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Abstract
Background. Microbial genes that produce or transform neuroactive compounds may contribute to autism heterogeneity, but their relation to dimensional symptoms is unclear.
Objective. To test whether neuroactive microbial pathways selected a priori were associated with symptom severity in autistic children and improved out-of-sample prediction beyond clinical covariates.
Methods. This secondary cross-sectional analysis used linked metagenomic and clinical data from 818 children (464 autistic). Six of twelve a priori neuroactive MetaCyc pathways, detected in at least 10% of autistic participants, were analyzed. Social Responsiveness Scale, Second Edition (SRS-2), Anxiety Scale for Children–Autism Spectrum Disorder (ASC-ASD), and Child Behavior Checklist (CBCL) Internalizing scores were regressed robustly on centered log-ratio pathway abundance, age, sex, and batch, with Benjamini–Hochberg correction within outcome. Sensitivity analyses varied covariates and transformation, modeled pathways jointly, and examined influential observations, sparse detection, and cross-validated ridge prediction.
Results. Sample sizes were 464 (SRS-2), 459 (ASC-ASD), and 144 (CBCL Internalizing). PWY-5088 was inversely associated with SRS-2 (β = −0.110, 95% CI −0.200 to −0.020; p = 0.017); the predefined false-discovery threshold was narrowly missed (q = 0.102), and the estimate persisted in sensitivity analyses. No pathway was consistently associated with ASC-ASD or CBCL Internalizing. Pathways added minimal SRS-2 prediction gain (mean ΔR² = 0.004) and worsened ASC-ASD prediction (mean ΔR² = −0.022).
Conclusion. Neuroactive pathway profiles were not broad or clinically useful correlates of symptom severity. A small inverse association between PWY-5088 and social-communication severity merits replication with longitudinal metabolomics; it is neither a diagnostic biomarker nor evidence of causality.
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