Functional and metabolic alterations of gut microbiota in children with new-onset type 1 diabetes Original paper

What was studied?

In this original research study on the gut microbiome in new-onset type 1 diabetes, investigators employed a multi-omics approach to elucidate how gut microbial composition, microbial functional capacity, and stool metabolites change in pediatric new-onset type 1 diabetes (T1D), and whether these shifts plausibly contribute to dysglycemia and islet injury. They integrated 16S rRNA profiling with shotgun metagenomics and targeted fecal metabolomics across discovery and validation cohorts, then tested causality using fecal microbiota transplantation (FMT) into antibiotic-treated mice and mechanistic supplementation in streptozotocin (STZ)-induced T1D mouse models, focusing on butyrate (protective) versus lipopolysaccharide.

Who was studied?

Children with newly diagnosed T1D and non-diabetic controls were recruited in China as independent discovery and validation cohorts. The discovery set comprised 64 children with new-onset type 1 diabetes (T1D) and 77 controls; the validation set consisted of 29 children with T1D and 29 controls, matched for age, sex, delivery mode, and feeding history. Key exclusions included recent antibiotics, probiotics/prebiotics, or other medical treatment within one month, and major inflammatory/infectious or gastrointestinal diseases. Samples for the T1D group were collected after ~1 week of conventional inpatient treatment to stabilize metabolic decompensation (eg, ketoacidosis when present).

Most important findings

Across cohorts, pediatric new-onset T1D showed reduced gut microbial richness/diversity and a compositional shift away from Firmicutes with relative expansion of Bacteroidetes/Proteobacteria. Taxonomically, many butyrate-producing taxa decreased (eg, Faecalibacterium prausnitzii, Eubacterium rectale, Roseburia intestinalis), while opportunistic/pathobiont patterns increased (eg, Escherichia coli, Enterobacteriaceae, Klebsiella pneumoniae). Functionally, metagenomics highlighted downregulation of butyrate-production genes, reduced carbohydrate-active enzyme potential, and decreased bile acid metabolism capacity (including lower bile salt hydrolase–related signals), alongside increased LPS biosynthesis potential. Metabolomics aligned with function: fecal short-chain fatty acids (including butyrate and acetate) were lower, while inflammatory surrogates (eg, higher LPS-binding protein and IL-1β) supported greater endotoxin signaling. In vivo, FMT from children with T1D increased fasting glucose and reduced insulin sensitivity in antibiotic-treated mice; butyrate supplementation mitigated these effects. In STZ-induced T1D mice, butyrate improved glycemic indices and preserved islet structure with increased pancreatic Ins1/Ins2 expression, whereas chronic low-dose LPS worsened glycemia, increased inflammatory transcriptional programs, and aggravated islet injury.

Key implications

Clinically, this work argues that T1D-associated dysbiosis is more usefully captured as a functional-metabolic syndrome—reduced SCFA (especially butyrate) production and bile-acid processing capacity with increased LPS-related inflammatory potential—rather than as a single “pathogen.” For microbiome-signature databases, the most portable signals are pathway-level features (butyrate-production modules, LPS biosynthesis, bile acid metabolism/BSH capacity) plus a small panel of discriminant taxa/metabolites that together strongly classify new-onset T1D. Translationally, the mouse data support mechanistic prioritization of interventions that raise colonic butyrate (dietary fiber, targeted prebiotics, or rational consortia) and/or reduce endotoxin burden and translocation, while recognizing that pediatric sampling occurred after initial stabilization, so future work should test whether these signatures predict risk before clinical onset.

Citation

Yuan X, Wang R, Han B, et al. Functional and metabolic alterations of gut microbiota in children with new-onset type 1 diabetes. Nat Commun. 2022;13:6356. doi:10.1038/s41467-022-33656-4