Scientists, Doctors, Companies
State of the artAutism Spectrum Disorders (ASD) is not a single disorder, but a spectrum of related disorders with a shared core of symptoms defined by deficits in communication, social reciprocity and repetitive, stereotypic behaviours. ASD represent a significant public health issue since it drammatically increased in the last decades reaching the prevalence of 1 in 59 children around the world (source: ADDM Network, www.cdc.gov/ncbddd/autism/addm.html ) with a strong sex bias (male:female=4:1). This pandemic is only partially attributable to extrinsic factors such as improved awareness and recognition and changes in clinical practice or service availability . Thus, other environmental factors are likely at play to explain this pandemic. Based on the gene/environment interaction theory, several therapeutic approaches have been proposed with conflicting results  probably due to a multifactorial cause of ASD and the fact that ASD is a final pathological destination that can be reached through different pathways. Therefore, it is imperative to stratify the ASD population based on the identification of specific biomarkers that can assist in personalizing interventions for the most effective preventive or therapeutic results. Tackling this major public health issue requires urgent action and the formation of interdisciplinary consortia in order to further our understanding of ASD and its possible treatment/prevention. Many individuals with ASD suffer from associated co-morbidities, including seizures, sleep problems, metabolic conditions, and gastrointestinal (GI) disorders, which have significant health, developmental, social, and educational impacts. The neuroanatomical and biochemical characteristics that have been associated with autism pathogenesis  involve mechanisms that are direct consequences of the effects of low-grade, feverless, systemic inflammatory events  while the protective mechanisms against autism pathogenesis have strong anti- inflammatory components . The gut microbiome drives immunoregulation (in particular during the 1000 days of life) and dysregulated immunoregulation  as well as inflammation predispose to psychiatric disorders, including autism, while psychological stress drives further inflammation via pathways that involve the gut microbiome . Children with ASD experience four times more GI symptoms than control groups and GI symptoms may identify a unique subgroup of children with ASD . Aberrant immune system activation and alterations in gut microbial composition that correlate with autism severity have also been suggested. Finally, a link between gut microbiome and immune function in ASD has been reported  as well as improvement of both GI and behavioural symptoms in ASD subjects in which the gut dysbiosis was corrected by microbiota transfer therapy .
ObjectivesThe scope of this project is to use high quality microbiome, metabolome, and other -omics data produced by large-scale international initiatives to link microbiome composition and function with specific disease for personalized prediction, prevention, and treatment of disease. Unfortunately, current large-scale datasets in ASD are mostly cross-sectional studies (cases vs controls) that do not allow the mechanistic link between microbiome composition/function with disease onset. Rather, prospective studies following infants at-risk from birth to identify potential biomarkers predictor of ASD development followed by validation on large multi-omic datasets are necessary in order to achieve this goal. The 3 patient recruitment centres will allow a global sampling based on their geographical coverage (2 European centres (Ireland and Italy) and MGH, a United States of America (US) partner) and their broad network covering over 9,500 families with ASD children, which will facilitate the recruitment of ~600 infants at risk of ASD (new-borns in families already with a child suffering from ASD). This is in line with the call’s recommendation to expand on current data in order to achieve the overall goal of this funding initiative. Therefore, the GEMMA consortia team has been designed with this approach in mind, in order to explore:
- 1) he hypothesis that gut bacterial dysbiosis leads to epigenetic modifications, changes in metabolite profiles, increased gut permeability, increased macromolecules (food- and/or microbial-derived) trafficking and, ultimately, to altered immune responses to promote disease in a subset of individuals at-risk of ASD
- 2) The hypothesis that the genome/metagenome interplay is responsible for the switch from immune tolerance to immune response to environmental stimuli (antigens) including dietary and microbial factors leading to neuroinflammation responsible of behavioural changes that characterize ASD and gut inflammation causing its GI co-morbidities.