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Shotgun metagenomics and metabolomics reveal glyphosate alters the gut microbiome of Sprague-Dawley rats by inhibiting the shikimate pathway

View ORCID ProfileRobin Mesnage, Maxime Teixeira, Daniele Mandrioli, Laura Falcioni, Quinten Raymond Ducarmon, Romy Daniëlle Zwittink, Caroline Amiel, Jean-Michel Panoff, View ORCID ProfileFiorella Belpoggi, Michael N Antoniou
doi: https://doi.org/10.1101/870105
Robin Mesnage
1Gene Expression and Therapy Group, King’s College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, Guy’s Hospital, London, SE1 9RT, UK
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  • ORCID record for Robin Mesnage
Maxime Teixeira
2UR Aliments Bioprocédés Toxicologies Environnements, EA 4651, University of Caen Normandy (UCN), Boulevard Maréchal Juin, CS 14032 Caen Cedex 5, France
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Daniele Mandrioli
3Ramazzini Institute, Via Saliceto, 3, 40010 Bentivoglio, Bologna, Italy
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Laura Falcioni
3Ramazzini Institute, Via Saliceto, 3, 40010 Bentivoglio, Bologna, Italy
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Quinten Raymond Ducarmon
4Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands
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Romy Daniëlle Zwittink
4Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands
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Caroline Amiel
2UR Aliments Bioprocédés Toxicologies Environnements, EA 4651, University of Caen Normandy (UCN), Boulevard Maréchal Juin, CS 14032 Caen Cedex 5, France
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Jean-Michel Panoff
2UR Aliments Bioprocédés Toxicologies Environnements, EA 4651, University of Caen Normandy (UCN), Boulevard Maréchal Juin, CS 14032 Caen Cedex 5, France
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Fiorella Belpoggi
3Ramazzini Institute, Via Saliceto, 3, 40010 Bentivoglio, Bologna, Italy
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  • ORCID record for Fiorella Belpoggi
Michael N Antoniou
1Gene Expression and Therapy Group, King’s College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, Guy’s Hospital, London, SE1 9RT, UK
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  • For correspondence: michael.antoniou@kcl.ac.uk
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Abstract

There is intense debate as to whether glyphosate can interfere with aromatic amino acid biosynthesis in microorganisms inhabiting the gastrointestinal tract, which could potentially lead to negative health outcomes. We have addressed this major gap in glyphosate toxicology by using a multi-omics strategy combining shotgun metagenomics and metabolomics. We tested whether glyphosate (0.5, 50, 175 mg/kg bw/day), or its representative EU commercial herbicide formulation MON 52276 at the same glyphosate equivalent doses, has an effect on the rat gut microbiome in a 90-day subchronic toxicity test. Clinical biochemistry measurements in blood and histopathological evaluations showed that MON 52276 but not glyphosate was associated with statistically significant increase in hepatic steatosis and necrosis. Similar lesions were also present in the liver of glyphosate-treated groups but not in the control group. Caecum metabolomics revealed that glyphosate inhibits the enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase in the shikimate pathway as evidenced by an accumulation of shikimic acid and 3-dehydroshikimic acid. Levels of caecal microbiome dipeptides involved in the regulation of redox balance (γ-glutamylglutamine, cysteinylglycine, valylglycine) had their levels significantly increased. Shotgun metagenomics showed that glyphosate affected caecum microbial community structure and increased levels of Eggerthella spp. and Homeothermacea spp.. MON 52276, but not glyphosate, increased the relative abundance of Shinella zoogleoides. Since Shinella spp. are known to degrade alkaloids, its increased abundance may explain the decrease in solanidine levels measured with MON 52776 but not glyphosate. Other glyphosate formulations may have different effects since Roundup® GT Plus inhibited bacterial growth in vitro at concentrations at which MON 52276 did not present any visible effect. Our study highlights the power of a multiomics approach to investigate effects of pesticides on the gut microbiome. This revealed the first biomarker of glyphosate effects on rat gut microbiome. Although more studies will be needed to ascertain if there are health implications arising from glyphosate inhibition of the shikimate pathway in the gut microbiome, our findings can be used in environmental epidemiological studies to understand if glyphosate can have biological effects in human populations.

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Posted December 11, 2019.
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Shotgun metagenomics and metabolomics reveal glyphosate alters the gut microbiome of Sprague-Dawley rats by inhibiting the shikimate pathway
Robin Mesnage, Maxime Teixeira, Daniele Mandrioli, Laura Falcioni, Quinten Raymond Ducarmon, Romy Daniëlle Zwittink, Caroline Amiel, Jean-Michel Panoff, Fiorella Belpoggi, Michael N Antoniou
bioRxiv 870105; doi: https://doi.org/10.1101/870105
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Shotgun metagenomics and metabolomics reveal glyphosate alters the gut microbiome of Sprague-Dawley rats by inhibiting the shikimate pathway
Robin Mesnage, Maxime Teixeira, Daniele Mandrioli, Laura Falcioni, Quinten Raymond Ducarmon, Romy Daniëlle Zwittink, Caroline Amiel, Jean-Michel Panoff, Fiorella Belpoggi, Michael N Antoniou
bioRxiv 870105; doi: https://doi.org/10.1101/870105

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