Metabolism, interactions, and toxicology of microbiome-derived endogenous toxins

背景：肠道细菌来源的毒素（如对甲酚、硫酸吲哚酚等）是一种天然化合物，当肾脏衰竭时，可在人体内积累到相对高浓度。这些毒素会导致多种疾病，如肾衰竭、心脏病和肝功能衰竭；但具体行动仍不得而知。这些毒素主要在肝脏中分解，在那里它们会干扰身体处理其他生物活性物质（如激素）的方式。这些毒素的分解物质(即。“代谢物”)本身也是有毒的。我的研究计划的长期目标是确定身体如何分解这些毒素，以及这些毒素如何干扰其他天然物质产生毒性。在一组肠道毒素中，我实验室的初步观察表明，“对甲酚”的毒性最大；因此，这个化合物将是我短期的重点。目的：本研究计划将解决3个具体目标：1)确定人类肝脏如何分解对甲酚；2)描述对甲酚如何影响人体处理其他物质的方式；3)确定对甲酚或其分解产物如何引起肝损伤。同样的方法将用于其他毒素作为我整体计划的一部分。科学方法：我的实验室将使用各种前沿方法来研究对甲酚。对于目标1，我们将使用肝脏制剂（例如人肝微粒体）来找出哪些特定的酶（即人体器官中的催化剂）负责分解对甲酚。对于目标2，我们将首先使用肝脏制剂来确定对甲酚是否会影响酶分解其他天然物质的方式；然后，我们将可视化啮齿动物之间的相互作用，以更好地了解相互作用。对于目标3，我们将使用培养皿培养的肝细胞来确定对甲酚或其分解产物如何产生毒性。新颖性和影响：从本研究项目中获得的知识将为肠道细菌衍生毒素的作用提供重要的见解。这些信息对基础科学的研究人员和学生很有用。本研究项目中开发的方法也将用于测试除对甲酚以外的其他毒素（例如硫酸吲哚酚）。该研究项目将为加拿大大学培养高素质的研究生。

Background: Gut bacteria-derived toxins (e.g. p-cresol, indoxyl sulfate, and others) are natural compounds that can accumulate to relatively high concentrations in the human body when the kidneys fail. These toxins are responsible for a variety of conditions such as kidney failure, heart disease, and liver failure; but the exact actions remain unknown. These toxins are primarily broken down in the liver where they can interfere with how the body handles other bioactive substances (e.g. hormones). The broken-down substances of these toxins (i.e. "metabolites") are also toxic themselves. The long-term goal of my research program is to determine how the body breaks down these toxins and how these toxins interfere with other natural substances to generate toxicity. In a panel of gut-derived toxins, initial observations in my laboratory showed that "p-cresol" was the most toxic; therefore, this compound will be my short term focus. Objectives: This research program will address 3 specific goals: 1) to determine how the human liver breaks down p-cresol; 2) to characterize how p-cresol affects the way the body handles other substances; and 3) to determine how p-cresol or its breakdown products cause liver injury. The same methods will be used for additional toxins as part of my overall program. Scientific Approach: My lab will use a variety of cutting-edge methods to study p-cresol. For objective 1, we will use liver preparations (e.g. human liver microsomes) to figure out which specific enzymes (i.e. catalysts in human organs) are responsible for breaking down p-cresol. For objective 2, we will first use liver preparations to determine if p-cresol can influence how enzymes break down other natural substances; then, we will visualize the interaction in rodents to get a better sense of interaction. For objective 3, we will use liver cells cultured in dishes to determine how p-cresol or its break-down products can generate toxicity. Novelty and Impact: The knowledge gained from this research program will provide important insights into the actions of gut bacteria-derived toxins. This information will be useful for researchers and students in basic science. The methods developed in this research program will also be used to test additional toxins other than p-cresol (e.g. indoxyl sulfate). This research program will help train highly qualified graduate students for Canadian universities.