Gut microbial degradation of organophosphate insecticides-induces glucose intolerance via gluconeogenesis

Abstract

BackgroundOrganophosphates are the most frequently and largely applied insecticide in the world due to their biodegradable nature. Gut microbes were shown to degrade organophosphates and cause intestinal dysfunction. The diabetogenic nature of organophosphates was recently reported but the underlying molecular mechanism is unclear. We aimed to understand the role of gut microbiota in organophosphate-induced hyperglycemia and to unravel the molecular mechanism behind this process.ResultsHere we demonstrate a high prevalence of diabetes among people directly exposed to organophosphates in rural India (n = 3080). Correlation and linear regression analysis reveal a strong association between plasma organophosphate residues and HbA1c but no association with acetylcholine esterase was noticed. Chronic treatment of mice with organophosphate for 180 days confirms the induction of glucose intolerance with no significant change in acetylcholine esterase. Further fecal transplantation and culture transplantation experiments confirm the involvement of gut microbiota in organophosphate-induced glucose intolerance. Intestinal metatranscriptomic and host metabolomic analyses reveal that gut microbial organophosphate degradation produces short chain fatty acids like acetic acid, which induces gluconeogenesis and thereby accounts for glucose intolerance. Plasma organophosphate residues are positively correlated with fecal esterase activity and acetate level of human diabetes.ConclusionCollectively, our results implicate gluconeogenesis as the key mechanism behind organophosphate-induced hyperglycemia, mediated by the organophosphate-degrading potential of gut microbiota. This study reveals the gut microbiome-mediated diabetogenic nature of organophosphates and hence that the usage of these insecticides should be reconsidered.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1134-6) contains supplementary material, which is available to authorized users.

Functional dynamics of bacterial species in the mouse gut microbiome revealed by metagenomic and metatranscriptomic analyses

“…To date, several reports have shown microbiota structure and microbiome function in the mouse gut under various environmental conditions by metatranscriptomic analysis [22,24,[27][28][29][30][31][32][33][34][35][36][37]. In particular, metatranscriptomic analysis of the mouse gut microbiome during targeted exposure to lard and primary bile acid diet [29], a high-protein diet [31], and vitamin and mineral deficiencies [32] uncovered significant alterations in both bacterial community structure and their gene expression profiles.…”

“…In particular, metatranscriptomic analysis of the mouse gut microbiome during targeted exposure to lard and primary bile acid diet [29], a high-protein diet [31], and vitamin and mineral deficiencies [32] uncovered significant alterations in both bacterial community structure and their gene expression profiles. In addition to diet conditions, targeted infection Functional dynamics of the mouse gut microbiome revealed by metagenomic and metatranscriptomic analyses with Clostridium difficile [30], specific exposure to organophosphate insecticides [34], and antibiotics [38] alter both the microbiome structure and its functional activity. In contrast, during a host gene deficiency, as in Perilipin-2 (Plin2)-deficient mice, high-fat diet causes the microbiota of Plin2-null mice to undergo significant shifts in transcript expression, despite no distinct change in overall community structure, as compared to wild-type mice [28].…”

What is Communicable? Unaccounted Injuries and “Catching” Diabetes in an Illegible Epidemic

“…Little pieces get eaten by fish, moving up the food chain and seeping into water, often leaching BPA also associated with diabetes risk (Vogel 2009). Another study of 3,080 farmworkers in rural India found that exposure to organophosphate chemicals contributed to diabetes, apparently because the insecticides designed to kill crop pests also interacted with the living microbes crucial to metabolic balance inside people's digestive tracts (Velmurugan et al 2017). This constitutes only one of several mechanisms by which endocrine‐disrupting chemicals can contribute to diabetes, a disease of the endocrine system (see Colborn, Dumanoski, and Myers 1997).…”

Gut microbiota in toxicological risk assessment of drugs and chemicals: The need of hour

“…Anaerobic culture methods can also be employed to assess the effect of drug or chemical on gut microbiota. 4,9 In this culture method, human or animal faeces can be cultured in presence/ absence of the specific chemical and after the culture period, the changes can be assessed. In our anaerobic culture with faeces and with organophosphate insecticides, we observed the increase in the activity of xenobiotic degrading enzymes, expression of specific genes and degradation of insecticides into glucogenic substrates.…”

“…4-6 food 7-8 and environmental chemicals [9][10][11] and its subsequent effect on physiology and pathology of humans. [4][5][6][7][8][9][10][11] Microbiota is today recognized as an organ of the human body that plays a vital role in human health and disease. 12 Besides their role in body physiology, it plays a key role in digestion and metabolization of xenobiotic compounds.…”