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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 abstractSupplementary Information  The online version contains supplementary material available at 10.1186/s40168-021-01103-z.

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