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The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota
BACKGROUND: Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axi...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268286/ https://www.ncbi.nlm.nih.gov/pubmed/34238386 http://dx.doi.org/10.1186/s40168-021-01103-z |
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author | Bermudez-Martin, Patricia Becker, Jérôme A. J. Caramello, Nicolas Fernandez, Sebastian P. Costa-Campos, Renan Canaguier, Juliette Barbosa, Susana Martinez-Gili, Laura Myridakis, Antonis Dumas, Marc-Emmanuel Bruneau, Aurélia Cherbuy, Claire Langella, Philippe Callebert, Jacques Launay, Jean-Marie Chabry, Joëlle Barik, Jacques Le Merrer, Julie Glaichenhaus, Nicolas Davidovic, Laetitia |
author_facet | Bermudez-Martin, Patricia Becker, Jérôme A. J. Caramello, Nicolas Fernandez, Sebastian P. Costa-Campos, Renan Canaguier, Juliette Barbosa, Susana Martinez-Gili, Laura Myridakis, Antonis Dumas, Marc-Emmanuel Bruneau, Aurélia Cherbuy, Claire Langella, Philippe Callebert, Jacques Launay, Jean-Marie Chabry, Joëlle Barik, Jacques Le Merrer, Julie Glaichenhaus, Nicolas Davidovic, Laetitia |
author_sort | Bermudez-Martin, Patricia |
collection | PubMed |
description | BACKGROUND: Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. RESULTS: Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. CONCLUSIONS: The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40168-021-01103-z. |
format | Online Article Text |
id | pubmed-8268286 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-82682862021-07-09 The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota Bermudez-Martin, Patricia Becker, Jérôme A. J. Caramello, Nicolas Fernandez, Sebastian P. Costa-Campos, Renan Canaguier, Juliette Barbosa, Susana Martinez-Gili, Laura Myridakis, Antonis Dumas, Marc-Emmanuel Bruneau, Aurélia Cherbuy, Claire Langella, Philippe Callebert, Jacques Launay, Jean-Marie Chabry, Joëlle Barik, Jacques Le Merrer, Julie Glaichenhaus, Nicolas Davidovic, Laetitia Microbiome Research BACKGROUND: Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. RESULTS: Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. CONCLUSIONS: The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40168-021-01103-z. BioMed Central 2021-07-08 /pmc/articles/PMC8268286/ /pubmed/34238386 http://dx.doi.org/10.1186/s40168-021-01103-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Bermudez-Martin, Patricia Becker, Jérôme A. J. Caramello, Nicolas Fernandez, Sebastian P. Costa-Campos, Renan Canaguier, Juliette Barbosa, Susana Martinez-Gili, Laura Myridakis, Antonis Dumas, Marc-Emmanuel Bruneau, Aurélia Cherbuy, Claire Langella, Philippe Callebert, Jacques Launay, Jean-Marie Chabry, Joëlle Barik, Jacques Le Merrer, Julie Glaichenhaus, Nicolas Davidovic, Laetitia The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota |
title | The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota |
title_full | The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota |
title_fullStr | The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota |
title_full_unstemmed | The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota |
title_short | The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota |
title_sort | microbial metabolite p-cresol induces autistic-like behaviors in mice by remodeling the gut microbiota |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268286/ https://www.ncbi.nlm.nih.gov/pubmed/34238386 http://dx.doi.org/10.1186/s40168-021-01103-z |
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