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
Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
Center for Molecular and Translational Medicine, Research Science Center, Georgia State University, Atlanta, GA, 30303, USA.
Genome Biol. 2017 Jan 24;18(1):8. 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.
由于有机磷酸酯具有可生物降解的特性，它们是世界上使用最频繁、用量最大的杀虫剂。肠道微生物被证明可降解有机磷酸酯并导致肠道功能障碍。最近有报道称有机磷酸酯具有致糖尿病的特性，但其潜在的分子机制尚不清楚。我们旨在了解肠道微生物群在有机磷酸酯诱导的高血糖中的作用，并揭示这一过程背后的分子机制。
我们发现，在印度农村直接接触有机磷酸酯的人群（n = 3080）中，糖尿病患病率很高。相关性和线性回归分析显示，血浆有机磷酸酯残留与糖化血红蛋白（HbA1c）之间存在强关联，但未发现与乙酰胆碱酯酶有关联。用有机磷酸酯对小鼠进行180天的长期治疗证实了葡萄糖不耐受的诱导，而乙酰胆碱酯酶没有显著变化。进一步的粪便移植和培养物移植实验证实了肠道微生物群参与了有机磷酸酯诱导的葡萄糖不耐受。肠道宏转录组学和宿主代谢组学分析表明，肠道微生物对有机磷酸酯的降解产生了乙酸等短链脂肪酸，这些短链脂肪酸诱导糖异生，从而导致葡萄糖不耐受。血浆有机磷酸酯残留与人糖尿病患者的粪便酯酶活性和乙酸水平呈正相关。
总的来说，我们的结果表明糖异生是有机磷酸酯诱导高血糖背后的关键机制，这一机制由肠道微生物群降解有机磷酸酯的能力介导。这项研究揭示了肠道微生物群介导的有机磷酸酯的致糖尿病特性，因此应该重新考虑这些杀虫剂的使用。
