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.