The brain is an extraordinarily complex organ that develops early on in embryonic life.Neurodevelopment results from the execution of epigenetic and genetic programs, and is strongly influenced by environmental factors. A precise sequence of events is initiated, hich, while disrupted by genetic defects or environmental insults such as infections, provokes non-recoverable developmental alterations leading to mental diseases. In addition to the synaptic and/or connectivity dysfunctions associated to neurodevelopmental disorders, inflammation in the brain (otherwise called neuroinflammation) is one of the hallmarks shared by different neurodevelopmental disorders, such as Down syndrome, Fragile X syndrome and Autism Spectrum Disorders. In fact, neuroinflammationdrastically affects brain activity and behaviour. Recent studies demonstrate the existence of a gutbrain axis through which the intestinal microbiota is able to modulate inflammation and impactbehaviour. The µNeuroINF project will explore the hypothesis that our gut bacteria may triggerneuroinflammation, which in turn impacts metabolism and behaviour, and ultimately contributes toneurodevelopmental disease progression. Using mouse models of Down syndrome, Fragile Xsyndrome and autism spectrum disorders, we will study the gut bacteria, their genes, proteins andmetabolites to identify which microbial metabolites common to these diseases are absorbed in the gut and diffuse into the bloodstream to reach the brain. The potential pro-inflammatory role of these metabolites will be investigated in vitro by screening their pharmacological targets in the host, and in vivo in the animal models of the disease. This will ultimately lead to novel therapeutic strategies for NDD driven by the gut microbiome. The µNeuroINF initiative is an innovative multidisciplinary projecttargeting the role of the gut bacteria in neuroinflammation. Our unique research strategy uses cuttingedge technologies to explore how guticrobes modulate brain inflammation in neurodevelopmentaldisorders. Not only the project will demonstrate one of the most fundamental mechanisms by whichour gut bacteria influence our behaviour, but it will also identify the microbial metabolites that can be used to better monitor brain inflammation ("biomarkers") or to lead to new drugs ("lead compounds") for the treatment of neuroinflammationTechnical SummaryNeurodevelopmental disorders (NDD) appear during nervous system development and maturation and originate from a variety of genetic and environmental causes or a combination of both. NDDsresult in lifelong intellectual disability and behavioural alterations (anxiety, hyperactivity, socialimpairment, communication deficits) and have therefore extremely heavy socio-economicalconsequences. Neuroinflammation is one of the hallmarks shared by NDD, including Down syndrome(DS, 1:800), Fragile X syndrome (FXS, 1:6000) and Autism Spectrum Disorders (ASD, 1:100). Recentstudies demonstrate the existence of a gut-brain axis through which the intestinal microbiota is able tomodulate inflammation. The µNeuroINF project is driven by our hypothesis that the gut microbiomemodulates neuroinflammation impacting metabolism and behaviour and contributing to NDDpathophysiology. By studying common effects across three mouse models of NDD: i) the Fmr1-KOmouse model of FXS, ii) the Ts65Dn trisomic mouse model of DS, and iii) the Maternal ImmuneActivation (MIA) ASD mouse model, we aim to unravel mechanisms by which gut microbialmetabolites modulate neuroinflammation and contribute to NDD-related behavioural phenotypes. Ourthree specific objectives are: 1) to acquire complete metabolomic, metagenomic and metaproteomicneuroinflammatory signatures in three NDD mouse models, 2) to identify microbial metabolitesmodulating neuroinflammation in NDD, 3) to screen their pharmacological targets and test in vivo their effect on neuroinflammation and behaviour. Meta-"omics" will reveal microbial genes, proteins andmetabolites associated with variations in brain cytokines, immune cell populations and behavioural phenotypes in NDD. Microbial metabolites will be screened for pharmacological targets such as receptors and kinases, and mechanisms will be validated in vivo to explore the modulatory role of the gut microbiome on immunity and behaviour. This will ultimately lead to ovel personalised medicineand therapeutic strategies for NDD and neuroinflammation, driven by the gut microbiome.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
