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

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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

Edité par CCSD ; BioMed Central -

International audience. 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.

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