State of the art

The rates of autism has 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 [1]. 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 [2][3][4] probably due to a multifactorial cause of autism and that autism is a final pathological destination that can be reached through different pathways. Therefore, it is imperative to understand the autism population based on the identification of specific biomarkers that can assist in personalizing interventions for the most effective therapeutic results. Tackling this major public health issue requires urgent action and the formation of interdisciplinary consortia in order to further our understanding of autism and its possible treatment of autism-related symptoms. Many individuals with autism 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 [5][6][7] involve mechanisms that are direct consequences of the effects of low-grade, feverless, systemic inflammatory events [8][9] while the protective mechanisms against autism pathogenesis have strong anti- inflammatory components [10]. The gut microbiome drives immunoregulation (in particular during the 1000 days of life) and dysregulated immunoregulation [11] as well as inflammation predispose to autism, while psychological stress drives further inflammation via pathways that involve the gut microbiome [12][13]. Children with autism experience four times more GI symptoms than control groups and GI symptoms may identify a unique subgroup of children with autism [14]. Aberrant immune system activation and alterations in gut microbial composition that correlate with autism-related symptoms have also been suggested [15]. Finally, a link between gut microbiome and immune function in autism has been reported [16] as well as improvement of both GI and autism-related symptoms in autism subjects in which the gut dysbiosis was corrected by microbiota transfer therapy [17].

Objectives

The 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 autism 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 who have a family history of autism from birth to identify potential biomarkers predictor of autism 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 children with autism, which will facilitate the recruitment of ~600 infants that have a family history of autism (new-borns in families already with a child with autism). 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. The 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 that have a family history of autism.
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 neuro-inflammation responsible of behavioral changes that characterize autism and gut inflammation causing its GI co-morbidities.

If proven correct, these hypotheses support the possibility that early identification and stratification of vulnerable patients through the exploitation of gut microbiome composition/function mechanistically associated with disease pathogenesis could translate in personalized targeted interventions prevent the onset of GI conditions and pave the way for earlier intervention for autism and treatment for autism-related symptoms.

Since microbiome changes have been associated to various human conditions including autism, this prospective cohort project (follow from birth a cohort who have a family history of autism (i.e. siblings of patients with autism) so that the composition and function of the microbiome can be compared in the same subject before and after the onset of the condition) will test for the first time, in human clinical studies, the causality in autism by alterations in gut microbiome composition and function mechanistically linked to the onset of the disease. The project will use a combination of patient cohorts, animal models and prospective patient samples to investigate whether specific patterns of gut dysbiosis influence epigenetic modification in the host, modifies metabolic pathways, altered gut permeability and immune response and, ultimately, trigger and/or increase the severity of autism-related symptoms and related GI comorbidities. Moreover, using specific to stratify patient populations for specific interventions, the project will attempt to validate the hypothesized mechanisms of ASD via the personalized correction of gut dysbiosis and the observation of whether changes in proposed condition-specific pathophysiology take place.