Published July 8, 2021
| Version v1
Journal article
The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota
Creators
- Bermudez-Martin, Patricia
- Becker, Jérôme
- Caramello, Nicolas
- Fernandez, Sebastian
- Costa-Campos, Renan
- Canaguier, Juliette
- Barbosa, Susana
- Martinez-Gili, Laura
- Myridakis, Antonis
- Dumas, Marc-Emmanuel
- Bruneau, Aurélia
- Cherbuy, Claire
- Langella, Philippe
- Callebert, Jacques
- Launay, Jean-Marie
- Chabry, Joëlle
- Barik, Jacques
- Le Merrer, Julie
- Glaichenhaus, Nicolas
- Davidovic, Laetitia
Contributors
Others:
- Institut de pharmacologie moléculaire et cellulaire (IPMC) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS) ; COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
- Physiologie de la reproduction et des comportements [Nouzilly] (PRC) ; Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (INRAE)
- Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ) ; Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Imperial College London
- Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)) ; Institut Pasteur de Lille ; Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
- McGill University and Genome Quebec Innovation Centre
- MICrobiologie de l'ALImentation au Service de la Santé (MICALIS) ; AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (INRAE)
- Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord
- Fondation FondaMental [Créteil]
- UK Research & Innovation (UKRI) Medical Research Council UK (MRC)MR/M501797/1
- Region the Centre-Val de Loire (ARD2020 Biomedicaments GPCRAb)
- ANR-19-CE14-0024,MICROBIAUTISM,L'axe microbiome-intestin-cerveau dans les troubles du spectre de l'autisme(2019)
- European Project: 291840,EC:FP7:HEALTH,FP7-ERANET-2011-RTD,ERA-NET NEURON II(2012)
Description
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.
Abstract
International audienceAdditional details
Identifiers
- URL
- https://hal.archives-ouvertes.fr/hal-03434993
- URN
- urn:oai:HAL:hal-03434993v1
Origin repository
- Origin repository
- UNICA