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

Title: The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota
Authors: Bermudez-Martin, P
Becker, JAJ
Caramello, N
Fernandez, SP
Costa-Campos, R
Canaguier, J
Barbosa, S
Martinez-Gili, L
Myridakis, A
Dumas, M-E
Bruneau, A
Cherbuy, C
Langella, P
Callebert, J
Launay, J-M
Chabry, J
Barik, J
Le Merrer, J
Glaichenhaus, N
Davidovic, L
Item Type: Journal Article
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.
Issue Date: 8-Jul-2021
Date of Acceptance: 27-May-2021
URI: http://hdl.handle.net/10044/1/91482
DOI: 10.1186/s40168-021-01103-z
ISSN: 2049-2618
Publisher: BioMed Central
Start Page: 1
End Page: 23
Journal / Book Title: Microbiome
Volume: 9
Issue: 1
Copyright Statement: © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Sponsor/Funder: Commission of the European Communities
Medical Research Council (MRC)
Funder's Grant Number: 305312
MR/M501797/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Microbiology
Microbiota
Autism
Behavior
Reward system
Metabolite
p-Cresol
4-Cresol
MU-OPIOID RECEPTOR
SPECTRUM DISORDER
GASTROINTESTINAL DYSFUNCTION
SEQUENCE ALIGNMENT
SOCIAL REWARD
MOUSE MODEL
CHILDREN
ANXIETY
SYMPTOMS
DOPAMINE
4-Cresol
Autism
Behavior
Metabolite
Microbiota
Reward system
p-Cresol
Animals
Autism Spectrum Disorder
Autistic Disorder
Cresols
Fecal Microbiota Transplantation
Gastrointestinal Microbiome
Humans
Mice
Animals
Humans
Mice
Cresols
Autistic Disorder
Autism Spectrum Disorder
Gastrointestinal Microbiome
Fecal Microbiota Transplantation
Science & Technology
Life Sciences & Biomedicine
Microbiology
Microbiota
Autism
Behavior
Reward system
Metabolite
p-Cresol
4-Cresol
MU-OPIOID RECEPTOR
SPECTRUM DISORDER
GASTROINTESTINAL DYSFUNCTION
SEQUENCE ALIGNMENT
SOCIAL REWARD
MOUSE MODEL
CHILDREN
ANXIETY
SYMPTOMS
DOPAMINE
0602 Ecology
0605 Microbiology
1108 Medical Microbiology
Publication Status: Published
Article Number: ARTN 157
Online Publication Date: 2021-07-08
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer
Faculty of Medicine



This item is licensed under a Creative Commons License Creative Commons