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

Author:

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 LaetitiaORCID

Abstract

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.

Funder

EraNet NEURON

Medical Research Council

Région Centre Val-de-Loire

Labex

Agence Nationale de la Recherche

Publisher

Springer Science and Business Media LLC

Subject

Microbiology (medical),Microbiology

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