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

Abstract

ABSTRACTBackgroundAutism Spectrum Disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis resulting in changes in microbiota composition as well as 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.ResultsMice 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 levels compared to mice transplanted with the microbiota of control mice and 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.ConclusionsThe microbial metabolite p-Cresol induces ASD core behavioral symptoms in mice via a gut microbiota-dependent mechanism. Our study paves the way for therapeutic interventions targeting the microbiota to treat patients with ASD.