Early-life iAs exposure: diabetes and gut microbiome

ABSTRACT: PROJECT 1 Inorganic arsenic (iAs) is a ubiquitous, naturally-occurring environmental toxicant affecting over 200 million people worldwide. Exposure to iAs has been associated with a plethora of human diseases, including diabetes, as established in numerous animal and epidemiological studies. Growing evidence has clearly indicated that distinct time periods of increased susceptibility to environmental exposures exist throughout the life course. The UNC-SRP team has shown that early life iAs exposure induces glucose intolerance in mice. Meanwhile, we have demonstrated that the gut microbiome plays a key role in iAs-induced diabetes in animal studies. Our team has also previously shown that gut microbiome alteration is associated with iAs exposure during a critical window of infant development in the New Hampshire Birth Cohort Study (NHBCS), a pregnancy cohort of private well users, further highlighting the potential role of early life gut microbiome perturbation in disease development and iAs toxicity. However, how the gut microbiome contributes to metabolic dysfunction due to early life iAs exposure remains to be elucidated, which will be tackled by Project 1 to address a fundamental gap in understanding mechanisms underlying early life iAs-induced diabetes. In addition, although the gut microbiome is a promising target for intervention in human disease, there is a major gap in developing microbiome-based solutions to protect against early life iAs-induced metabolic dysfunction. Our overarching hypothesis is that the gut microbiome serves as a key regulator of early life iAs exposure-induced metabolic dysfunction/diabetes, and that microbiome modulation protects against these adverse effects. To test this hypothesis, we will pursue three specific aims: Aim 1: Examine the functional perturbations of the gut microbiome by early life exposure to iAs and its role in iAs-induced metabolic dysfunction; Aim 2: Develop rationally designed bacterial consortia consisting of gut bacterial species involved in arsenic detoxification and metabolic regulation to mitigate early life iAs exposure-induced metabolic dysfunction; and Aim 3: Determine the effects of diet-based microbiome modulation using black raspberry to protect against early life iAs exposure-induced metabolic dysfunction. This project is led by a strong team (Drs. Lu, Sartor, Styblo, Karagas and Howe) with complimentary expertise in arsenic toxicity, gut microbiome, iAs-induced diabetes and epidemiology. We use innovative techniques to characterize largely unknown contributions of the gut microbiome in early life iAs-induced diabetes and the project supports the theme of the UNC-SRP “Protecting vulnerable populations from arsenic-induced metabolic dysfunction with a vision for exposure reduction and disease prevention.” This application is both significant and innovative, as it will reveal the key role of the gut microbiome in early life iAs exposure-induced metabolic dysfunction. It will also develop novel solutions to reduce iAs-induced adverse outcomes through mechanism-guided rationally designed bacterial consortia and diet-based microbiome modulation.