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

• Published in: Genome Biology Vol. 18; no. 1; p. 8
• Main Authors: Velmurugan, Ganesan, Ramprasath, Tharmarajan, Swaminathan, Krishnan, Mithieux, Gilles, Rajendhran, Jeyaprakash, Dhivakar, Mani, Parthasarathy, Ayothi, Babu, D D Venkatesh, Thumburaj, Leishman John, Freddy, Allen J, Dinakaran, Vasudevan, Puhari, Shanavas Syed Mohamed, Rekha, Balakrishnan, Christy, Yacob Jenifer, Anusha, Sivakumar, Divya, Ganesan, Suganya, Kannan, Meganathan, Boominathan, Kalyanaraman, Narayanan, Vasudevan, Varadaraj, Kamaraj, Raju, Karthik, Maruthan, Jeyakumar, Balakrishnan, Abhishek, Albert, Paul, Eldho, Pushpanathan, Muthuirulan, Rajmohan, Rajamani Koushick, Velayutham, Kumaravel, Lyon, Alexander R, Ramasamy, Subbiah
• Format: Journal Article
• Language: English
• Published: England BioMed Central 24.01.2017
• Subjects: Acetic acid; Acetic Acid - metabolism; Acetylcholinesterase; Animals; Biodegradability; Biomarkers; Blood Glucose; Diabetes; Diabetes mellitus; Diabetes Mellitus - etiology; Diabetes Mellitus - metabolism; Digestive system; Disease Models, Animal; Esterase; Fatty acids; Feces - chemistry; Feces - enzymology; Gastrointestinal Microbiome; Gastrointestinal tract; Gluconeogenesis; Gluconeogenesis - drug effects; Glucose; Glucose Intolerance - drug therapy; Glucose tolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Hyperglycemia - blood; Hyperglycemia - etiology; Hyperglycemia - metabolism; Insecticides; Insecticides - metabolism; Insecticides - toxicity; Intestinal microflora; Intestine; Intolerance; Life Sciences; Metabolomics; Methods; Mice; Microbiomes; Microbiota; Neurons and Cognition; Organophosphates; Organophosphates - metabolism; Organophosphates - toxicity; Oxidative Stress; Pesticides; Plasma; Transplantation; Gut microbiota; Metabolomics; Fecal transplantation; Glucose intolerance; Metatranscriptomics; Diabetes; Acetic acid; Gluconeogenesis; Organophosphates
• ISSN: 1474-760X; 1474-7596; 1465-6906; 1474-760X
• DOI: 10.1186/s13059-016-1134-6

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.