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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES033988&format=word)
| Principal Investigator: O'Toole, George A. | |
|---|---|
| Institute Receiving Award | Dartmouth College |
| Location | Hanover, NH |
| Grant Number | R01ES033988 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 07 Dec 2022 to 31 Oct 2027 |
| DESCRIPTION (provided by applicant): | ABSTRACT The gut microbiome is directly impacted by metals exposure and changes in the gut microbiome affect downstream health. An individual’s microbiome also modifies the health effects of toxicants such as arsenic by transforming them into potentially more or less harmful substances. Thus, understanding the impacts of arsenic on the microbiome, and vice versa, is key to achievable prevention and interventions to mitigate the risk of arsenic to human health – a key goal of the NIEHS. Our team’s prior work using the New Hampshire Birth Cohort Study, with ongoing enrollment and a projected size of 3,000 mother-infant dyads, identified an impact of toxic metals on the developing microbiome during the critical window of 0–3 years of age, when microbes are required for immune development. Specifically, our team showed both a sex-specific dysbiosis and a depletion of the immune-training microbe Bacteroides in arsenic-exposed infants/children. Importantly, this work revealed associations between arsenic exposure, changes in the microbiome, and early immune-mediated health outcomes, including respiratory disease. Our team’s recent work indicates a gut-lung link for arsenic-exposed infants depleted for Bacteroides, thus strongly supporting the hypothesis that gut microbiome composition is a key driver of airway health. This project will test the hypothesis that in the sensitive early-life window (0–3 years), when the developing immune system requires interaction with microbes, arsenic affects the developing microbiome, resulting in a paucity of Bacteroides and its secreted metabolites and ultimately associating with increased inflammation and risk of respiratory diseases such as wheeze, upper respiratory tract infection, and pneumonia later in life (out to 12 years of age). AIM 1. Test the hypotheses, using the longitudinal NHBCS and novel bioinformatic tools, that (i) early-life As exposures via food/water are related to sex-specific perturbations in the intestinal microbiome and (ii) the early- life intestinal microbiome modifies or mediates the effects of As exposure on respiratory health outcomes. AIM 2. Test the hypothesis that As enhances secretion of IL-8 from intestinal epithelia due to lack of a key Bacteroides-secreted short chain fatty acid, propionate, ultimately resulting from changes in the epigenome. AIM 3. Test the hypothesis that add-back of Bacteroides can reverse the effect of Bacteroides-depleted stool in a mouse model, thus serving as a proof-of-concept for probiotic interventions. |
| Science Code(s)/Area of Science(s) |
Primary: 68 - Microbiome Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Anika Dzierlenga |