Objectives: Systemic lupus erythematosus (SLE) frequently affects the central nervous system, leading to neuropsychiatric SLE (NPSLE).Major depressive disorder in SLE (SLE MDD ) is the most frequent manifestation of NPSLE and is believed to arise from an immune-mediated process.However, biomarkers for SLE MDD remain lacking.The aim of this study was to identify candidate immunometabolic biomarkers associated with SLE MDD .Methods: We analysed deep flow cytometry immune phenotyping, gut microbiota profiling, and targeted mass spectrometry-based metabolomics from 99 patients from the LUPIL-2 study (NCT02955615).Biological signatures were identified using unsupervised principal component analysis and supervised decision tree classification.They were then validated in an independent cohort from the TRANSIMMUNOM study (NCT02466217).Results: SLE MDD patients exhibited a distinct immune profile with decreased nave CD4 T cells and nave regulatory T cells (Tregs), alongside increased ICOS effector memory Tregs (94% classification accuracy).Gut microbiota diversity was reduced with depletion of Akkermansia muciniphila and enrichment of Faecalibacterium prausnitzii.Metabolomic analyses revealed disruptions in kynurenine and short-chain fatty acid pathways, including decreased butyrate levels.Integrative analyses demonstrated coordinated alterations linking Treg activation, microbial metabolites, and immune pathways, distinguishing SLE MDD from SLE non-MDD with up to 85% accuracy.Conclusions: SLE MDD is associated with an immunometabolic signature involving alterations in Treg phenotype, gut microbiota composition, and metabolic pathways.These findings provide a rationale for future immunoregulatory or microbiota-targeted therapeutic strategies in SLE MDD .
Ellul et al. (Sun,) studied this question.