Gut Metabolites Influence Brain Activity in Autism

The behavioral symptoms seen in autism spectrum disorder (ASD) might be shaped by the gut, as well as the brain.

A new study from the University of Southern California (USC), published in Nature Communications, has linked gut-derived metabolites to altered brain activity and autism-related behaviors in children. The research builds a compelling case for a gut-brain-behavior connection in ASD.

The gut-brain link in autism

ASD is a complex neurodevelopmental condition characterized by a wide range of behavioral symptoms, including challenges with social interaction, communication difficulties and repetitive behaviors. Increasingly, researchers are approaching ASD not just as a brain-based disorder, but as a systemic condition – one that involves interactions between the brain, the gut and broader physiological systems.

Among individuals with autism, there is a high prevalence of gastrointestinal (GI) issues. Estimates suggest that between 46–84% of autistic individuals experience persistent digestive problems, such as constipation or food sensitivities. These GI symptoms are more than just co-occurring conditions; they may hold clues to underlying biological pathways linked to core features of autism.

Central to this view is the "gut-brain axis" – a bidirectional communication network connecting the enteric and central nervous systems. The gut is home to trillions of microbes that collectively make up the gut microbiome, a key player in this axis. These microbes produce a variety of neuroactive compounds, including metabolites derived from tryptophan, an essential amino acid. Some of these metabolites influence serotonin levels, a neurotransmitter implicated in mood, emotion and social behavior.

Previous studies have revealed that autistic individuals often show distinct gut microbiota profiles from early infancy through adulthood. In parallel, researchers have identified disruptions in tryptophan metabolism, altered serotonin signaling and consistent differences in brain regions involved in emotional and sensory processing, particularly the insula and cingulate cortex.

“We know that children with autism have brain differences – certain parts of their brain are either less active or more active compared to typically developing children,” said Dr. Lisa Aziz-Zadeh, a professor at the Brain and Creativity Institute at the USC Dornsife College of Letters, Arts and Sciences and first author of the study.  “We also know they often experience gastrointestinal issues, such as constipation, stomach pain and other digestive problems.”

Despite this knowledge, the field has lacked a clear mechanistic framework linking these gut-derived biochemical signals to brain function and behavioral symptoms. 

Connecting gut metabolites, brain activity and behavior in autism

The team conducted a cross-sectional study involving 84 children – 43 diagnosed with ASD and 41 neurotypical controls, all between the ages of 8 and 17. The study employed a multi-modal approach, combining stool sample analysis, functional magnetic resonance imaging (fMRI) and detailed behavioral assessments.

The research zeroed in on the tryptophan metabolic pathway – a route by which gut microbes transform dietary tryptophan into a range of compounds, including serotonin and other neuroactive metabolites. Of particular interest were kynurenate, indolelactate and tryptophan betaine, all of which have been previously implicated in neural regulation.

Aziz-Zadeh and the team saw a significant reduction in fecal kynurenate levels in children with autism. Kynurenate is known for its neuroprotective properties and its ability to cross the blood-brain barrier. This deficit persisted even after accounting for potential confounding factors such as diet and gastrointestinal symptoms. Several other tryptophan-derived metabolites also showed altered abundance in the ASD group.

These gut-derived metabolites were also strongly associated with altered patterns of brain activity, especially in regions known for interoception, emotion processing and sensory integration. Specifically, differences were observed in the mid-insula and mid-cingulate cortex, areas frequently implicated in ASD neurobiology.

By analyzing task-based fMRI responses during scenarios involving facial expressions, disgust-inducing images and social touch, the team found that brain activity in these regions was not only linked to metabolite levels but also mediated their relationship with behavioral symptoms. For example, decreased levels of indolelactate were associated with increased activity in the mid-insula during disgust processing, which in turn correlated with higher autism severity scores. Similarly, altered activity in the mid-cingulate cortex mediated the relationship between tryptophan betaine and heightened disgust sensitivity.

“We demonstrated that gut metabolites impact the brain, and the brain, in turn, affects behavior. Essentially, the brain acts as the intermediary between gut health and autism-related behaviors,” said Aziz-Zadeh. “Previous studies highlighted differences in gut microbiomes and brain structures in autism, but our research connects the dots.”

Can targeting the gut microbiome help treat autism?

By mapping specific biochemical signals from the gut to neural activity and behavioral traits, the research strengthens the growing case for the gut-brain-behavior axis as a mechanistic framework in ASD.

If gut-derived metabolites like kynurenate and indolelactate are involved in shaping neural circuits associated with ASD symptomatology, they could serve as targets for novel therapeutic interventions. Approaches such as probiotic supplementation, dietary modifications or fecal microbiota transplants may offer non-invasive means to influence brain function and mitigate behavioral challenges.

“We’re excited by the possibility of interventions that might target the gut and influence neural activity and behavior – while also hopefully alleviating some of the symptoms that are the most uncomfortable for them,” said co-author Sofronia Ringold, a doctoral candidate at USC.

The work also hints at the future development of biomarkers for autism based on gut chemistry. Reduced kynurenate levels, for instance, may one day aid in early detection or in tailoring personalized treatment strategies. However, further research is needed to validate such biomarkers and establish their specificity and clinical utility.

Looking ahead, the authors underscore the need for longitudinal studies to determine how early-life gut microbial dynamics may influence neurodevelopment. Future research should incorporate serum-based metabolomics, genome-level analysis of gut microbiota and interventional designs capable of testing causality.

Of particular interest is the prenatal period, when both maternal microbiota and fetal brain development are especially susceptible to environmental influences.

“Although our study design is unable to demonstrate causality,” the authors conclude, “these findings represent an important step toward mechanistic integrated models of body-brain-behavior relationships in ASD, with potential implications for future interventions.”

Reference: Aziz-Zadeh L, Ringold SM, Jayashankar A, et al. Relationships between brain activity, tryptophan-related gut metabolites, and autism symptomatology. Nat Comm. 2025;16(1):3465. doi: 10.1038/s41467-025-58459-1

This article is a rework of a press release issued by the University of Southern California. Material has been edited for length and content.