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

Abstract

Introduction: Critical phases of neurodevelopment and gut microbiota diversification occur in early life and both processes are impacted by genetic and environmental factors. Recent studies have shown the presence of gut microbiota alterations in neurodevelopmental disorders. Here we performed a systematic review of alterations of the intestinal microbiota composition and function in pediatric and adult patients affected by autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Rett syndrome (RETT).

Methods: We searched selected keywords in the online databases of PubMed, Cochrane, and OVID (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.

Results: Our systematic review identified 18, 7, and 3 original articles describing intestinal microbiota profiles in ASD, ADHD, and RETT, respectively. Decreased Firmicutes and increased Bacteroidetes were observed in the gut microbiota of individuals affected by ASD and ADHD. Proinflammatory cytokines, short-chain fatty acids and neurotransmitter levels were altered in ASD and RETT. Constipation and visceral pain were related to changes in the gut microbiota in patients affected by ASD and RETT. Hyperactivity and impulsivity were negatively correlated with Faecalibacterium (phylum Firmicutes) and positively correlated with Bacteroides sp. (phylum Bacteroidetes) in ADHD subjects. Five studies explored microbiota-or diet-targeted interventions in ASD and ADHD. Probiotic treatments with Lactobacillus sp. and fecal microbiota transplantation from healthy donors reduced constipation and ameliorated ASD symptoms in affected children. Perinatal administration of Lactobacillus sp. 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.

Discussion: 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, larger sample sizes and multi-omics technologies are warranted to identify the functional contribution of the intestinal microbiota in developmental trajectories of the human brain and neurobehavior.

Systematic review registration: https://clinicaltrials.gov/, CRD42020158734.

Keywords: Rett syndrome; attention deficit hyperactivity disorder; autism spectrum disorder; children; metabolites; microbiota; neurodevelopment; pediatric.

Figure 1

PRISMA-ScR systematic flowchart of the systematic review process.

Figure 2

Microbiota-gut-brain axis alterations in ASD, ADHD, and Rett syndrome. Schematic representation of the main findings emerged from the studies included in our systematic review, portraited as alterations across the microbiota-gut-brain axis in ASD (left panel), ADHD (middle panel), and Rett’s syndrome (RETT; right panel). Changes in the intestinal microbiota of subjects with ASD are associated with a high prevalence of GI symptoms and low-quality diet. The family household might have an influence in shaping gut microbiota communities, as ASD and family unrelated NT subjects have a different microbiota, however no differences are observed when ASD subjects are compared with their siblings. RETT subjects present intestinal inflammation (indicated by increased ESR and fecal calprotectin) and constipation and there are changes in the gut microbiota depending upon the type of diet (solid food vs. formula). No information is provided on the presence of GI disorders in ADHD subjects, however differences in dietary habits between ADHD subjects and NT controls have been shown even though their impact on the gut microbiota has not been investigated. Intestinal dysbiosis is mainly characterized by decreased Faecalibacterium (phylum Firmicutes) and Prevotella (phylum Bacteroides) in all three disorders. Increased Bacteroides sp. (phylum Bacteroidetes) were identified in ASD and ADHD. Lactobacillus (phylum Firmicutes) was increased in ASD and RETT. Bifidobacterium (phylum Actinobacteria) increased in ADHD and RETT and decreased in ASD. Desulfovibrio (phylum Proteobacteria) increased in ASD and decreased in RETT. Escherichia (phylum Proteobacteria) increased in RETT and decreased in ASD. Increased abundances of Candida sp. were identified whithin the mycobiota of ASD and RETT. Microbiota associated metabolites such as SCFAs and gut-brain neurotransmitters GABA, glutamine, tryptophan, and tyrosine are altered in ASD and RETT, however they have not been explored in ADHD studies. Increased p-cresol, isopropanol in the stool and trace elements As, Hg, Pb, Cu, Zn, Mg, Ca in the hair were found in ASD subjects. ASD is also associated with a dysregulation of the immune system (and potential inflammation), as blood cytokines IL-1α, TNFα, IL-1β, IL-15, IFNɣ, MCP-1, eotaxin are increased and GROα, IFN-a2, TGFβ1 are reduced. Conversely, no sign of inflammation was reported by studies investigating ADHD. Possible correlation between changes in microbial taxa and disease severity can be extrapolated across the three disorders. ASD severity is positively correlated with Desulfovibrio (phylum Proteobacteria). Hyperactivity and impulsivity (ADHD symptoms) are negatively correlated with Faecalibacterium (phylum Firmicutes) and positively correlated with Bacteroides sp. (phylum Bacteroidetes) in ADHD. A reduced alpha-diversity and increased beta diversity are associated with severe RETT (compared to mild/moderate). CDT was increased in the ADHD bacteriome. CDT is responsible of producing phenylalanine, an essential AA that crosses the BBB and acts as a precursor for dopamine and noradrenaline, key neurotransmitters involved in modulating behavior-related neuronal pathways in the brain. AA, amino acid; ADI-RRB, autism diagnostic interview-restricted and repetitive behaviors; ADHD, attention deficit hyperactivity disorder; ASD, Autism Spectrum Disorder; BBB, blood brain barrier; BCFAs, branched chain fatty acids; CDT, cyclohexadienyl dehydratase; GABA, Gamma-aminobutyric acid; GI, gastrointestinal; GROα, growth-related oncogene alpha; IL, Interleukin; IFN, Interferon; MCP-1, monocyte chemoattractant protein; NT, neurotypical controls; RETT, Rett syndrome; SCFAs, short chain fatty acids.