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