PROJECT: JTC2014: mNeuroINF

The Role of the Gut Microbiome on Neuroinflammation and Neurodevelopmental Disorders

Abstract

Neurodevelopmental disorders (NDD) appear during nervous system development and maturation and originate from a variety of genetic and environmental causes. NDDs result in lifelong intellectual deficiency and behavioural alterations (anxiety, hyperactivity, social impairment, communication deficits) and have therefore extremely heavy socio-economical consequences. Neuroinflammation (NI) is one of the hallmarks shared by NDD, incl. Down Syndrome (DS, 1:800), Fragile X syndrome (FXS, 1:6000) and Autism Spectrum Disorders (ASD, 1:100). Our hypothesis is that the gut microbiome modulates NI and contributes to NDD pathophysiology impacting metabolism and behaviour. By studying common effects across three mouse models of NDD - the Ts65Dn aneuploidy mouse (DS), the Fmr1-KO mouse (FXS) and the maternal immune activation (MIA) of ASD-, our three specific objectives are: 1) to acquire metabolomic, metagenomic and metaproteomic signatures in three NDD mouse models, 2) to identify microbial metabolites modulating NI in NDD, 3) to screen their pharmacological targets and test in vivo their effect on NI and behaviour. Meta-“omics” will reveal microbial genes, proteins and metabolites associated with variations in brain cytokines, immune cell populations and behavioural phenotypes in NDD. Microbial metabolites will be screened for pharmacological targets (receptors, kinases) and mechanisms will be validated in vivo to explore novel therapeutic strategies for NI opened by the gut microbiome.

Keywords

Pharmacology, Behavioural methodologies, proteomics, neuroinflammation, "omics" approaches, metagenomics, metabolomics, FACS

Call topic

Neuroinflammation

Proposed runtime

2014 - 2018

Project team

Dumas (Coordinator)
United Kingdom (MRC)
Davidovic
France (ANR)
Macek
Germany (BMBF)
Altafaj
Spain (MINECO)