ERA-NET NEURON: The Gut Microbiome in Neuroinflammation and Neurodevelopmental Disorders

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, neuroinflammation
drastically 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 impact
behaviour. The µNeuroINF project will explore the hypothesis that our gut bacteria may trigger
neuroinflammation, which in turn impacts metabolism and behaviour, and ultimately contributes to
neurodevelopmental disease progression. Using mouse models of Down syndrome, Fragile X
syndrome and autism spectrum disorders, we will study the gut bacteria, their genes, proteins and
metabolites 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 project
targeting the role of the gut bacteria in neuroinflammation. Our unique research strategy uses cuttingedge technologies to explore how gut microbes modulate brain inflammation in neurodevelopmental
disorders. Not only the project will demonstrate one of the most fundamental mechanisms by which
our 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 neuroinflammation

Neurodevelopmental disorders (NDD) appear during nervous system development and maturation and originate from a variety of genetic and environmental causes or a combination of both. NDDs
result in lifelong intellectual disability and behavioural alterations (anxiety, hyperactivity, social
impairment, communication deficits) and have therefore extremely heavy socio-economical
consequences. 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). Recent
studies demonstrate the existence of a gut-brain axis through which the intestinal microbiota is able to
modulate inflammation. The µNeuroINF project is driven by our hypothesis that the gut microbiome
modulates neuroinflammation impacting metabolism and behaviour and contributing to NDD
pathophysiology. By studying common effects across three mouse models of NDD: i) the Fmr1-KO
mouse model of FXS, ii) the Ts65Dn trisomic mouse model of DS, and iii) the Maternal Immune
Activation (MIA) ASD mouse model, we aim to unravel mechanisms by which gut microbial
metabolites modulate neuroinflammation and contribute to NDD-related behavioural phenotypes. Our
three specific objectives are: 1) to acquire complete metabolomic, metagenomic and metaproteomic
neuroinflammatory signatures in three NDD mouse models, 2) to identify microbial metabolites
modulating 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 and
metabolites 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 novel personalised medicine
and therapeutic strategies for NDD and neuroinflammation, driven by the gut microbiome.