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

2021; BioMed Central; Volume: 9; Issue: 1 Linguagem: Inglês

10.1186/s40168-021-01103-z

2049-2618

Patricia Bermudez-Martin, Jérôme A. J. Becker, Nicolas Caramello, Sebastián P. Fernández, 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, Laëtitia Davidovic,

Tryptophan and brain disorders

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.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.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.