In vivo Wireless Sensors for Gut Redox Monitoring to Understand Host and Microbe Physiology

项目摘要 非传染性疾病，包括肥胖症、2型糖尿病、炎症性肠病 （IBD）和癌症对全球经济和生活质量造成了惊人的负担。越来越多的证据 许多非传染性疾病，特别是胃肠道疾病， 微生物组和宿主免疫系统。将微生物、生活方式和非传染性疾病联系起来的一个主要假设是， 不健康的饮食和抗生素的使用选择了促进肠道化学氧化的微生物。该氧化 破坏宿主和微生物组的稳态，导致不适当的和自我强化的免疫和代谢 失调然而，定量假设检验目前是不可能的，因为研究人员缺乏 这是直接测试模型生物（大鼠和小鼠）肠道氧化的必要工具。现有数据具有相关性，或 依赖于不精确的措施（如基因消融和竞争实验），阻止实验研究 微生物群的变化是如何导致疾病的 我们的建议概述了一个平台的发展，实时自动测量在体内 啮齿动物的肠道氧化。该平台包括可植入/可摄入的氧化还原电位（ORP） 传感器和可穿戴数据收集设备。ORP是化学环境的综合量度 失去或获得电子的倾向，或者换句话说，它倾向于被氧化或还原。最近的工作已经 将ORP传感应用于来自小鼠和人类的粪便样品，证明由于抗生素引起的ORP变化 急性营养不良。虽然这些结果强烈暗示了肠道氧化的致病作用， 在病理生理学中，粪便ORP与肠道生理条件的相关性尚不清楚。 我们提出了两个主要目标，我们的工作，以解决现有的离体技术的限制，并促进 更好地理解肠道氧化还原病理生理学：1）开发技术，使长期自动体内 清醒啮齿动物中的ORP测量，2）确定微生物组的变化如何影响体内ORP，以及 确定肠道氧化还原状态的特定化学相关物。在实现这些目标的过程中，我们将使用新的超声波 唤醒和电流耦合技术，以克服器件小型化的根本挑战 用于植入啮齿动物胃肠道，对动物运动和内部器械运动具有鲁棒性，以及 数据收集自动化，用于实际的、可扩展的实验。 这项工作是重要的，因为新的工具，以确定即将发生的变化，在肠道氧化还原状态是 可能通过测试该领域的一个关键新兴假设来推进基础科学。同时， 这项研究所需的技术进步使得探索用于诊断的氧化还原模式成为可能， 与氧化还原失衡相关的疾病的治疗策略，为 翻译工作。

PROJECT SUMMARY Non-communicable diseases (NCDs) including obesity, type 2 diabetes, inflammatory bowel diseases (IBDs), and cancer impose a staggering burden on global economies and quality of life. Evidence is mounting that many NCDs – particularly those of the gastrointestinal tract – are influenced by the interplay of the microbiome and the host immune system. A leading hypothesis connecting microbes, lifestyle, and NCDs is that an unhealthy diet and antibiotic use select for microbes that promote chemical oxidation in the gut. This oxidation disrupts host and microbiome homeostasis leading to inappropriate, and self-reinforcing, immune and metabolic dysregulation. However, quantitative hypothesis testing is currently impossible because researchers lack the necessary tools to directly test gut oxidation in model organisms (rats and mice). Existing data is correlative or relies on imprecise measures (e.g. genetic ablation and competition experiments) preventing experimental study of how changes in the microbiota lead to disease. Our proposal outlines the development of a platform for real-time automated measurement of in vivo gut oxidation in rodents. The platform comprises implantable / ingestible Oxidation Reduction Potential (ORP) sensors and a wearable data collection device. ORP is an integrated measure of a chemical environment’s propensity to lose or gain electrons, or in other words its tendency to get oxidized or reduced. Recent work has applied ORP sensing to fecal samples from mice and humans, demonstrating ORP changes due to antibiotics and acute malnutrition. While these results are strongly suggesting of a causative role for gut oxidation in pathophysiology, the relevance of fecal ORP to gut physiological conditions is unclear. We propose two major aims for our work to address existing ex vivo technique limitations, and promote better understanding of gut redox pathophysiology: 1) Develop technology to enable long-term automated in vivo ORP measurements in awake rodents, 2) determine how changes to the microbiome affect in vivo ORP, and identify specific chemical correlates of the gut redox state. In achieving these goals, we will use novel ultrasound wake-up and galvanic coupling technologies to overcome the fundamental challenges of device miniaturization for implantation in the rodent GI-tract, robustness against animal movement and internal device movement, and data collection automation for practical, scalable experiments. This work is significant because new tools to identify impending changes in redox status in the gut are likely to advance basic science by testing a critical emerging hypothesis in the field. Simultaneously, the technological advances required for this study make it possible to explore redox patterns for diagnosis, and strategies for treatment, of diseases associated with redox imbalance, providing significant opportunities for translational work.