High-CoverageMetabolomics Reveals Gut Microbiota-RelatedMetabolic Traits of Type‑2 Diabetes in Serum

Metabolic perturbations of the gut microbiome have been implicated in the pathogenesis of multiple human diseases, including type-2 diabetes (T2D). However, our understanding of the global metabolic alterations of the gut microbiota in T2D and their functional roles remains limited. To address this, we conducted a high-coverage metabolomics profiling analysis of serum samples from 1282 Chinese individuals with and without T2D. Among the 220 detected microbiota-associated compounds detected, 111 were significantly altered, forming a highly interactive regulatory network associated with T2D development. Pathway enrichment and correlation analyses revealed aberrant metabolic pathways, primarily including the activation of pyrimidine metabolism, unsaturated fatty acid biosynthesis, and diverse amino acid metabolisms such as Tryptophan metabolism, Lysine metabolism, and Branched-chain amino acid biosynthesis. A microbiota-dependent biomarker panel, comprising pipecolinic acid, methoxysalicylic acid, <i>N</i>-acetylhistamine, and 3-hydroxybutyrylcarnitine, was defined and validated with satisfactory sensitivity (>78%) for large-scale, population-based T2D screening. The functional role of a gut microbial product, <i>N</i>-acetylhistamine, was further elucidated in T2D progression through its inhibition of adenosine monophosphate-activated protein kinase phosphorylation. Overall, this study expands our understanding of gut microbiota-driven metabolic dysregulation in T2D and suggests that monitoring these metabolic changes could facilitate the diagnosis and treatment of T2D.