TY - JOUR
T1 - Use of shotgun metagenomics and metabolomics to evaluate the impact of glyphosate or roundup mon 52276 on the gut microbiota and serum metabolome of sprague-dawley rats
AU - Mesnage, Robin
AU - Teixeira, Maxime
AU - Mandrioli, Daniele
AU - Falcioni, Laura
AU - Ducarmon, Quinten Raymond
AU - Zwittink, Romy Daniëlle
AU - Mazzacuva, Francesca
AU - Caldwell, Anna
AU - Halket, John
AU - Amiel, Caroline
AU - Panoff, Jean Michel
AU - Belpoggi, Fiorella
AU - Antoniou, Michael Nicolas
N1 - Funding Information:
We thank N. Segata and F. Asnicar for assistance in metagenomics data analysis using their preprocessing package and useful discussions on metagenomics analytical pipelines. This work was funded by the Sustainable Food Alliance (USA) and in part by the Sheepdrove Trust (UK).
Publisher Copyright:
© 2021, Public Health Services, US Dept of Health and Human Services. All rights reserved.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - BACKGROUND: There is intense debate on whether glyphosate can inhibit the shikimate pathway of gastrointestinal microorganisms, with potential health implications. OBJECTIVES: We tested whether glyphosate or its representative EU herbicide formulation Roundup MON 52276 affects the rat gut microbiome. METHODS: We combined cecal microbiome shotgun metagenomics with serum and cecum metabolomics to assess the effects of glyphosate [0.5, 50, 175 mg/kg body weight (BW) per day] or MON 52276 at the same glyphosate-equivalent doses, in a 90-d toxicity test in rats. RESULTS: Glyphosate and MON 52276 treatment resulted in ceca accumulation of shikimic acid and 3-dehydroshikimic acid, suggesting inhibition of 5-enolpyruvylshikimate-3-phosphate synthase of the shikimate pathway in the gut microbiome. Cysteinylglycine, γ-glutamylglutamine, and valylgly-cine levels were elevated in the cecal microbiome following glyphosate and MON 52276 treatments. Altered cecum metabolites were not differen-tially expressed in serum, suggesting that the glyphosate and MON 52276 impact on gut microbial metabolism had limited consequences on physiological biochemistry. Serum metabolites differentially expressed with glyphosate treatment were associated with nicotinamide, branched-chain amino acid, methionine, cysteine, and taurine metabolism, indicative of a response to oxidative stress. MON 52276 had similar, but more pronounced, effects than glyphosate on the serum metabolome. Shotgun metagenomics of the cecum showed that treatment with glyphosate and MON 52276 resulted in higher levels of Eggerthella spp., Shinella zoogleoides, Acinetobacter johnsonii, and Akkermansia muciniphila. Shinella zoogleoides was higher only with MON 52276 exposure. In vitro culture assays with Lacticaseibacillus rhamnosus strains showed that Roundup GT plus inhibited growth at concentrations at which MON 52276 and glyphosate had no effect. DISCUSSION: Our study highlights the power of multi-omics approaches to investigate the toxic effects of pesticides. Multi-omics revealed that glypho-sate and MON 52276 inhibited the shikimate pathway in the rat gut microbiome. Our findings could be used to develop biomarkers for epidemiologi-cal studies aimed at evaluating the effects of glyphosate herbicides on humans.
AB - BACKGROUND: There is intense debate on whether glyphosate can inhibit the shikimate pathway of gastrointestinal microorganisms, with potential health implications. OBJECTIVES: We tested whether glyphosate or its representative EU herbicide formulation Roundup MON 52276 affects the rat gut microbiome. METHODS: We combined cecal microbiome shotgun metagenomics with serum and cecum metabolomics to assess the effects of glyphosate [0.5, 50, 175 mg/kg body weight (BW) per day] or MON 52276 at the same glyphosate-equivalent doses, in a 90-d toxicity test in rats. RESULTS: Glyphosate and MON 52276 treatment resulted in ceca accumulation of shikimic acid and 3-dehydroshikimic acid, suggesting inhibition of 5-enolpyruvylshikimate-3-phosphate synthase of the shikimate pathway in the gut microbiome. Cysteinylglycine, γ-glutamylglutamine, and valylgly-cine levels were elevated in the cecal microbiome following glyphosate and MON 52276 treatments. Altered cecum metabolites were not differen-tially expressed in serum, suggesting that the glyphosate and MON 52276 impact on gut microbial metabolism had limited consequences on physiological biochemistry. Serum metabolites differentially expressed with glyphosate treatment were associated with nicotinamide, branched-chain amino acid, methionine, cysteine, and taurine metabolism, indicative of a response to oxidative stress. MON 52276 had similar, but more pronounced, effects than glyphosate on the serum metabolome. Shotgun metagenomics of the cecum showed that treatment with glyphosate and MON 52276 resulted in higher levels of Eggerthella spp., Shinella zoogleoides, Acinetobacter johnsonii, and Akkermansia muciniphila. Shinella zoogleoides was higher only with MON 52276 exposure. In vitro culture assays with Lacticaseibacillus rhamnosus strains showed that Roundup GT plus inhibited growth at concentrations at which MON 52276 and glyphosate had no effect. DISCUSSION: Our study highlights the power of multi-omics approaches to investigate the toxic effects of pesticides. Multi-omics revealed that glypho-sate and MON 52276 inhibited the shikimate pathway in the rat gut microbiome. Our findings could be used to develop biomarkers for epidemiologi-cal studies aimed at evaluating the effects of glyphosate herbicides on humans.
UR - http://www.scopus.com/inward/record.url?scp=85100023327&partnerID=8YFLogxK
U2 - 10.1289/EHP6990
DO - 10.1289/EHP6990
M3 - Article
AN - SCOPUS:85100023327
SN - 0091-6765
VL - 129
SP - 1
EP - 15
JO - Environmental Health Perspectives
JF - Environmental Health Perspectives
IS - 1
M1 - 017005-1
ER -