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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要膀胱癌 (BC) 是世界上第十大确诊癌症，与环境密切相关化学物质暴露，包括苯并[a]芘 (BaP)。 BaP 是一种多环芳烃 (PAH)，汽车尾气、烟草烟雾和烧焦的食物中广泛存在污染物，但其机制 BaP 和 BC 之间的潜在联系仍不清楚。此外，并非所有接触 BaP 的人发展为 BC，表明存在与 BC 相关的其他未定义或个体化风险因素。虽然人类细胞可以代谢 BaP，但宿主相关微生物也可以。此外，与主机相关的微生物组与宿主基因组一样，都是个体化的，这可能会导致宿主对 BaP 反应的差异接触。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 的情况在很大程度上尚未被探索。迫切需要评估化学-微生物-宿主相互作用与高风险化学物质（如 BaP）有关的膀胱健康。该应用程序的目标是定义 BaP 的体外和体内微生物代谢，并评估这种代谢对尿路上皮的影响。 BaP 及其代谢物通过尿液排出，与 BC 相关，并且可以通过以下途径代谢：微生物。然而，目前尚不清楚 BaP 的微生物代谢是否在体内发生以及微生物组如何进行可能会影响这种新陈代谢。我们的首要假设是 BaP 的微生物代谢发挥着重要作用在膀胱癌发生中的作用。具体来说，我们预测尿液和粪便微生物可以“中毒”或 “解毒”BaP，此处的“毒化”代谢定义为产生更多次生代谢物的代谢对宿主细胞有损害或致癌作用。在我们的第一个目标中，我们将通过以下方式表征 BaP 的体外代谢：尿路上皮细胞以及肠道或尿路相关微生物。宿主细胞和细菌将在 BaP 是否存在，单独或一起，我们将应用靶向代谢组学 (GC-MS) 来量化 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。瞄准目标三，我们将使用体外和体内评估尿路上皮对 BaP 暴露的反应（毒性和炎症）前两个目标的样本。拟议的研究具有创新性，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来摆脱现状上皮。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。完成拟议目标后，我们将确定了哪些微生物可以代谢 BaP、它们是如何代谢的、这种代谢是否在体内发生、如何进行不同的微生物群落影响这种新陈代谢，以及它如何影响尿路上皮反应。这研究意义重大，因为它将建立一个新的化学-微生物-宿主框架来评估化学品安全、膀胱健康和 BC 发展。