In:
Microbiome, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2021-12)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
2049-2618
DOI:
10.1186/s40168-021-01103-z
DOI:
10.21203/rs.3.rs-966212/v1
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2021
detail.hit.zdb_id:
2697425-3
Bookmarklink