Introduction and Objective: The concept of endotypes, disease subgroups with distinct pathomechanisms, offers a framework to explain biological and therapeutic response variability in T1D. We previously identified two age-independent, immunologically distinct T1D subgroups. Subgroup 1 exhibited elevated plasma cytokine/chemokine levels, increased circulating Th1 T-cells, and a better therapeutic response to anti-CD20. Subgroup 2 had elevated levels of plasma microRNAs and a better therapeutic response to CTLA4-Ig that was associated with reductions in central memory T-cells and preservation of regulatory T-cells. Here, we analyzed plasma metabolomic profiles of these two subgroups. Methods: A cohort of individuals with new onset T1D were recruited (n=47, age=11.6 years, male=53%). Participants were assigned to subgroups using an established plasma-induced transcription assay and classification analyses with 97% accuracy. Untargeted plasma metabolomics utilized liquid chromatography-tandem mass-spectrometry. Pathway analysis utilized IPA. Results: Subgroup 1 exhibited elevated levels of pro-inflammatory liver-conjugated secondary bile acids (BAs), glycodeoxycholate and taurolithocholate, and reduced gut microbiota-derived protective secondary BAs, ursodeoxycholate and isoursodeoxycholate, compared to Subgroup 2 (FC1.5; BH p0.05). Subgroup 1 showed activation of inflammatory and tissue damage pathways including hepatic fibrosis and cytokine signaling (LPS, TNF, NFKB), but inhibition of homeostasis (LXR/RXR) and metabolic PPAR pathways, and cholesterol and BA regulators (INSIG1, ATP8B1, CYP7B1, and FOXA3) relative to subgroup 2 (-log(BH) p3, Zscore2). Conclusion: These findings extend previously defined subgroup differences, with BA dysregulation as a key feature. Given the dependence of BA homeostasis on liver-gut microbiota interactions, these results suggest the presence of a putative liver-gut-pancreas axis that may contribute to biological heterogeneity in T1D and warrants further mechanistic investigation. Disclosure A. Bedrat: None. N.A. Truchan: None. S. Jia: None. M. Roethle: None. M.J. Hessner: None. Funding NIDDK (R01DK125014)NIDDK (R01DK121528)
Bedrat et al. (Fri,) studied this question.