Aflatoxin Exposure, Growth Faltering, and the Gut Microbiome among Children in Rural Guatemala

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Project Summary Aflatoxin B1 (AFB1) is a carcinogen produced by Aspergillus flavus and A. parasiticus which grow on maize. Given the high prevalence of stunting and other nutritional disorders in low- and middle-income countries where maize is highly consumed, the role of aflatoxin exposure is worth investigating. Observational reports have shown associations between aflatoxin exposure and child growth. However, most have been cross-sectional and have not assessed seasonal variations in aflatoxin, food preparation, and dynamic changes in growth. In addition, biological mechanistic data on how aflatoxin may exert impact on growth is missing. We will advance the science of aflatoxin and child growth by assessing temporal changes in diet, aflatoxin exposure, and growth faltering in a prospective cohort of children from rural Guatemala, a country that has one of the highest rates of child stunting and aflatoxin exposure in the world. In addition, we will use bioreactors to investigate possible biological mechanisms, specifically direct aflatoxin-gut microbiome interactions. We hypothesize that aflatoxin exposure negatively impacts child growth by inducing inflammation and disrupting the gut microbiome. In Aim 1, we will prospectively evaluate aflatoxin exposure and height-for-age difference trajectories among 185 children between 6-9 and 24-27 months of age. We will assess aflatoxin exposure using serum AFB1-albumin adduct levels, and we will measure biomarkers of systemic and gut inflammation. In Aim 2, we will evaluate the association between aflatoxin exposure, stunting status, and gut microbiome composition and function. We will evaluate the fecal microbiome of each child using 16S rRNA gene amplicon and whole genome sequencing to identify key species and metabolic pathways for differing AFB1 exposure levels and stunting status. In parallel, we will use bioreactors inoculated with fecal samples to evaluate the response of the gut microbiome composition to varying levels of AFB1 exposure. In Aim 3, we will evaluate the impact of aflatoxin exposure on microbial nutrient metabolism and the impact of gut microbiota on aflatoxin detoxification/metabolism by monitoring key nutrient metabolites (e.g., short-chain fatty acids) and AFB1 biotransformation products in bioreactors. We will also evaluate the effect of inflammation, aflatoxin, and microbiome composition on child stunting based on the results from the three aims using path analysis. Significance and Innovation: Through a multidisciplinary approach that leverages access to an exposed population and expertise on epidemiology, toxicology, environmental engineering and human microbiome, we will be able to evaluate the impact of aflatoxin exposure on growth and its possible mediation by the gut microbiome. Impact: Completion of this R01 proposal will advance understanding of the physiologic mechanism of aflatoxin- mediated growth restriction, pointing the way toward new public health strategies for mitigation of aflatoxin exposure and for microbiome-directed treatments.