Relationships between brain activity, tryptophan-related gut metabolites, and autism symptomatology

Lisa Aziz-Zadeh (), Sofronia M. Ringold, Aditya Jayashankar, Emily Kilroy, Christiana Butera, Jonathan P. Jacobs, Skylar Tanartkit, Swapna Mahurkar-Joshi, Ravi R. Bhatt, Mirella Dapretto, Jennifer S. Labus and Emeran A. Mayer
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Lisa Aziz-Zadeh: University of Southern California
Sofronia M. Ringold: University of Southern California
Aditya Jayashankar: University of Southern California
Emily Kilroy: University of Southern California
Christiana Butera: University of Southern California
Jonathan P. Jacobs: University of California Los Angeles
Skylar Tanartkit: University of California Los Angeles
Swapna Mahurkar-Joshi: University of California Los Angeles
Ravi R. Bhatt: University of Southern California
Mirella Dapretto: University of California Los Angeles
Jennifer S. Labus: University of California Los Angeles
Emeran A. Mayer: University of California Los Angeles

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract While it has been suggested that alterations in the composition of gut microbial metabolites may play a causative role in the pathophysiology of autism spectrum disorder (ASD), it is not known how gut microbial metabolites are associated with ASD-specific brain alterations. In this cross-sectional, case-control observational study, (i) fecal metabolomics, (ii) task-based functional magnetic resonance imaging (fMRI), and (iii) behavioral assessments were obtained from 43 ASD and 41 neurotypical (NT) children, aged 8–17. The fMRI tasks used socio-emotional and sensory paradigms that commonly reveal strong evoked brain differences in ASD participants. Our results show that fecal levels of specific tryptophan-related metabolites, including kynurenate, were significantly lower in ASD compared to NT, and were associated with: 1) alterations in insular and cingulate cortical activity previously implicated in ASD; and 2) ASD severity and symptoms (e.g., ADOS scores, disgust propensity, and sensory sensitivities). Moreover, activity in the mid-insula and mid-cingulate significantly mediated relationships between the microbial tryptophan metabolites (indolelactate and tryptophan betaine) and ASD severity and disgust sensitivity. Thus, we identify associations between gut microbial tryptophan metabolites, ASD symptoms, and brain activity in humans, particularly in brain regions associated with interoceptive processing.

Date: 2025
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DOI: 10.1038/s41467-025-58459-1

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