Microbiome‐Based Clustering Identifies Glycemic Control‐Related Subtypes in Youth With Recent‐Onset Type 1 Diabetes

ABSTRACT Type 1 diabetes (T1D) in children exhibits substantial heterogeneity in glycemic control, yet the biological mechanisms underlying this variation remain unclear. We aimed to explore endotype heterogeneity in youth with recent‐onset T1D using unsupervised clustering based on multi‐omics data, and to identify associated molecular signatures and underlying mechanisms. In a discovery cohort of 69 children and adolescents with recent‐onset T1D, unsupervised clustering of fecal metagenomic profiles revealed two robust subgroups distinguished by hemoglobin A1c (HbA1c) levels. The High‐HbA1c group was enriched in Bacteroidota , while the Low‐HbA1c group was enriched in Firmicutes and certain Bacteroides species ( Bacteroides ovatus , Bacteroides xylanisolvens , Bacteroides nordii , and Bacteroides cellulosilyticus ). Metabolomics revealed significant enrichment of tryptophan‐derived metabolites in the Low‐HbA1c group. Bacteroides species signatures are positively correlated with tryptophan metabolite skatole. In an independent validation cohort, Bacteroides signatures discriminated individuals with good versus poor glycemic control (AUC = 0.854). Similar microbial patterns were observed in healthy children stratified by glycemic risk, indicating broader relevance of these signatures. Together, microbiome‐based clustering identified glycemic control‐related subtypes in T1D youth and suggested a potential role of Bacteroides and skatole in glycemic control. Mechanistic studies are warranted to confirm its role as a glycemic control‐related endotype with distinct pathophysiology.