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Genome, Environment, Microbiome & Metabolome in Autism: an integrated multi-omic systems biology approach to identify biomarkers for personalized treatment and primary prevention of Autism Spectr

Periodic Reporting for period 1 - GEMMA (Genome, Environment, Microbiome & Metabolome in Autism: an integrated multi-omic systems biology approach to identify biomarkers for personalized treatment and primary prevention of Autism Spectr)

Reporting period: 2019-01-01 to 2019-12-31

GEMMA has received funding from the EU Horizon 2020 programme under Grant Agreement No 825033. GEMMA aims to employ an integrated multi-omic systems biology approach to identify biomarkers for personalized treatment and primary prevention of Autism Spectrum Disorders (ASD). The project plan will consist on recruiting 600 infants at risk of autism and analyze, at multi-omics level, their biological samples over a 36 month period along the project’s 5-years-period, followed by an interventional arm to manipulate the gut microbiome in order to mitigate infiammation both at the gastrointestinal level and in the brain of children that will develop ASD during the study. It has been widely demonstrated that 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 behaviors. ASD represent a significant public health issue since it dramatically increased in the last decades reaching the prevalence of 1 in 59 children around the world with a strong sex bias (4:1 male:female ratio). Moreover, it was found that in families with a children with ASD, the chances that a siblings will develop autism are around one in five, thus considering the presence of inherited risk factors. Many individuals with ASD suffer from associated co-morbidities (i.e. metabolic conditions, and gastrointestinal disorders), and the neuroanatomical and biochemical characteristics associated with autism pathogenesis involve mechanisms that are direct consequences of the effects of systemic inflammatory events. The scope of the project is to use high quality microbiome, metabolome, and other -omics data to link microbiome composition and function with specific disease for personalized prediction, prevention, and treatment of disease: the prospective study to identify potential biomarkers, able to predict ASD development followed by validation on large multi-omic datasets will be the main goal of GEMMA. 3 infants recruitment centers will allow a global sampling based on their geographical coverage (Europe and US) and their broad network, which will facilitate the recruitment of 600 newborns in families already with a child suffering from ASD. GEMMA workflow was based on two non-mutually exclusive hypotheses: the first, affirming that the gut bacterial dysbiosis leads to epigenetic modifications, changes in metabolite profiles, increased gut permeability, increased macromolecules trafficking and, ultimately, to altered immune responses to promote disease in a subset of individuals at-risk of ASD; the second, asserting that the genome/metagenome interplay is responsible for the switch from immune tolerance to immune response to environmental stimuli, including dietary and microbial factors leading to neuroinflammation responsible of behavioral changes that characterize ASD and gut inflammation causing its GI co-morbidities.
"Two clinical studies will be performed, one observational and one intervention trial, in children with susceptibility to develop ASD. The intervention trial will take place in children developing ASD during the observation period. Initially, infants at risk will be monitored in the observation trial from birth over a 36 month period along with their affected ASD sibling. Collected specimens (blood, stool, urine and saliva) will be subjected to microbiome, immune and multiple biochemical and genetic analyses. The interventional trial will further employ data from the preclinical studies to formulate a ""pre-, pro-, sym-biotic"" therapies for ASD subjects. The review of the relevant scientific literature allowed to construct the first set of qualitative models of ASDs pathogenesis, its relationship with the intestinal microbiome and the interactions with the hosts’ functions. Indeed, linking microbiome and host-response alterations could increase sensitivity and specificity of ASDs diagnosis in children: furthermore, shifting the focus from alterations in the ratios of microbial taxa to species distribution and function, may carry greater analytical relevance. Additionally, it is conceivable that environmental conditions (including maternal microbiome) are more likely to influence ASDs pathogenesis during fetal development through RNA editing phenomena, thus explaining for example altered neuronal migration trajectories. The resulting neuroanatomical alterations likely affect the balance between the sympathetic and parasympathetic systems, allegedly inducing deregulation of the gut-brain axis, thereby reducing intestinal immunity and osmotic homeostasis.
Contextually, sample collection protocols suggested for specimen processing pointed at ensuring both the use of the best practices in each -omic field and the reliability required in an integrated multi-omic approach. The biobank set up will ensure a strict compliance with appropriate European and international ethical standards. Consortium additionally have implemented a dedicated protocol to drive the process to collect information on exploitable foreground among partners, intended to acquire and process data that support the identification of exploitable foreground and their potential application. In parallel, tools for microbiome, genome, epigenome, and metabolome profile analysis were tested: SWs provide a platform for dynamic data analysis and interpretation, and will be essential to support the overall prognostic and diagnostic process.
Pre-clinical trials will consist in Fecal Microbiota Transplantation from human autistic children to germ-free mice. To this end, stools were collected from ASD children with GI symptoms and without GI symptoms, and their respective siblings that will be used as controls. Experiments will represent an essential tool to support diagnosis and provide preliminary data for interventional trials. To this aim, the process of selection of candidate probiotics microorganisms also started.
In addition, activities were focused on project dissemination strategies to reach out to potential users. The project website (gemma-project.eu) together with profiles on social media platforms were released to communicate the project, news and events and disseminate the results to all society. Due to the topic of the project regarding a neuro developmental disorder that involves many children and their families, the communication has been based on the “emotional” and the “inclusion” aspects by the development of an accessible website."
GEMMA consortium has been creating a tight network to ease multi-omics data exchange between the leading research groups in Europe and the US. The main purpose will be the generation of a continuously updated multi-omics open data portal for autism, integrated with existing omics databases. The availability of a biobank, composed by specimens collected from a cohort of 600 infants as risk of ASD, observed from birth, may leverage future multi-omics studies, not only for ASD, but for the majority of multi-factorial disorders. The expected results will be promptly shared during the project, with an increasingly strengthened open data management, complemented with dynamic data analysis, for the identification of reliable markers to efficiently diagnosing autism. The opportunity to diagnose ASD, predicting the onset of clinical manifestations, may allow the primary prevention, by intervening with tailored probiotic therapies.
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