The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota
Abstract 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-b...
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| Format: | Article |
| Language: | English |
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BMC
2021-07-01
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| Series: | Microbiome |
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| Online Access: | https://doi.org/10.1186/s40168-021-01103-z |
| _version_ | 1818864718678327296 |
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| author | Patricia Bermudez-Martin Jérôme A. J. Becker Nicolas Caramello Sebastian P. Fernandez Renan Costa-Campos Juliette Canaguier Susana Barbosa Laura Martinez-Gili Antonis Myridakis Marc-Emmanuel Dumas Aurélia Bruneau Claire Cherbuy Philippe Langella Jacques Callebert Jean-Marie Launay Joëlle Chabry Jacques Barik Julie Le Merrer Nicolas Glaichenhaus Laetitia Davidovic |
| author_facet | Patricia Bermudez-Martin Jérôme A. J. Becker Nicolas Caramello Sebastian P. Fernandez Renan Costa-Campos Juliette Canaguier Susana Barbosa Laura Martinez-Gili Antonis Myridakis Marc-Emmanuel Dumas Aurélia Bruneau Claire Cherbuy Philippe Langella Jacques Callebert Jean-Marie Launay Joëlle Chabry Jacques Barik Julie Le Merrer Nicolas Glaichenhaus Laetitia Davidovic |
| author_sort | Patricia Bermudez-Martin |
| collection | DOAJ |
| description | Abstract 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. Video abstract |
| first_indexed | 2024-12-19T10:36:07Z |
| format | Article |
| id | doaj.art-528d90be0f624b76bc049fae162ed6dc |
| institution | Directory Open Access Journal |
| issn | 2049-2618 |
| language | English |
| last_indexed | 2024-12-19T10:36:07Z |
| publishDate | 2021-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Microbiome |
| spelling | doaj.art-528d90be0f624b76bc049fae162ed6dc2022-12-21T20:25:36ZengBMCMicrobiome2049-26182021-07-019112310.1186/s40168-021-01103-zThe microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiotaPatricia Bermudez-Martin0Jérôme A. J. Becker1Nicolas Caramello2Sebastian P. Fernandez3Renan Costa-Campos4Juliette Canaguier5Susana Barbosa6Laura Martinez-Gili7Antonis Myridakis8Marc-Emmanuel Dumas9Aurélia Bruneau10Claire Cherbuy11Philippe Langella12Jacques Callebert13Jean-Marie Launay14Joëlle Chabry15Jacques Barik16Julie Le Merrer17Nicolas Glaichenhaus18Laetitia Davidovic19Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d’AzurPhysiologie de la Reproduction et des Comportements, UMR0075 INRAE, UMR7247 CNRS, IFCE, Inserm, Université François RabelaisInstitut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d’AzurInstitut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d’AzurInstitut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d’AzurInstitut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d’AzurInstitut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d’AzurDivision of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College LondonDivision of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College LondonDivision of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College LondonAgroParisTech, INRAE, Institut Micalis, Université Paris-SaclayAgroParisTech, INRAE, Institut Micalis, Université Paris-SaclayAgroParisTech, INRAE, Institut Micalis, Université Paris-SaclayUMR-S 942, INSERM, Department of Biochemistry, Lariboisière HospitalUMR-S 942, INSERM, Department of Biochemistry, Lariboisière HospitalInstitut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d’AzurInstitut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d’AzurPhysiologie de la Reproduction et des Comportements, UMR0075 INRAE, UMR7247 CNRS, IFCE, Inserm, Université François RabelaisInstitut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d’AzurInstitut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d’AzurAbstract 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. Video abstracthttps://doi.org/10.1186/s40168-021-01103-zMicrobiotaAutismBehaviorReward systemMetabolitep-Cresol |
| spellingShingle | Patricia Bermudez-Martin Jérôme A. J. Becker Nicolas Caramello Sebastian P. Fernandez Renan Costa-Campos Juliette Canaguier Susana Barbosa Laura Martinez-Gili Antonis Myridakis Marc-Emmanuel Dumas Aurélia Bruneau Claire Cherbuy Philippe Langella Jacques Callebert Jean-Marie Launay Joëlle Chabry Jacques Barik Julie Le Merrer Nicolas Glaichenhaus Laetitia Davidovic The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota Microbiome Microbiota Autism Behavior Reward system Metabolite p-Cresol |
| 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 | Microbiota Autism Behavior Reward system Metabolite p-Cresol |
| url | https://doi.org/10.1186/s40168-021-01103-z |
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