Autism spectrum disorders (ASD) are a heterogeneous and yet incurable group of neuro-developmental disorders. Their prevalence has dramatically increased in the world, rising from 0.02% in 1975 to 1.2 % in 2012. Besides behavioural symptoms, a large subset of patients with ASD presents gastro-intestinal symptoms. Major gaps still remain in our understanding of aetiological and pathophysiological mechanisms underlying ASD. These latter are increasingly recognized as resulting from a complex interplay between genetic and environmental factors. In particular, recent studies have emphasized a putative role of gut microbiota as a co-factor associated with ASD development. However, the pathophysiological role of the gut microbiota in ASD and the mechanisms underlying microbiota-induced gut-brain axis dysfunctions remain unknown.
To lift this scientific barrier, we hypothesize in the Microbioautism project that gut dysbiosis in patients with ASD results in an abnormal composition of metabolites contributing to altered gut and brain functions. To address this hypothesis, Microbioautism have the following aims:
1) Determine in mice the impact of fecal supernatant of ASD patients (FS-ASD) on gut and brain functions and associated cellular and molecular changes.
2) Identify the role of the secondary bile acids, desoxycholic acid (DCA), as a putative candidate in gut and brain dysfunctions induced by FS-ASD.
3) To discover bacterial signatures in ASD patients associated with functional and transcriptomic pathological traits
The feasibility of achieving these aims is supported by strong preliminary results already obtained by a consortium of clinicians expert in the field of autism (M Leboyer, University Hospital Henri Mondor, Créteil) and researchers expert in functional microbiology (J Doré, Inra, Jouy en Josas), neuroimmunology (L Davidovic, CNRS , Nice), and neurogastroenterology (M Neunlist, Inserm 1235, Nantes) which are the core partners of the current project. Indeed, our teams have established a cohort of patients with ASD and healthy controls with the corresponding stool bio-collection. Metagenomic and metabolomics analysis performed on feces from patients with ASD and controls showed modifications of microbial communities and increased concentration of the bacterial-derived metabolite DCA in ASD compared to controls. Furthermore, fecal supernatant (FS) transferred into mice induced functional changes in gastrointestinal functions that were associated with altered expression, both in gut and brain, of key molecules related to neuronal connectivity.
We believe that Microbiautism will have major scientifical and societal impacts. First, it will bring novel important scientific knowledge on ASD pathophysiological mechanisms for which environment/health interactions are increasingly suspected to be an underlying mechanisms of disease. Microbiautism is therefore also fully in line with priority defined in the present ANR call, as well as with strategic priority defined by the government. In addition, discovering bacterial signatures in ASD patient’s associated with pathological traits will set the basis for future development of novel therapeutical symptoms-based strategies aimed at modulating the gut microbiota in ASD. Finally, Microbiautism has also the ambition to increase public and political awareness to support the development of research in Autism and more generally in psychiatric conditions.
Monsieur Michel NEUNLIST (The Enteric Nervous System in Gut and Brain Disorders)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
IPMC Institut de pharmacologie moléculaire et cellulaire
IMRB Institut Mondor de recherche biomédicale
TENS The Enteric Nervous System in Gut and Brain Disorders
Help of the ANR 458,946 euros
Beginning and duration of the scientific project: December 2019 - 48 Months