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,Environmental Health Perspectives

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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
Environmental Health Perspectives ( IF 10.1 ) Pub Date : 2021-1-27 , DOI: 10.1289/ehp6990
Robin Mesnage ₁ , Maxime Teixeira ₂ , Daniele Mandrioli ₃ , Laura Falcioni ₃ , Quinten Raymond Ducarmon ₄ , Romy Daniëlle Zwittink ₄ , Francesca Mazzacuva ₅ , Anna Caldwell ₅ , John Halket ₅ , Caroline Amiel ₂ , Jean-Michel Panoff ₂ , Fiorella Belpoggi ₃ , Michael Nicolas Antoniou ₁

Affiliation

Abstract

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, $175 milligrams per kilogram body weight per day$ ] 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, $lowercase gamma-glutamylglutamine$ , and valylglycine levels were elevated in the cecal microbiome following glyphosate and MON 52276 treatments. Altered cecum metabolites were not differentially 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 glyphosate and MON 52276 inhibited the shikimate pathway in the rat gut microbiome. Our findings could be used to develop biomarkers for epidemiological studies aimed at evaluating the effects of glyphosate herbicides on humans. https://doi.org/10.1289/EHP6990

中文翻译：

使用鸟枪法宏基因组学和代谢组学评估草甘膦或农达 MON 52276 对 Sprague-Dawley 大鼠肠道微生物群和血清代谢组的影响

抽象的

背景：

关于草甘膦是否可以抑制胃肠道微生物的莽草酸途径以及潜在的健康影响存在着激烈的争论。

目标：

我们测试了草甘膦或其代表性欧盟除草剂配方 Roundup MON 52276 是否影响大鼠肠道微生物组。

方法：

我们将盲肠微生物群鸟枪法宏基因组学与血清和盲肠代谢组学相结合，以评估草甘膦的效果 [0.5, 50, $175 毫克 / 千克体重（体重）每天$ ] 或 MON 52276 以相同的草甘膦当量剂量，在大鼠中进行 90 天毒性试验。

结果：

草甘膦和 MON 52276 处理导致盲肠积聚莽草酸和 3-脱氢莽草酸，表明肠道微生物组中莽草酸途径的 5-烯醇丙酮莽草酸-3-磷酸合酶受到抑制。半胱氨酰甘氨酸， $γ -谷氨酰谷氨酰胺$ 草甘膦和 MON 52276 处理后盲肠微生物组中的缬氨酰甘氨酸水平升高。改变的盲肠代谢物在血清中没有差异表达，这表明草甘膦和 MON 52276 对肠道微生物代谢的影响对生理生化的影响有限。草甘膦处理差异表达的血清代谢物与烟酰胺、支链氨基酸、蛋氨酸、半胱氨酸和牛磺酸代谢相关，表明对氧化应激的反应。 MON 52276 对血清代谢组的影响与草甘膦相似，但更显着。盲肠鸟枪法宏基因组学显示，用草甘膦和 MON 52276 处理会导致Eggerthella spp.、 Shinella Zoogleoides 、 Acinetobacter johnsonii和Akkermansia muciniphila水平升高。仅当暴露于 MON 52276 时，Shinella Zoogleoides才较高。鼠李糖乳酸杆菌菌株的体外培养测定表明，Roundup GT plus 在 MON 52276 和草甘膦没有影响的浓度下抑制生长。