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

Ganesan Velmurugan, Tharmarajan Ramprasath, Krishnan Swaminathan, Gilles Mithieux, Jeyaprakash Rajendhran, Mani Dhivakar, Ayothi Parthasarathy, D.D. Venkatesh Babu, Leishman John Thumburaj, Allen J. Freddy, Vasudevan Dinakaran, Shanavas Syed Mohamed Puhari, Balakrishnan Rekha, Yacob Jenifer Christy, Sivakumar Anusha, Ganesan Divya, Kannan Suganya, Boominathan Meganathan, Narayanan Kalyanaraman, Varadaraj Vasudevan, Raju Kamaraj, Maruthan Karthik, Balakrishnan Jeyakumar, Albert Abhishek, Eldho Paul, Muthuirulan Pushpanathan, Rajamani Koushick Rajmohan, Kumaravel Velayutham, Alexander R. Lyon, Subbiah Ramasamy

Organophosphates 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. Here 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. Collectively, 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.