Research shows that the gut microbiome significantly influences bodily processes through the production of 40% of circulating metabolites, which include neuroactive substances and inflammatory compounds. Brain function along the brain-gut-microbiome (BGM) axis is affected by metabolites that transmit through blood circulation and use the vagus nerve and spinal pathways, while 90% of vagal fibers serve sensory functions. The development of autism spectrum disorder (ASD), along with other neurodevelopmental disorders, becomes more likely when neural or microbial development is altered early in life. The research analyzes the biological connection between metabolites produced in the gut, which affects brain patterns and ASD behavioral manifestations in children.
The research used 43 children with ASD diagnoses and 41 neurotypical (NT) controls between 8 and 17 years of age for their cross-sectional study. The behavioral assessment included tests for sensory processing as well as gastrointestinal (GI) symptoms, as well as social difficulties. The researchers used functional magnetic resonance imaging (fMRI) to study brain activity in areas linked to interoception and emotion, as well as sensory processing. Research analysts examined kynurenine (KYN) alongside kynurenic acid (KA) and other tryptophan derivatives using samples of stool from participants. The research examined relationships among metabolites and their connections to brain signal patterns, as well as ASD symptom severity.
The ASD group demonstrated multiple important variations in their scores compared to the NT participants during the assessment. Children with ASD possessed higher body mass index scores, experienced prenatal antibiotic exposure, and displayed gastrointestinal symptoms together with sensory hypersensitivity while exhibiting lower test scores and worse sleep patterns. Analysis of tryptophan metabolites confirmed ASD participants held significantly lower KA levels than NT controls with a statistical significance of p = 0.02 along with a magnitude d = 0.82. The analysis of KA confirmed its significance at p = 0.009 with a large effect size d = 1.15 even after adjusting for GI symptoms.
Functional MRI analysis demonstrated that brain activity in the mid-cingulate cortex (MCC) and insula was related specifically to tryptophan metabolites. The right inferior frontal gyrus operculum (IFGop) activated more strongly during facial expression processing when people had elevated anthranilate levels. Brain activity in the right MCC increased in response to N-acetyltryptophan, and the magnitude of change correlated with their capacity to process hand actions.
Research findings validate the proposed mechanism that modifications in gut microbiota, along with associated tryptophan metabolic compounds, affect both ASD symptom presentation and brain neural responses. The reduction of KA levels within ASD patients suggests dysregulation of the kynurenine pathway operation that research links to toxic effects in developmental brain disorders. The tryptophan metabolite-based connections between MCC and insula brain regions, which handle emotion and interoception, showed vital correlations that strengthen the understanding of the gut-brain axis effects on ASD behaviors.
The link between indolelactate levels and autism severity found its relationship was mediated through mid-insular brain activity, whereas MCC activity provided the connection between tryptophan betaine and disgust sensitivity. Prior studies support the connection between gut microbiota disruptions and ASD-associated brain disorders because the vagus nerve serves as a possible transmission path. Research needs to explore the effect of prenatal antibiotic exposure on gut microbial composition together with its influence on neurodevelopment because the ASD group showed elevated exposure rates.
The research establishes strong empirical support, showing that gastrointestinal metabolites play an essential role in ASD development through the tryptophan metabolic pathway. Brain activity changes along with ASD symptoms are linked directly to reduced kynurenic acid levels and variations in additional metabolites in the study. The research supports the gut-brain-behavior model in ASD through evidence that brain activity acts as a possible connection between gut metabolites and ASD behavioral symptoms, though causality remains unproven. More longitudinal research needs to be carried out because it will help verify these findings while testing possible therapeutic approaches that target the ASD-related microbiome.
The research findings demonstrate that gut microbiota plays a vital role in developing ASD and related neurodevelopmental conditions. New research avenues aimed at improving ASD diagnosis and treatment continue to develop because scientists better understand these metabolic and neurobiological mechanisms through gut microbiota modification strategies.
References: Aziz-Zadeh L, Ringold SM, Jayashankar A, et al. Relationships between brain activity, tryptophan-related gut metabolites, and autism symptomatology. Nat Commun. 2025;16:3465. doi:10.1038/s41467-025-58459
