Exposure to chlorpyrifos pesticide at a realistic dose modulates gut microbiome and induces non-obese associated diabetes

During the last decade, there has been a significant rise in the incidence of diabetes particularly, in Asian and African countries. Although obesity is an established risk factor for diabetes, more than 50% of diabetes patients in Asian and African countries are non-obese, which is in contrast to the Western population. The pathophysiology of non-obese diabetes remains largely unexplored, and recent studies have highlighted the possible role of endocrine-disrupting chemicals and gut microbiota in the prevalence of non-obese type 2 diabetes. Among the endocrine-disrupting chemicals, chlorpyrifos, a widely used organophosphate insecticide, has been associated with the prevalence of non-obese associated type 2 diabetes. However, experiments on animal models have shown that CPF-induces obesity and lipogenesis, contributing to insulin resistance. Notably, all these animal experiments were conducted at doses not equivalent to human exposure levels. Therefore, this study aimed to investigate the impact of chronic exposure of CPF at a realistic dose in mice. C57/Bl6 mice were treated with CPF at 0.02 mg/kg body weight daily, which is equivalent to the daily exposure of humans based on theoretical maximum daily intake. After 120 days of treatment, the chlorpyrifos-treated group showed a significant increase in fasting blood glucose levels with no changes in body weight in comparison with untreated controls. 16S rDNA sequencing and metabolomics analyses revealed the role of gut microbiota in chlorpyrifos-induced hyperglycemia in mice. CPF disrupted gut microbial balance, with depletion of beneficial taxa (Lactobacillus, Akkermansia, Blautia, Bifidobacterium and Faecalibaculum) and enrichment of pathobionts (Oscillospiraceae_uncultured, Helicobacter, Colidextrobacter, Desulfovibrioceae_uncultured and Alistipes). Overall, this is the first animal study demonstrating the impact of exposure to chlorpyrifos at a realistic dose equivalent to human exposure that correlates with the observations from the human epidemiological studies.