16SrRNA from gut-microbiota of a mouse orally exposed to p-Cresol through drinkwater Targeted loci

Autism 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.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, and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal matter transplantation (FMT). We also showed that mice which were transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol levels compared to those transplanted with the microbiota of control mice. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability and fecal p-Cresol levels when transplanted to p-Cresol-treated mice.