Functional contribution of the intestinal microbiome in autism spectrum disorder, attention deficit hyperactivity disorder, and Rett syndrome: a systematic review of pediatric and adult studies

Authors: Caputi, Valentina; HILL, LEE - McMaster University; FIGUEIREDO, MELANIE - McMaster University; POPOV, JELENA - Boston Children'S Hospital; HARTUNG, EMILY - McMaster University; MARGOLIS, GROSS - New York University; BASKARAN, KANISHTRAYEN - McMaster University; JOHARAPURKER, PAPIHA - McMaster University; MOSHKOVICH, MICHAL - McMaster University; PAI, NIKHIL - McMaster University

Submitted to: Frontiers in Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/2/2024
Publication Date: 3/7/2024
Citation: Caputi, V., Hill, L., Figueiredo, M., Popov, J., Hartung, E., Margolis, G.K., Baskaran, K., Joharapurker, P., Moshkovich, M., Pai, N. 2024. Functional contribution of the intestinal microbiome in autism spectrum disorder, attention deficit hyperactivity disorder, and Rett syndrome: a systematic review of pediatric and adult studies. Frontiers in Neuroscience. 18. Article 1341656. http://doi.org/10.3389/fnins.2024.1341656.
DOI: https://doi.org/10.3389/fnins.2024.1341656

Interpretive Summary: ASD, ADHD, and Rett syndrome are neurodevelopmental disorders characterized by clinically significant disturbances in emotional regulation, mood, and behavior that severely impact an individual’s quality of life. These disorders are increasing worldwide and affect both pediatric and adult populations. Genetic- and environmental factors are believed to cause multiple biological alterations in brain development during critical phases of human perinatal life that persist until adulthood. However, the exact cause of these disorders is still unclear, and the available therapy is sufficient to treat only the symptoms. Recently the microbes in our gut (or gut microbiota) have been recognized to influence brain health, thus offering a new point of view for understanding the origin of the onset of such disorders and providing a novel avenue to formulate therapeutic strategies for prevention and treatment. This study summarized the recent research on the alterations in gut microbial communities in pediatric and adult patients affected by ASD, ADHD, and Rett syndrome. We found changes in gut microbiota composition and metabolite production in individuals affected by these disorders. Some of the changes in the gut microbiota were associated with the severity of the disease. We also found preliminary data on how microbiota- or diet-targeted interventions can ameliorate neurological and behavioral symptoms. Our study highlighted critical factors that can have influenced the observed changes in gut microbiota dynamics in patients with ASD, ADHD, and Rett syndrome, such as dietary habits, household environment, and gastrointestinal symptoms. Therefore, future studies with larger sample sizes are warranted to determine the role of gut microbiota in modulating human brain development and behavior.

Technical Abstract: Background: Critical phases of neurodevelopment and gut microbiota diversification occur in early life and both processes are impacted by genetic and environmental factors. Accumulating evidence supports the presence of gut microbiota alterations in neurodevelopmental disorders. In this manuscript, we performed a systematic review of alterations of the intestinal microbiota in autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and Rett's syndrome (RTT). Methods and Findings: Electronic literatures searches were conducted using PubMed, Cochrane, and OVID electronic databases (January 1980 to December 2021) with secondary review of references of eligible articles. Two reviewers independently performed critical appraisals on the included articles using the Critical Appraisal Skills Program for each study design. Our systematic review identified 18, 7, and 3 original articles describing intestinal microbiota profiles in ASD, ADHD, and RTT, respectively. Decreased Firmicutes and increased Bacteroidetes were observed in the gut microbiota of individuals affected by ASD, ADHD, and RTT. Proinflammatory cytokines, short-chain fatty acids and neurotransmitters levels were altered in ASD and RTT but not in ADHD. Constipation and visceral pain were related to changes in the gut microbiota in patients affected by ASD and RTT. Hyperactivity and impulsivity correlated with bacterial taxa from Firmicutes, Bacteroidetes and Actinobacteria phyla in ADHD subjects. Five studies explored microbiota-or diet-targeted interventions in ASD and ADHD. Probiotic treatments with Lactobacillus species and fecal microbiota transplantation from healthy donor reduced constipation and ameliorated ASD symptoms in affected children. Perinatal administration of Lactobacillus species prevented the onset of Asperger and ADHD symptoms in adolescence. Micronutrient supplementation improved disease symptomatology in ADHD without causing significant changes in microbiota communities’ composition. Conclusions: Findings from this systematic review offer the most comprehensive review of interactions between the gut microbiota and neurodevelopmental disorders in pediatric and adult subjects. Several discrepancies were found among the included studies, primarily due to sample size, variations in dietary practices, and a high prevalence of functional gastrointestinal symptoms. Further studies employing longitudinal study designs and larger sample sizes are warranted to strengthen relationships between changes in microbiota and developmental trajectories of the human brain and neurobehavior.