Project GEMMA

• 03 October 2018

GEMMA is an innovative scientific research project for the evaluation of interactions between microbiome, metabolome, epigenome and immune responses in order to provide new diagnostic and preventive approaches to autism.

Salerno and Brussels - Wednesday 3 October 2018

Autism Spectrum Disorders (ASDs) in the world affect 1 child out of 59 (1 in every 37 males and 1 in every 151 females, a 40-fold increase in cases compared to 1960) are among the biggest concerns of families and national health systems. According to a study by the London School of Economics, these disorders result in higher social costs than those associated with the sum of cancer and cardiovascular disorders combined

While the world faces an ASD pandemic, the scientific community cannot understand the complex set of risk factors that cause it. To date, the diagnosis of ASD is entirely linked to behavioural assessments, while there are no biomarkers able to allow instrumental analysis. Familiarity factors are involved in the development of these disorders, as demonstrated by the risk factor of developing ASD 10 times higher for the brother of a child with ASD than those who have no familiarity factors. Despite this awareness today there are no preventive protocols able to reduce or eliminate this risk.

GEMMA (Genome, Environment, Microbiome and Metabolome in Autism) will be the first project to combine rigorous analysis of environmental data with the most recent multi-omic analysis. Through this strategy it will be possible to obtain an analysis of the composition and function of the complex set of microorganisms of the gastrointestinal tract (called microbiome) and, consequently, develop protocols of personalized medicine for the treatment and prevention of ASD.

The aim of the GEMMA project is to provide data on the development and progression of ASDs, with particular attention to how changes in the microbiota are related to ASD. These analyses will allow to identify possible targets for the prevention of the treatment of these disorders. The observations will be based on the in-depth study of 600 children characterized by risk factors for ASD. These children will be monitored from birth by evaluating the epigenetic modifications that control intestinal permeability and the functions of the immune system. The collected data will be integrated with preclinical studies in order to bring to light the relationship between the composition and the function of the human microbiota with the development of ASD. These results will allow us to design preclinical studies based on modern human feces transplantation strategies for the prevention of ASD.

This international project involves numerous brilliant centers based in Europe and the United States. The collaboration network will be able to validate the results obtained and integrate them on a large scale by exploiting already existing multi-room data libraries. In the same way, clinical trial data will be shared and harmonized. Only a conglomeration of high-level research centers can be able to analyze the huge amount of data obtained which includes changes in microbiota, genomics, epigenetics, metabolome integrity of the mucosal barrier and the immune response all related to the development of ASD.

The GEMMA project will identify the needs of individual patients (personalized treatment) and prevention strategies (primary prevention) aimed at modulating the microbiota to restore / maintain the correct intestinal homeostasis. The identified biomarkers will help to clarify the pathogenesis of ASDs in children who have family members with ASD and to formulate innovative approaches that can radically change the progress of ASDs by manipulating the microbiota (by administering pre / pro / symbiotics) as a preventive intervention strategy.

The GEMMA project brought together a team of scientists from EBRIS, Nutricia Research, Medinok, Bio-Modeling Systems, Euformatics, Theoreo, National University of Ireland Galway, Salerno Local Health Authority, National Research Council, INRA, INSERM, Utrecht University, Tampere University, Imperial College London, John Hopkins University and Massachusetts General Hospital for Children (the hospital connected to the Harvard Medical School).

The project has a duration of 5 years and a total budget of € 14.2M.

The institute that coordinates the project

The mission of the EBRIS foundation is to provide a multidisciplinary platform to discover the molecular basis of human pathologies and transform knowledge into new strategies for treatment and prevention. The EBRIS foundation represents a junction between the basic sciences and the creation of new strategies for the prevention of human diseases, new pharmacological interventions and new drug delivery strategies. The EBRIS mission is characterized by the use of the most innovative technologies available and the commitment to using preclinical models for in vitro studies of numerous human diseases. The goal of EBRIS is to create a network with other European research institutes and share the excellence to develop innovative research projects that can define the role of the environment on human health. Patterns of diseases such as celiac disease, type 1 diabetes, autism and schizophrenia are rigorously studied to determine the effects that the environment plays (especially during the first year of life) in defining the composition of the microbiota, metabolism and activation of the immune system.

STATEMENT FROM DR. ALESSIO FASANO

Despite all the advances in the knowledge of Autism Spectrum Disorders (ASD), there are still many pieces to be filled in order to understand why some individuals develop this disorder. One thing is certain that we are in the middle of an epidemic of ASD that is parallel to that of chronic inflammatory diseases. However, one difference is represented by the growth curve in the frequency of ASDs which went from 1 case every 500 in the mid 70s to 1 every 59 in 2018. This suggests that the environment in which we live is involved in the outbreak of this epidemic.

Lately, there has been an increase in interest in the study of microbiota as a possible cause of many chronic inflammatory diseases, including ASD. The greatest limitation of current studies is that these are observational studies of a descriptive nature that associate possible symbioses to pathologies without proving their causality.

The ambitious experimental design of GEMMA provides for the enlistment of infants at risk ASD to be followed step by step for 5 years until the possible occurrence of ASD. In this way we will be able to understand what genetic predisposition, what environmental stimulus, what kind of microbiota or metabolic profile and what role the intestinal permeability play in creating the perfect storm that leads to the development of ASD.

We have employed a formidable group of experts in genomics, microbiology, metabolomics, epidemiology, models of preclinical experimentation, biostatistics and bioinformatics to create a mathematical model that will be able to predict who will develop ASD and under what circumstances. The final aim of the project is to obtain the necessary information to create customized strategies for the prevention and treatment of ASD.

STORY:

It is the year 2025: Gemma, a 12-month-old girl is in the pediatrician's office accompanied by her mother and her 3 and a half – year – old brother with autism. A month earlier, Gemma was treated with an oral antibiotic therapy for a form of average otitis. Her mother told the pediatrician that the otitis was resolved, but Gemma now suffers from constipation and stomachache.

The doctor may recommend a series of specific analyses for siblings of children with Autism Spectrum Disorders (ASD), including a whole genome sequencing. The doctor knows very well that Gemma has a much higher probability of developing ASD, therefore he prescribes analyses for intestinal permeability, a blood immune profile test, meta - genomic analysis, meta – transrhythmic and metabolomics on feces and urine.

While instrumental analyses are carried out in search of predictive biomarkers, Gemma is accompanied by a physical and behavioral examination, both showing satisfactory growth and reaching the goals of a 12-month-old girl. At the end of the examination the blood and stool analyses results are ready.

The results of the analyses are worrying: zonulin (a marker associated with high intestinal permeability) is high, the pro-inflammatory immune cells are activated and the microbiota shows a decrease in F. prausnitzii and an increase in Enterobacteria. Metatrascrittoma also indicates that the genes involved in lactate production by Lactobacilli are suppressed and the metabolome analyses confirm a decrease in lactate in the feces and an increase in cresol in the urine. Based on the sequencing and epigenetic data it is established that the genes involved in immune activation are high and in fact the PET scan of Gemma confirms a neuro-inflammation in the brain.

The doctor then performs a comparative analysis that reveals how the combination of Gemma's biomarkers leads to a risk of developing ASD within 9 months 55 times higher than the average. The doctor then prescribes the administration of Lactobacillus GG (LGG) 1010 CFU / day for 3 months in order to correct the composition of the microbiota and restore lactate production in order to prevent the development of ASD.

Gemma's mother is stunned by the scientific findings that led to personalized preventive medicine and tells the doctor: "When we had our first child in 2018, autism was incurable and there was certainly no strategy for prevention."

The doctor explains: "Medicine has made a big leap forward when a project of the European Community's Horizon 2020 framework program has demonstrated the link between some biomarkers and the microbial intestinal groups that cause neuro-inflammation that can cause ASD. Once this bond has been demonstrated, we have been able to intervene to restore the correct microbiota with personalized probiotics capable of preventing autism. To date, that project has been the most important study related to ASD”.

Three months later Gemma returns to the pediatrician's office. All the blood and stool tests reveal that the biomarkers have returned to normal and from the PET scan the brain is no longer inflamed. Gemma may have a normal and healthy childhood. Meanwhile, Gemma's brother has also been offered new treatments to mitigate the immune response caused by specific biomarkers deriving from the intestinal microbiota, these treatments act by attenuating the inflammatory pathway by acting on the Toll-like family receptors.