Julie Brouillet

Research project: 

Autism Spectrum Disorder and Gut Microbiota-Host Interactions. 

Autism Spectrum Disorder (ASD) is a group of heterogenous neurodevelopmental disorders, showing a dramatically increasing prevalence (currently observed in 1 in 160 people worldwide). The absence of treatment for patients with Autism and the poor understanding of its pathogenesis make it a major health problem. Core symptoms of ASD are impairments in social interaction and communication skills, as well as repetitive behaviours. These symptoms most likely result from a combination of genetic and environmental factors, but mechanisms underlying Autism pathophysiology remain largely unclear. Despite intensive research and recent breakthroughs, a great part of ASD cases remain idiopathic.

The gut-brain axis is the bidirectional communication between the central nervous system, the gastrointestinal tract and the gut microbiota. It is involved in neurodevelopment and immune function and is now known to play a major role in Autism. Indeed, many gut abnormalities can be found in ASD: gastrointestinal symptoms (up to 70% of autistic patients), gut permeability, immune dysregulations, gut dysbiosis, and elevated levels of serotonin which is mostly synthesised in the gut. Complying with these features, a recent clinical study showed that faecal transplant can reduce core symptoms of Autism as well as gastrointestinal symptoms. As Autism is now defined as a spectrum, huge clinical and aetiological heterogeneity is encountered and limits therapeutic innovation. Clinical trials results are often contradictory, therefore precise characterisation and stratification of patients is largely needed, to identify mechanisms and to develop mechanism-based treatment.

During my PhD, we will first analyse metagenomic profiles of  patients with Autism having three types of aetiologies: genetic (SHANK3 mutations), environmental (in utero valproate exposition), and idiopathic. Different aetiologies of Autism are probably associated with different gut microbiota compositions. Nonetheless, these different compositions likely have common metagenomic determinants on which we can act to test new therapeutic strategies for ASD. Second, we will perform bioinformatic analysis on the collected metagenomic data to identify a common signature in patients with different aetiologies of Autism. To date, no medical treatments are available that significantly improve the core symptoms of ASD. Probiotics are beneficial strains of micro-organisms. They are particularly interesting because they act on various aspects of gut homeostasis, which are altered in many chronic diseases including psychiatric diseases. Thus, the third aim of my project is to test a novel microbiotherapy combining a probiotic strain and bioactive molecules targeting together gut barrier permeability, inflammation and gut microbiota composition. We will perform a preclinical trial on the same three murine models of Autism mimicking aetiological differences (i.e. genetic, environmental and idiopathic) found in patients, to test the efficacy of a microbiotherapy to improve Autism-like symptoms in mouse models. 

In conclusion, my PhD project aims at targeting the gut microbiota, inflammation and intestinal permeability in order to improve Autism symptoms. This transdisciplinary study - investigating ASD on immunologic, psychiatric, microbiological, neurobiological aspects -  in multiple models will allow us to demonstrate the robustness of the microbial intervention.