Bladders and biomes: Environmental compounds as modifiers of microbiomes, metabolomes, and urothelium

膀胱和生物群落：环境化合物作为微生物群、代谢组和尿路上皮的调节剂

• 批准号: 10740296
• 负责人: Vanessa L Hale
• 金额: $ 16.7万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740296
• 关键词: Acinetobacter baumannii; Affect; Air; Animal Model; Aromatic Polycyclic Hydrocarbons; Automobile Exhaust; Bacteria; Benzo(a)pyrene; Bladder; Bladder Urothelium; Cells; Chemicals; Coal; Development; Disease; Drug Metabolic Detoxication; Engineering; Enterococcus faecalis; Environment; Epithelium; Epoxy Compounds; Escherichia coli; Excretory function; Experimental Designs; Exposure to; Feces; Female; Food; Foundations; Fusobacterium nucleatum; Gases; Genes; Genome; Health; Homeostasis; Human; Hydroxylation; Immune response; In Vitro; Inbred BALB C Mice; Individual; Inflammation; Ingestion; Lactobacillus; Link; Maintenance; Malignant neoplasm of urinary bladder; Mass Fragmentography; Meta-Analysis; Metabolic; Metabolism; Microbe; Mus; Oils; Outcome; Parents; Pathogenesis; Pathway interactions; Poison; Predisposition; Pseudomonas aeruginosa; Public Health; Ralstonia; Reporting; Research; Risk Factors; Role; Salvelinus; Sampling; Soil; Sphingomonas; System; Taxonomy; Tobacco; Tobacco smoke; Toxic effect; Urinary tract; Urine; Urothelial Cell; Urothelium; Vendor; Water; Work; cancer diagnosis; carcinogenesis; carcinogenicity; chemical safety; combinatorial; cytotoxic; environmental chemical; environmental chemical exposure; estrogenic; experimental group; genotoxicity; gut microbiota; high risk; host-associated microbial communities; host-microbe interactions; in vivo; innovation; insight; male; metabolome; metabolomics; microbial; microbial community; microbial composition; microbiome; mouse model; novel; pollutant; response; secondary metabolite; sex

PROJECT SUMMARY / ABSTRACT Bladder cancer (BC) is the tenth most diagnosed cancer in the world, and is strongly linked to environmental chemical exposures including benzo[a]pyrene (BaP). BaP is a polycyclic aromatic hydrocarbon (PAH) and widespread pollutant found in automobile exhaust, tobacco smoke, and charred food, but the mechanisms underlying the links between BaP and BC remain unclear. Additionally, not all individuals exposed to BaP develop BC, indicating that there are additional undefined or individualized risk factors associated with BC. While human cells can metabolize BaP, host-associated microbes can too. Moreover, host-associated microbiomes, like host genomes, are individualized, which could drive differences in host responses to BaP exposure. However, the role of microbes in BC, and specifically, how the gut and urine microbiome modulate exposure to BaP, is largely unexplored. There is a critical need to evaluate chemical-microbe-host interactions in relation to high-risk chemicals – like BaP – on bladder health. The objective of this application is to define microbial metabolism of BaP in vitro and in vivo and asses the effects of this metabolism on the urothelium. BaP along with its metabolites are excreted in urine, have been linked to BC, and can be metabolized by microbes. However, it is unknown if microbial metabolism of BaP is occurring in vivo and how the microbiome may influence this metabolism. Our overarching hypothesis is that microbial metabolism of BaP is playing a role in bladder carcinogenesis. Specifically, we predict that urine and stool microbes can either “toxify” or “detoxify” BaP, with “toxifying” metabolism defined here as that which yields secondary metabolites more damaging or carcinogenic to host cells. In our first aim, we will characterize metabolism of BaP in vitro by urothelial cells and by gut or urinary tract-associated microbes. Host cells and bacteria will be grown in the presence or absence of BaP, separately and together, and we will apply targeted metabolomics (GC-MS) to quantify BaP metabolism. In the second aim, we will characterize metabolism of BaP in vivo through the gut and urine microbiome and metabolome of mouse models with differing microbial community profiles. In aim three, we will evaluate urothelial response (toxicity and inflammation) to BaP exposure in vitro and in vivo using samples from the first two aims. The proposed research is innovative because it represents a substantive departure from the status quo by defining chemical-microbe interactions and their direct impact on the bladder epithelium. This approach will create novel opportunities for bladder health and BC management through microbial community manipulation and engineering. Upon completion of the proposed aims, we will have identified which microbes can metabolize BaP, how they do so, if this metabolism is occurring in vivo, how differing microbial communities influence this metabolism, and how this affects urothelial response. This research is significant because it will establish a novel chemical-microbe-host framework for evaluating chemical safety, bladder health, and BC development.

项目总结/摘要 膀胱癌（BC）是世界上第十大诊断癌症，与环境密切相关。 苯并[a]芘（BaP）等化学品暴露。BaP是多环芳烃（PAH）， 广泛存在于汽车尾气、烟草烟雾和烧焦的食物中的污染物， BaP和BC之间的联系仍然不清楚。此外，并非所有接触苯并[a]芘的人 发展BC，表明存在与BC相关的额外的未定义或个体化的风险因素。 虽然人体细胞可以代谢BaP，但宿主相关的微生物也可以。此外，主机相关 微生物组与宿主基因组一样是个体化的，这可能导致宿主对BaP的反应存在差异 exposure.然而，微生物在BC中的作用，特别是肠道和尿液微生物组如何调节 暴露于BaP，在很大程度上未被探索。迫切需要评估化学-微生物-宿主相互作用 与高风险化学品（如BaP）对膀胱健康的影响有关。本申请的目的是定义 微生物代谢的苯并（a）芘在体外和体内，并评估这种代谢对尿路上皮的影响。 BaP沿着其代谢产物经尿液排泄，与BC相关，并可通过 微生物然而，尚不清楚BaP的微生物代谢是否在体内发生，以及微生物组如何在体内发生代谢。 可能会影响这种新陈代谢。我们的总体假设是，微生物代谢苯并（a）芘发挥了重要作用。 在膀胱癌发生中的作用。具体地说，我们预测尿液和粪便微生物可以“分解”， “解毒”苯并（a）芘，“解毒”代谢在此定义为产生更多次级代谢物的代谢。 对宿主细胞有害或致癌。在我们的第一个目标中，我们将通过以下方法表征BaP的体外代谢： 尿路上皮细胞和肠道或尿路相关微生物。宿主细胞和细菌将在 存在或不存在BaP，单独和一起，我们将应用靶向代谢组学（GC-MS）， 定量BaP代谢。在第二个目标中，我们将表征BaP在体内通过肠道的代谢 以及具有不同微生物群落特征的小鼠模型的尿液微生物组和代谢组。在aim中 第三，我们将评估尿路上皮反应（毒性和炎症）BaP暴露在体外和体内使用 前两个目标的样本。拟议的研究是创新的，因为它代表了实质性的 通过定义化学-微生物相互作用及其对膀胱的直接影响， 上皮这种方法将为膀胱健康和BC管理创造新的机会， 微生物群落操纵和工程。在完成建议的目标后， 确定哪些微生物可以代谢BaP，它们是如何代谢的，如果这种代谢发生在体内， 不同的微生物群落影响这种代谢，以及这如何影响尿路上皮反应。这 本研究将建立一个新的化学-微生物-宿主的评价框架， 化学品安全、膀胱健康和BC发展。