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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
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
Descripción
Sumario: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.