Functional Heterogeneity of the Autism Spectrum Disorder‐Associated Gut Microbial Ecosystem Revealed by Fecal Lipopolysaccharides and Bacterial Proteomic Profiling

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The etiology of pediatric autism spectrum disorder (ASD) has been increasingly linked to alterations in the gut‐brain axis, highlighting the intricate bidirectional communication between gut microbiota and central nervous system. The molecular mechanisms of this communication are poorly understood. Here we investigated whether ASD‐associated gut microbiota could exhibit altered inflammatory molecular outputs by integrating chemistry‐driven profiling of fecal lipopolysaccharides (LPS), functional bacterial proteomics, and neuroimmune cellular assays. Structural analyses revealed that LPS from non‐autistic healthy donors (NASD) displayed highly conserved carbohydrate and lipid A signatures dominated by hypo‐acylated mono ‐phosphorylated species typically associated with immunomodulatory Bacteroides ‐derived LPS. In contrast, LPS from ASD children exhibited increased structural heterogeneity. These molecular alterations were functionally reflected in human HMC3 microglial cells, where ASD‐derived fecal LPS induced stronger IL‐6 and IL‐8 release compared with NASD‐derived LPS, indicating enhanced neuroinflammatory potential. Functional proteomic profiling disclosed broadly comparable microbial compositions but marked metabolic divergence. These findings suggest that gut microbiota in ASD children are associated with a functionally heterogeneous microbial ecosystem characterized by altered immunostimulatory molecular outputs despite the absence of massive taxonomic shifts, with potential relevance for neuroimmune dysregulation.