Table 3_Commonalities and differences in the microbiota-metabolism-immune axis dysregulation patterns between fragile X syndrome and autism spectrum disorder.xlsx

IntroductionFragile 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.
MethodsIn 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.
Results16S 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.
ConclusionThis 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.

引言
脆性X综合征（Fragile X Syndrome, FXS）是引发自闭症谱系障碍（Autism Spectrum Disorder, ASD）的主要单基因病因之一，为解析自闭症谱系障碍的病理生理学机制提供了关键研究模型。然而，目前针对这两类疾病间的微生物群-代谢物-免疫（Microbiota-Metabolite-Immune, MMI）轴的比较研究仍较为匮乏。本研究旨在识别二者共享及特异性的MMI轴失调模式，以揭示潜在的神经生物学机制与潜在生物标志物。

方法
本项横断面研究开展了多组学分析，包括肠道菌群16S rRNA测序、基于超高效液相色谱-质谱（UPLC-MS）的非靶向血清代谢组学，以及13种血清细胞因子的定量检测。通过统计学分析，鉴定了自闭症谱系障碍组与脆性X综合征组间差异富集的菌群分类群、代谢物及细胞因子。

结果
16S rRNA测序结果显示，两组的微生物群落结构（β多样性）存在显著差异，共鉴定出11个差异富集的菌群分类群，但两组的α多样性无显著差异。非靶向代谢组学共鉴定出152种显著差异的血清代谢物，其中自闭症谱系障碍组中参与咖啡因代谢与类固醇激素生物合成的代谢物呈现上调表达。在13种检测的细胞因子中，脆性X综合征组的白细胞介素17A（IL-17A）水平显著高于自闭症谱系障碍组。

结论
本研究表明，脆性X综合征与自闭症谱系障碍在MMI轴上存在共同的失调框架，但同时呈现出疾病特异性的差异模式，佐证了脆性X综合征作为自闭症谱系障碍单基因研究模型的价值。本研究鉴定出的差异代谢物，以及脆性X综合征中升高的IL-17A，揭示了二者独特的潜在病理生理学机制，为后续生物标志物发掘与精准干预提供了潜在靶点。