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

## TL;DR

This study finds that gut microbes in children with type 1 diabetes are linked to blood sugar control, suggesting potential for personalized treatment strategies.

## Contribution

The study introduces microbiome-based clustering to identify glycemic control-related subtypes in youth with T1D.

## Key findings

- Two subgroups of T1D youth were identified based on gut microbiome profiles and HbA1c levels.
- Bacteroides species and tryptophan-derived metabolites like skatole are associated with better glycemic control.
- Microbial signatures were validated in an independent cohort and showed relevance in healthy children with glycemic risk.

## 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.

Microbiome‐based clustering investigated possible glycemic control‐related endotypes in youth with recent‐onset T1D, and found a potential role of Bacteroides and skatole production in glycemic control. This study offers novel perspectives on the influence of intestinal microbes and its metabolites in T1D heterogeneity and lays a foundation for future studies investigating microbiome‐targeted strategies for personalized glycemic control.