在营养代谢、免疫训练和预防感染方面发挥着关键作用。然而，尽管细菌微生物群与人类健康之间存在明确的联系，但确定每种细菌在人类生理和疾病中所起的功能作用仍然很困难。这主要是由于缺乏可访问的工具，使研究人员能够仔细研究和操纵肠道内的微生物组组成。该项目将研究微生物如何与生物材料相互作用，以改进微生物组工程新材料工具的设计。为了实现这一目标，该团队将探索肠道微生物与基于碳水化合物和肽的生物材料的相互作用，确定这些微生物材料的相互作用如何改变微生物群落，并利用所获得的见解来设计可以控制肠道微生物生态的新生物材料。这些研究的发现将使我们更深入地了解胃肠道中的微生物如何与外来物质相互作用，并在此过程中产生变革性的新生物材料技术，可用于更好地研究、诊断和治疗肠道感染、紊乱和疾病。该研究项目与宾夕法尼亚州立大学工业生物技术卓越中心和CSL Behring发酵设施的整合，将共同教育学生生产微生物衍生产品，将在材料科学、糖生物学和微生物生物技术等新兴领域吸引和培养一支现代化和多样化的STEM劳动力。本提案的总体目标是建立一个合理的设计框架，用于开发生物材料，从而实现肠道微生物群生态的精确原位工程。为了实现这一目标，研究小组将研究益生菌微生物与碳水化合物和肽基生物材料的序列依赖性相互作用，并阐明这些微生物-物质相互作用如何塑造肠道微生物群落。这项工作的基础是使用由PI实验室最近开发的碳水化合物肽生物胶囊，它可以在接触时杀死病原体，并用确定的益生菌有效载荷取代它们。以这些材料为研究平台，本项目将研究多糖的组成和结构如何影响微生物生理学，阐明控制多肽材料涂层杀菌性能的结构-活性关系，并确定控制生物胶囊递送到不同肠道隔间的物理化学特性。从这项工作中获得的知识将推动生物材料的发展，以探测和操纵复杂胃肠道中的微生物生态。此外，这项工作可能会确定生物材料在操纵微生物组方面所起的作用，以及它们在推进针对肠道疾病的新型定制细菌疗法设计方面的潜力。该研究项目将与宾夕法尼亚州立大学工业生物技术卓越中心整合，为参与的学生提供前所未有的材料科学，糖生物学和微生物学界面的培训机会。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

PART 1: NON-TECHNICAL SUMMARYThe human body is colonized by trillions of bacteria, fungi, protozoa and viruses; collectively referred to as the microbiome. The bacterial microbiome, particularly in the human gastrointenstinal tract, play critical roles in nutrient metabolism, immune training and prevention of infections. Yet, despite a clear link between the bacterial microbiome and human health, it remains difficult to determine the functional role each bacteria plays in human physiology and disease. This is largely due to a lack of accessible tools that allow researchers to carefully study and manipulate the microbiome composition within the gut. This project will study how microbes interact with biologic materials to improve the design of new materials-enabled tools for microbiome engineering. To achieve this, the team will explore the interactions of gut microbes with carbohydrate- and peptide-based biomaterials, determine how these microbe-material interactions alter microbiome communities, and utilize the insights gained to design new biomaterials that can control gut microbiome ecology. Findings from these studies will lead to a deeper understanding of how the microbes in our gastrointestinal tract interact with foreign materials, and in doing so yield transformative new biomaterial technologies that can be used to better study, diagnose and treat gut infections, disorders and diseases. Integration of this research program with the Penn State Center of Excellence in Industrial Biotechnology and the CSL Behring Fermentation Facility, which together educate students in the production of microbial-derived products, will engage and train a modern and diverse STEM workforce in emerging areas of materials science, glycobiology and microbial biotechnology.PART 2: TECHNICAL SUMMARYThe overarching goal of this proposal is to establish a rational design framework for the development of biomaterials that can enable precision, in situ engineering of gut microbiome ecology. To achieve this, the research team will investigate the sequence-dependent interactions of probiotic microbes with carbohydrate- and peptide-based biomaterials, and elucidate how these microbe-material interactions shape the gut microbiome community. Fundamental to this work is the use of carbohydrate-peptide biocapsules, recently developed by the PI’s lab, that can kill pathogens on contact and replace them with defined probiotic payloads. Using these materials as research platforms, this project will investigate how glycan composition and structure impacts microbial physiology, elucidate structure-activity relationships governing the bactericidal properties of polypeptide material coatings, and identify the physicochemical properties controlling the delivery of biocapsules to various gut compartments. Knowledge gained from this work will advance the development of biomaterials to probe and manipulate microbial ecology in the complex gastrointenstinal tract. Further, this work may identify the role biomaterials can play in manipulating the microbiome and their potential in advancing the design of new tailored bacteriotherapies against gut disorders. This research program will be integrated with the Penn State Center of Excellence in Industrial Biotechnology to offer unprecedented training opportunities for participating students at the interface of materials science, glycobiology and microbiology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.