The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

  • Microbiome. 2021 Jul 8;9(1):157. doi: 10.1186/s40168-021-01103-z.
Patricia Bermudez-Martin  1 ,  Jérôme A J Becker  2  3 ,  Nicolas Caramello  1  4 ,  Sebastian P Fernandez  1 ,  Renan Costa-Campos  1 ,  Juliette Canaguier  1 ,  Susana Barbosa  1 ,  Laura Martinez-Gili  5 ,  Antonis Myridakis  5 ,  Marc-Emmanuel Dumas  5  6  7  8 ,  Aurélia Bruneau  9 ,  Claire Cherbuy  9 ,  Philippe Langella  9 ,  Jacques Callebert  10  11 ,  Jean-Marie Launay  10  11 ,  Joëlle Chabry  1 ,  Jacques Barik  1 ,  Julie Le Merrer  2  3 ,  Nicolas Glaichenhaus  1  12 ,  Laetitia Davidovic  13  14
Affiliations
  • 1. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France.
  • 2. Physiologie de la Reproduction et des Comportements, UMR0075 INRAE, UMR7247 CNRS, IFCE, Inserm, Université François Rabelais, 37380, Nouzilly, France.
  • 3. UMR 1253, iBrain, Université de Tours, Inserm, CNRS, Tours, 37200, France.
  • 4. Current address: Structural Biology, Radiation Facility, European Synchrotron, Grenoble, France.
  • 5. Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK.
  • 6. Genomic and Environmental Medicine, National Heart & Lung Institute, Faculty of Medicine, Imperial College London, London, SW3 6KY, UK.
  • 7. European Genomic Institute for Diabetes, CNRS UMR 8199, INSERM UMR 1283, Institut Pasteur de Lille, Lille University Hospital, University of Lille, 59045, Lille, France.
  • 8. McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montréal, QC, H3A 0G1, Canada.
  • 9. AgroParisTech, INRAE, Institut Micalis, Université Paris-Saclay, Jouy-en-Josas, France.
  • 10. UMR-S 942, INSERM, Department of Biochemistry, Lariboisière Hospital, Paris, France.
  • 11. Centre for Biological Resources, BB-0033-00064, Lariboisière Hospital, Paris, France.
  • 12. Fondation FondaMental, Créteil, France.
  • 13. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d'Azur, 660 route des Lucioles, 06560, Valbonne, France. [email protected].
  • 14. Fondation FondaMental, Créteil, France. [email protected].
PMID: 34238386 DOI: 10.1186/s40168-021-01103-z
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.

Keywords
4-Cresol; Autism; Behavior; Metabolite; Microbiota; Reward system; p-Cresol.
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