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

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.

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

ABSTRACTBrain development and behavioral responses are influenced by gut microbiota. Perturbations of the microbiota-gut-brain axis have been identified in autism spectrum disorders (ASD), suggesting that the microbiota could be involved in abnormal social and stereotyped behaviors in ASD patients. Notably, changes in microbiota composition and fecal, serum or urine levels of microbial metabolites are associated with ASD. Yet, a causal relationship between abnormal microbiota composition, altered microbial metabolite production, and ASD remains to be demonstrated. We hypothesized that p-Cresol (also known as 4-Cresol), a microbial metabolite that was described as more abundant in ASD patients, contributes to ASD core behavioral symptoms. Here we show that 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 modified the relative abundance of specific bacterial taxa which correlated with social behavior. In addition, social behavior deficits were transferrable from p-Cresol-treated mice to control mice by fecal matter transplantation. In contrast, the microbiota from control mice restored both social interactions and dopamine neurons excitability when transplanted to p-Cresol-treated mice. Altogether, our results suggest that microbial metabolites p-Cresol could be involved in the development of core autistic behaviors via a gut microbiota-dependent mechanism. Further, this study paves the way for therapeutic interventions targeting the production of p-Cresol by gut bacteria to treat patients with ASD.