Commonalities and differences in the microbiota-metabolism-immune axis dysregulation patterns between fragile X syndrome and autism spectrum disorder

Introduction: Fragile X syndrome (FXS), a leading monogenic cause of autism spectrum disorder (ASD), provides a crucial model for elucidating ASD pathophysiology. However, comparative studies on the Microbiota-Metabolite-Immune (MMI) axis between these disorders are lacking. This study aims to identify shared and distinct MMI dysregulation patterns to uncover underlying neurobiological mechanisms and potential biomarkers. Methods: In this cross-sectional study, multi-omics analyses were performed, including 16S rRNA sequencing of gut microbiota, untargeted UPLC-MS-based serum metabolomics, and quantification of 13 serum cytokines. Statistical analyses identified differentially abundant taxa, metabolites, and cytokines between the ASD and FXS groups. Results: 16S rRNA sequencing revealed distinct microbial community structures (beta-diversity) and 11 differentially abundant taxa between groups, though alpha-diversity was comparable. Untargeted metabolomics identified 152 significantly altered serum metabolites, with ASD showing upregulation of metabolites involved in caffeine metabolism and steroid hormone biosynthesis. Cytokine profiling showed significantly elevated IL-17A in FXS vs. ASD among the 13 cytokines analyzed. Conclusion: This study reveals that FXS and ASD share a common dysregulation framework within the MMI axis, yet exhibit distinct disease-specific patterns, supporting the value of FXS as a monogenic model for ASD. The identified differential metabolites and elevated IL-17A in FXS uncover unique underlying pathophysiological mechanisms, thereby providing potential targets for future biomarker discovery and precise interventions.