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

点击翻译按钮获取中文摘要

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.