Gemma Published scientific articles

Autism research

Troisi et al., 2020. Genome, Environment, Microbiome and Metabolome in Autism (GEMMA) Study Design: Biomarkers Identification for Precision Treatment and Primary Prevention of Autism Spectrum Disorders by an Integrated Multi-Omics Systems Biology Approach. Brain Sci. 2020 Oct 16;10(10):743. DOI: 10.3390/brainsci10100743

Autism Spectrum Disorder (ASD) affects about 1 in 54 children in the U.S.A., with a significant increase since 1960. While improved awareness and clinical practices may explain some of this rise, they do not fully account for it. Research suggests a link between ASD and gut microbiota due to gastrointestinal issues in many affected children. Current studies are limited in understanding the mechanisms of ASD. The GEMMA study, supported by the European Commission, aims to follow at-risk infants (because they are siblings of autistic children) from birth to identify biomarkers for ASD development, involving both clinical trials and pre-clinical studies to explore microbiome associations and potential treatment responses.

Needham et al., 2021. Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder. Biol Psychiatry. 2021 Mar 1;89(5):451-462. doi: 10.1016/j.biopsych.2020.09.025

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and repetitive behaviors, along with metabolic imbalances and gastrointestinal dysfunction. This study aimed to explore non-behavioral features of ASD by analyzing molecular signatures in plasma and fecal samples from children with ASD and typically developing controls using mass spectrometry. Key differences in amino acid, lipid, and xenobiotic metabolism were identified, indicating oxidative stress and mitochondrial dysfunction. The study also found correlations between metabolite profiles and clinical behavior scores, suggesting a link between metabolism, gut physiology, and behavioral traits, which may help in developing molecular biomarkers for ASD.

Beopoulos A. et al. Autonomic Nervous System Neuroanatomical Alterations Could Provoke and Maintain Gastrointestinal Dysbiosis in Autism Spectrum Disorder (ASD): A Novel Microbiome-Host Interaction Mechanistic Hypothesis. Nutrients. 2021 Dec 24;14(1):65. doi: 10.3390/nu14010065

The article discusses how dysbiosis, often caused by environmental and lifestyle factors, may play a role in autism spectrum disorder (ASD). It suggests that gut microbiota imbalance in ASD might be linked to dysfunction in the autonomic nervous system, leading to a vicious cycle of gut-brain axis disruption and persistent dysbiosis.

Lombardi and Troisi, 2021. Gut Reactions: How Far Are We from Understanding and Manipulating the Microbiota Complexity and the Interaction with Its Host? Lessons from Autism Spectrum Disorder Studies. Nutrients 2021, 13(10), 3492; DOI: 10.3390/nu13103492

Autism is a group of neurodevelopmental disorders marked by early difficulties in social communication and repetitive behaviors, with both genetic and environmental factors contributing to its development. This review examines the role of the gut microbiome in autism, highlighting how methodological differences in studies have led to inconsistent results regarding the balance of harmful and beneficial bacteria. It also discusses the effects of gut microbial and dietary interventions on autism symptoms, noting the lack of standardized methods that hinder comparability. The authors suggest that a multi-omic longitudinal approach could help study metabolic changes related to microbiome alterations.

Zheng et al., 2021. The Role of Bacterial-Derived Aromatic Amino Acids Metabolites Relevant in Autism Spectrum Disorders: A Comprehensive Review. Front Neurosci. 21;15:738220. doi: 10.3389/fnins.2021.738220

Recent studies have highlighted the involvement of gut microbiota in the pathogenesis of autism spectrum disorders (ASD), showing microbial dysregulation in autistic patients and animal models. The gut microbiota influences food metabolism and produces metabolites that may be linked to neurodevelopmental disorders. Two specific metabolites, p-cresol sulfate and 4-ethylphenyl sulfate, have been associated with ASD and are derived from bacterial fermentation by commensal bacteria. These metabolites may enter the bloodstream, cross the blood-brain barrier, and impact microglial cells, potentially influencing neuroinflammation. This review discusses the significance of these metabolites as ASD potential biomarkers and intervention targets, while emphasizing the need for further research to establish their causal link with ASD pathophysiology.

Zheng et al., 2022. The Autism Spectrum Disorder-Associated Bacterial Metabolite p-Cresol Derails the Neuroimmune Response of Microglial Cells Partially via Reduction of ADAM17 and ADAM10 Int J Mol Sci. 23(19):11013. doi: 10.3390/ijms231911013

Children with autism show high levels of the bacterial metabolite p-cresol and its derivative pCS. This study reveals that pCS alters brain immune cell (microglia) activity by affecting key proteins ADAM10 and ADAM17, disrupting inflammation and immune responses. These findings suggest that gut-derived metabolites may contribute to autism by influencing brain immunity.

Beopoulos et al., 2022. Autism spectrum disorders pathogenesis: Toward a comprehensive model based on neuroanatomic and neurodevelopment considerations. Front Neurosci. 2022 Nov 3;16:988735. doi: 10.3389/fnins.2022.988735

Autism spectrum disorder (ASD) involves abnormal early brain development, with disrupted neural connections and an imbalance between brain excitation and inhibition. These changes begin in the womb due to faulty cortical layer formation and affect postnatal brain pruning, leading to a wide range of symptoms. The authors suggest that environmental changes affecting serotonin in early pregnancy may trigger ASD by altering brain development during a critical prenatal window.

Beopoulos et al., 2023. RNA epitranscriptomics dysregulation: A major determinant for significantly increased risk of ASD pathogenesis. Front Neurosci. 2023 Feb 16;17:1101422. doi: 10.3389/fnins.2023.1101422

Autism spectrum disorders (ASDs) are complex and highly variable neurodevelopmental conditions with unclear causes. While genetic and epigenetic factors are known to contribute, this study highlights the potential central role of RNA epitranscriptomics in ASD pathogenesis. These RNA-based mechanisms, influenced by environmental factors like maternal inflammation, can disrupt early brain development by altering protein expression patterns. Even small early changes may lead to a wide range of neurological and behavioral abnormalities, helping explain ASD’s clinical and genetic diversity.

Zheng et al., 2023. The interaction between intestinal bacterial metabolites and phosphatase and tensin homolog in autism spectrum disorder. Mol Cell Neuroscience 124:103805. doi: 10.1016/j.mcn.2022.103805

Some substances produced by gut bacteria, like pCS and 4EPS, are found at higher levels in people with autism and can trigger autism-like behaviors in mice. This study looked at whether these substances affect a gene called PTEN, linked to autism. The results showed that PTEN is not involved in gut inflammation, but its levels are reduced in the brains of affected mice. In lab tests, pCS and 4EPS also lowered PTEN in brain immune cells, without directly altering immune responses. More research is needed to understand whether reduced PTEN affects brain connections and function in autism.

Gastrointestine and nutrition research

Prince N. et al. Prebiotic diet normalizes aberrant immune and behavioral phenotypes in a mouse model of autism spectrum disorder. Acta Sinica Pharmacologica 2024 doi.org/10.1038/s41401-024-01268-x

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders marked by difficulties in communication and behavior. Recent studies suggest that the gut-brain axis—especially involving the gut microbiota and the immune system—may play a key role in ASD development. Digestive issues and imbalanced gut bacteria have been linked to autism symptoms. This study explored whether a prebiotic-rich diet (with galacto-oligosaccharides and fructo-oligosaccharides, GOS/FOS) could improve symptoms in mice prenatally exposed to valproic acid (VPA), a chemical known to induce autism-like traits. Mice on the GOS/FOS diet showed normalized gut bacteria, better gut barrier function, balanced immune responses, and reduced brain inflammation. Importantly, they also showed improved social behavior and cognitive function. These findings suggest that dietary interventions targeting the gut microbiota may mitigate ASD-related symptoms and offer new therapeutic strategies.

Chiappori et al. Analysis of Faecal Microbiota and Small ncRNAs in Autism: Detection of miRNAs and piRNAs with Possible Implications in Host-Gut Microbiota Cross-Talk. Nutrients. 2022 Mar 23;14(7):1340. DOI: 10.3390/nu14071340

The gut is full of microorganisms that help keep our digestive system healthy and support the immune system. When this balance is disrupted—a condition called gut dysbiosis—it has been linked to various health issues, including autism. In children with autism, gut dysbiosis is associated with more severe symptoms and fewer beneficial bacteria. This study looked at how gut microbes interact with the body’s gene regulators, especially small RNA molecules like miRNAs and piRNAs, which can influence both human and microbial functions. Using advanced “omics” techniques, researchers analyzed the gut microbiome, fungi (mycobiome), and non-coding RNAs in children with and without autism. They found that children with autism had fewer healthy microbes, more inflammatory signals, and altered RNAs that may affect gut function and brain health. For the first time, specific RNAs were found in the stool of autistic children, offering a new way to study the gut–brain connection in autism.

Zheng et al, 2021. The Gut-Brain Axis in Autism Spectrum Disorder: A Focus on the Metalloproteases ADAM10 and ADAM17. Int. J. Mol. Sci. 2021, 22(1), 118; DOI: 10.3390/ijms22010118.

Autism Spectrum Disorder (ASD) is a range of conditions marked by difficulties in social interaction and repetitive behaviors. While it’s believed to stem from early brain development issues, the exact causes are still unclear. Many people with ASD also experience gut problems, pointing to a possible brain–gut connection. This review focuses on two enzymes, ADAM10 and ADAM17, which are involved in both brain and gut functions. These enzymes can affect key proteins tied to brain development and inflammation—processes that are altered in ASD. Interestingly, they are also active in the intestines, where they help regulate gut health and immune responses. The review explores how ADAM10 and ADAM17 may play a role in linking gut and brain health in ASD, and how they could become targets for future treatments.

Gromova et al., 2021. Mechanisms of Glucose Absorption in the Small Intestine in Health and Metabolic Diseases and Their Role in Appetite Regulation. Nutrients 13: 2474, 2021. DOI: 10.3390/nu13072474

Metabolic diseases like obesity, metabolic syndrome, and type 2 diabetes are becoming more common worldwide. These conditions often involve high blood sugar (hyperglycemia), sometimes linked to overeating (hyperphagia). The small intestine plays a key role in absorbing glucose and helping regulate blood sugar levels, making it a target for new diabetes treatments. Scientists have discovered that a protein called SGLT1 is central to this process. However, while blocking glucose absorption in the gut can help lower blood sugar, it doesn’t necessarily help reduce appetite. This review highlights how glucose absorption works in the small intestine, how it changes in metabolic diseases, and why treating both high blood sugar and overeating may require different strategies.

Asbjornsdottir et al., 2020. Zonulin-Dependent Intestinal Permeability in Children Diagnosed with Mental Disorders: A Systematic Review and Meta-Analysis. Nutrients. 2020 Jul 3;12(7):1982. doi: 10.3390/nu12071982

Mental health issues affect up to 20% of children and teens worldwide, and they’re the leading cause of disability in young people. Recent studies suggest that problems with the gut—specifically increased “leakiness” of the intestinal barrier—might play a role in mental disorders. This review analyzed five observational studies looking at markers of intestinal permeability, like zonulin, in kids with ADHD, autism (ASD), and OCD. Children with ADHD and autism showed signs of altered gut barrier function, especially those with digestive issues or social difficulties. In contrast, kids with OCD didn’t show changes in zonulin but had other markers affected. Overall, higher levels of zonulin were found in kids with mental disorders, suggesting a possible gut-brain connection. More research is needed to fully understand how gut health and brain function are linked in these conditions.

Paediatric research

Patrone et al., 2022. Optimization of Peripheral Blood Mononuclear Cell Extraction from Small Volume of Blood Samples: Potential Implications for Children-Related Diseases. Methods Protoc 2022;5(2):20. doi: 10.3390/mps5020020

Taking blood samples from children with autism can be particularly challenging, especially for medical tests and research. However, studying certain blood cells, like peripheral blood mononuclear cells (PBMCs), is very important to understand immune responses and how the body reacts to medications. Among these, monocytic cells play a key role in inflammation and changes in the immune system, which are often seen in autism. This study presents a simple and reliable method to extract these cells from very small amounts of blood—making the process easier, less invasive, and more suitable for children with autism.

Microbiology

Roussin L. et al. Microbiota influence on behavior: Integrative analysis of serotonin metabolism and behavioral profile in germ-free mice. FASEB J. 2024 Jun 15;38(11):e23648. doi: 10.1096/fj.202400334R.

Studies using germ-free (GF) animal models (those without any gut bacteria) have shown that the microbiota can affect behavior and brain chemistry. In this study, researchers compared GF male mice with conventionally raised mice to understand how gut bacteria influence behavior and serotonin, a key neurotransmitter that affects mood.
They found that germ-free mice were less active and showed more signs of anxiety. While no major differences were seen in serotonin-related genes in the brain, there were clear changes of this neurotrasmitter in the gut. The levels of several genes involved in serotonin production and signaling varied across different parts of the intestine.
Overall, the findings suggest that gut bacteria help regulate behavior and serotonin activity, particularly in the digestive system. However, differences between studies indicate that genetics and environment also play important roles in how the microbiome affects the brain and behavior.

Peralta-Marzal et al., 2021. The Impact of Gut Microbiota-Derived Metabolites in Autism Spectrum Disorders. Int. J. Mol. Sci. 2021, 22, 10052. DOI: 10.3390/ijms221810052

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions marked by difficulties in behavior, social interaction, and communication. It affects about 1 in 89 children in Europe. Since ASD varies greatly from person to person, diagnosing it is complex, and there’s no specific treatment yet. Many individuals with ASD also experience other health issues, especially intestinal problems, which may be linked to a disrupted communication system between the brain and the gut. This review highlights new studies showing that changes in the gut microbiota’s metabolism could play a role in ASD. These changes might influence both brain development and behavior. Understanding how gut bacteria and their metabolic activity interact with the body could help us uncover better diagnostic tools and new treatment approaches for autism.

Roussin et al., 2020. Role of the gut microbiota in the pathophysiology of autism spectrum disorder: clinical and pre-clinical evidence. Microorganisms 2020, 8(9), 1369. DOI: 10.3390/microorganisms8091369

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects about 1 in 160 people globally. While genetics play a major role, environmental factors are also thought to contribute. One area gaining attention is the gut: people with ASD often experience gastrointestinal issues at a much higher rate than others. Researchers have found that individuals with autism tend to have an altered gut microbiota—meaning their intestinal bacteria are out of balance—and this could affect brain function. Early studies suggest this imbalance may disrupt the immune system and the metabolism of tryptophan, a key amino acid involved in mood regulation. Promising results from both animal studies and a few human trials show that adjusting the gut microbiota through probiotics, antibiotics, or even fecal transplants might help improve behavior. Although research is still at an early stage, these findings suggest that the gut-brain connection may play a real role in autism and deserves further study.

Computational biology

Salenius et al. Exploring autism spectrum disorder and co-occurring trait associations to elucidate multivariate genetic mechanisms and insights. BMC Psychiatry 24, 934 (2024). DOI:https://doi.org/10.1186/s12888-024-06392-w

Autism spectrum disorder (ASD) is a partially heritable neurodevelopmental trait, and people with ASD may also have other co-occurring trait such as ADHD, anxiety disorders, depression, mental health issues, learning difficulty, physical health traits and communication challenges. The concomitant development of ASD and other neurological traits is assumed to result from a complex interplay between genetics and the environment. We conducted to-date the largest multivariate GWAS on ASD and 8 ASD co-occurring traits (ADHD, ADHD childhood, anxiety stress (ASDR), bipolar (BIP), disruptive behaviour (DBD), educational attainment (EA), major depression, and schizophrenia (SCZ)) using summary statistics from leading studies. Our study, combining multivariate GWAS with systematic decomposition, identified 322 novel genetic associations related to ASD and ASD co-occurring driver traits. Statistical tests were applied to discern evidence for shared and interpretable liability between ASD and co-occurring traits. These findings expand upon the current understanding of the complex genetics regulating ASD and reveal insights of neuronal brain disruptions potentially driving development and manifestation.

Peralta-Marzal L.N. et al. A robust microbiome signature for autism spectrum disorder across different studies using machine learning. Sci Rep. 2024 Jan 8;14(1):814. doi: 10.1038/s41598-023-50601-7

Autism Spectrum Disorder (ASD) is a complex condition marked by social difficulties and repetitive behaviors, often accompanied by other health issues. Many people with ASD also have gut problems, suggesting a link between the gut microbiome and autism. However, previous studies have struggled to agree on which specific gut bacteria are involved. This study used a machine learning method called recursive ensemble feature selection (REFS) to analyze gut bacteria in children with ASD and their siblings. The researchers found 26 bacterial taxa that can help distinguish between ASD cases and non-ASD controls. Their approach showed good accuracy, with an AUC (Area Under Curve) of over 80% in one dataset and about 75% in two independent groups. These findings show that gut bacteria could be used to help classify and understand ASD, and suggest the gut microbiome may be a promising target for future treatments. This method could also be applied to study microbiome patterns in other diseases.

Mosca et al. Characterization and comparison of gene-centered human interactomes. Brief Bioinform. 2021 Nov 5;22(6):bbab153. DOI: 10.1093/bib/bbab153

Inside our cells, proteins and other molecules constantly interact in complex networks, known as the interactome. Scientists use these networks to understand how cells function and how diseases develop. However, there’s no single, agreed-upon map of the human interactome. Different versions exist, created using various experimental techniques and databases. This study compared many of these interactome maps to see how similar or different they really are. The researchers analyzed aspects like network structure, how well the maps represent known protein complexes, biological pathways, and their ability to predict disease-related genes. The results revealed significant differences between the maps. This study helps researchers choose the most appropriate interactome for future studies, offering useful guidelines based on the strengths and weaknesses of each version.

Di Nanni et al. Gene relevance based on multiple evidence in complex networks. Bioinformatics, Volume 36, Issue 3, 1 February 2020, Pages 865–871, DOI: 10.1093/bioinformatics/btz652

Multi-omics approaches combine different types of biological data—like genes, proteins, and metabolites—to give a more complete view of what’s happening in diseases such as cancer. However, analyzing this complex data is challenging. In this study, researchers developed a new method called mND, which uses network-based analysis to identify important genes by looking at how closely connected they are to other altered genes in a biological network. This method performs better than previous techniques in spotting key genes involved in disease, especially when combining multiple layers of biological information. It’s also effective at identifying known cancer-related genes. Because it’s so flexible, this method can also be used in other fields like single-cell studies, making it a powerful tool for biomedical research.

Di Nanni et al., 2020. Network Diffusion Promotes the Integrative Analysis of Multiple Omics. Front. Genet. 11:106. DOI: 10.3389/fgene.2020.00106.

One of the biggest challenges in bioinformatics is finding effective ways to combine different types of genetic data. Network-based methods help by using the known relationships between genes. A particularly powerful technique called network diffusion (or network propagation) has become popular in recent years. This method spreads information across gene networks, helping researchers detect patterns and connections between genes that are close to each other. It works with many kinds of biological data and helps make sense of complex datasets by highlighting system-wide changes. This review looks at how network diffusion is currently used to integrate omics data (like genomics or proteomics), the advantages it offers, and how it might evolve in the future. As new data types emerge—such as single-cell data—network diffusion is expected to become even more central in discovering how biological systems work.

Di Nanni et al. Network-Based Integrative Analysis of Genomics, Epigenomics and Transcriptomics in Autism Spectrum Disorders. Int J Mol Sci. 2019 Jul 9;20(13). pii: E3363. DOI: 10.3390/ijms20133363.

Autism Spectrum Disorders (ASDs) are thought to be influenced by many different genes, which makes understanding their causes complex. To tackle this, researchers are now using gene networks and multi-omics data (like genomics, epigenomics, and transcriptomics) to get a fuller picture of what’s happening at the molecular level. In this study, scientists performed a network-based meta-analysis of genes previously linked to autism. They ranked these genes based on how important they are in cell signaling networks, how strong the evidence is for their role in ASD, and how many different types of molecular changes affect them. Many of the top-ranked genes matched those in trusted autism databases, like SFARI. The study helps prioritize key genes involved in autism, making it easier to identify potential targets for new treatments and encouraging more focused research in the future.

Generalised science

Cupaioli et al., 2019. Assessment of haptoglobin alleles in autism spectrum disorders. Sci Rep. 2020 May 8;10(1):7758. DOI 10.1038/s41598-020-64679-w. 5

One theory about the causes of Autism Spectrum Disorders (ASD) involves a weakened intestinal barrier, which might allow harmful substances to reach the body and brain, especially in individuals with gastrointestinal (GI) issues. A protein called zonulin, encoded by the HP2 gene, is known to increase intestinal permeability by loosening the tight junctions between intestinal cells. Researchers studied whether the HP2 gene variant was more common in Italian individuals with ASD compared to healthy controls. They used both genetic testing and computational analysis to detect this variant. Surprisingly, they found no link between HP2 and ASD, even in individuals with GI problems. This suggests that other members of the zonulin family or environmental factors might be responsible for increased gut permeability in ASD, not the HP2 gene. The study also introduced a new method to detect HP gene variants with good accuracy.

Cupaioli et al. Change of Communication Strategy to Increase Engagement during the SARS-Cov-2 Pandemic: The Experience of the European GEMMA Project in Italy. International Journal of Humanities Social Sciences and Education 7(9)128-137 2020 DOI: 10.20431/2349-0381.0709013

Effective communication is crucial for scientific research. The GEMMA project, part of the EU’s Horizon 2020 program, studies autism and aims to enroll 600 at-risk infants across several countries. Early on, the project’s communication team focused on engaging stakeholders, especially via social media and a dedicated website, to support recruitment. However, the COVID-19 lockdown disrupted both recruitment and traditional schooling. Children with autism, who often struggle with changes in routine, faced particular challenges with remote education. In response, GEMMA adapted its communication plan to the pandemic by promoting inclusive webinars and educational apps focused on technology and inclusion. These tools helped autistic children, their parents, and teachers cope with remote learning and stay engaged. The initiative proved that tailored digital tools can be effective not only for education but also for maintaining public involvement and communication during emergencies.