title: Gut microbial degradation of organophosphate insecticides-induces glucose intolerance via gluconeogenesis.
abstract: 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.
authors.affiliation: Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India. oomvel@gmail.com.
authors.forename: Ganesan
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authors.lastname: Velmurugan
authors.affiliation: Center for Molecular and Translational Medicine, Research Science Center, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Tharmarajan
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authors.affiliation: KMCH Research Foundation, Kovai Medical Centre and Hospital, Coimbatore, Tamil Nadu, 641014, India.
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authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1213, Lyon, 69372, France.
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authors.lastname: Mithieux
authors.affiliation: Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Jeyaprakash
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authors.lastname: Rajendhran
authors.affiliation: Department of Immunology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
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authors.lastname: Dhivakar
authors.affiliation: Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Ayothi
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authors.lastname: Parthasarathy
authors.affiliation: Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: D D Venkatesh
authors.initials: DD
authors.lastname: Babu
authors.affiliation: Department of Immunology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Leishman John
authors.initials: LJ
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authors.affiliation: Deparment of Zoology, Madras Christian College, Chennai, Tamil Nadu, 600059, India.
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Freddy
authors.affiliation: Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Vasudevan
authors.initials: V
authors.lastname: Dinakaran
authors.affiliation: Department of Biochemistry, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Shanavas Syed Mohamed
authors.initials: SS
authors.lastname: Puhari
authors.affiliation: Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Balakrishnan
authors.initials: B
authors.lastname: Rekha
authors.affiliation: Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
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authors.initials: YJ
authors.lastname: Christy
authors.affiliation: Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Sivakumar
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authors.lastname: Anusha
authors.affiliation: Department of Biochemistry, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
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authors.lastname: Divya
authors.affiliation: Department of Microbial Technology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
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authors.lastname: Suganya
authors.affiliation: Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Boominathan
authors.initials: B
authors.lastname: Meganathan
authors.affiliation: Department of Immunology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
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authors.lastname: Kalyanaraman
authors.affiliation: Department of Biochemistry, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Varadaraj
authors.initials: V
authors.lastname: Vasudevan
authors.affiliation: Department of Immunology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
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authors.initials: R
authors.lastname: Kamaraj
authors.affiliation: Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Maruthan
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authors.lastname: Karthik
authors.affiliation: Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Balakrishnan
authors.initials: B
authors.lastname: Jeyakumar
authors.affiliation: Department of Biochemistry, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
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authors.initials: A
authors.lastname: Abhishek
authors.affiliation: Department of Biochemistry, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Eldho
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authors.lastname: Paul
authors.affiliation: Laboratory of Gene Regulation and Development, Program in Cellular Regulation and Development, National Institute of Child Health and Human Development, NIH, Bethesda, MD, 20892, USA.
authors.forename: Muthuirulan
authors.initials: M
authors.lastname: Pushpanathan
authors.affiliation: Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India.
authors.forename: Rajamani Koushick
authors.initials: RK
authors.lastname: Rajmohan
authors.affiliation: Institute of Diabetes & Endocrinology, Alpha Hospital and Research Centre, Madurai, Tamil Nadu, 625009, India.
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authors.lastname: Velayutham
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and Imperial College, London, UK.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Lyon
authors.affiliation: Department of Molecular Biology, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India. subbiahr@nrcbsmku.org.
authors.forename: Subbiah
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mesh_terms: D019342:Acetic Acid / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D001786:Blood Glucose; D003920:Diabetes Mellitus / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D005243:Feces / Q000737:chemistry / Q000201:enzymology; D000069196:Gastrointestinal Microbiome; D005943:Gluconeogenesis / Q000187:drug effects; D018149:Glucose Intolerance / Q000188:drug therapy; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000209:etiology / Q000378:metabolism; D007306:Insecticides / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D010755:Organophosphates / Q000378:metabolism* / Q000633:toxicity; D018384:Oxidative Stress
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007306:Insecticides; D010755:Organophosphates; D019342:Acetic Acid
keywords: Acetic acid; Diabetes; Fecal transplantation; Gluconeogenesis; Glucose intolerance; Gut microbiota; Metabolomics; Metatranscriptomics; Organophosphates