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

Patricia Bermudez-Martin, Jérôme A. J. Becker, Nicolas Caramello and 17 more

Microbiome · 2021 · CC BY

doi:10.1186/s40168-021-01103-z

Abstract

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. Video abstract

Supplementary Information. The online version contains supplementary material available at 10.1186/s40168-021-01103-z.

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    Mohsen A, Park J, Chen YA, Kawashima H, Mizuguchi K. Impact of quality trimming on the efficiency of reads joining and diversity analysis of Illumina paired-end reads in the context of QIIME1 and QIIME2 microbiome analysis frameworks. BMC Bioinformatics. 2019;20(1):581.

    Not in our library10.1186/s12859-019-3187-5

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    Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. DADA2: high-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13(7):581-583.

    Not in our library10.1038/nmeth.3869

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    Kuraku S, Zmasek CM, Nishimura O, Katoh K. aLeaves facilitates on-demand exploration of metazoan gene family trees on MAFFT sequence alignment server with enhanced interactivity. Nucleic Acids Res. 2013;41(Web Server issue):W22-W28.

    Not in our library10.1093/nar/gkt389

  89. 89.

    Katoh K, Rozewicki J, Yamada KD. MAFFT online service: multiple sequence alignment, interactive sequence choice and visualization. Brief Bioinform. 2019;20(4):1160-1166.

    Not in our library10.1093/bib/bbx108

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    Price MN, Dehal PS, Arkin AP. FastTree: computing large minimum evolution trees with profiles instead of a distance matrix. Mol Biol Evol. 2009;26(7):1641-1650.

    Not in our library10.1093/molbev/msp077

  91. 91.
    A Novel Sparse Compositional Technique Reveals Microbial Perturbations · 2019
    No notice
  92. 92.
    Ultrafast and accurate 16S rRNA microbial community analysis using Kraken 2 · 2020
    No notice
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    BLAST+: architecture and applications · 2009
    No notice
  94. 94.

    Bazinet AL, Ondov BD, Sommer DD, Ratnayake S. BLAST-based validation of metagenomic sequence assignments. PeerJ. 2018;6:e4892.

    Not in our library10.7717/peerj.4892

  95. 95.
    phyloseq: An R Package for Reproducible Interactive Analysis and Graphics of Microbiome Census Data · 2013
    No notice
  96. 96.
    Analysis of Microbiome Data in the Presence of Excess Zeros · 2017
    No notice
  97. 97.
    Compact graphical representation of phylogenetic data and metadata with GraPhlAn · 2015
    No notice
  98. 98.
    ClustVis: a web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap · 2015
    No notice

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