Shared fecal metabolomic signatures define cross-disease subtypes in primary Sjögren’s disease and systemic lupus erythematosus

Primary Sjögren’s disease (pSjD) and systemic lupus erythematosus (SLE) share overlapping clinical and serological features and exhibit highly similar gut microbiota compositions. We aimed to determine whether they also share fecal metabolomic signatures and whether these signatures could define subgroups across the two diseases. We enrolled 141 patients with pSjD or SLE and 42 age- and gender-matched healthy controls (HCs). Untargeted fecal metabolomics and targeted serum sphingolipidomics were performed in all participants. Consensus clustering based on shared fecal metabolic features was used to identify patient subtypes, which were then compared with respect to clinical, serological, and immune-related characteristics. Patients with pSjD and SLE showed similar fecal metabolic alterations, involving amino acid, cholesterol, bile acid, sphingolipid, and glyceride metabolism. Based on these shared features, patients were classified into three subtypes (C1, C2 and C3). C1 subtype was characterized mainly by increased ceramide (Cer). C2 showed the most pronounced metabolic dysregulation, with increased amino acids, Cer, hexosylceramide (HexCer), cholic acid, and sphingosine, together with decreased diacylglycerol (DG) and deoxycholic acid. C3 exhibited a metabolomic profile similar to that of HCs. Targeted serum sphingolipidomic analysis further confirmed abnormalities in circulating sphingolipids in both pSjD and SLE, and the sphingosine-1-phosphate/sphingosine (S1P/Sph) ratio was associated with subtype classification. In addition, correlations between metabolites and clinical parameters differed markedly among the three subtypes, suggesting distinct biological processes across metabolically defined patient groups. We identified three shared metabolic subtypes across pSjD and SLE, highlighting heterogeneous sphingolipid dysregulation. These findings provide insight into disease heterogeneity beyond conventional diagnostic categories and may support biologically informed stratification in systemic autoimmune diseases. • Patients with pSjD and SLE showed a shared fecal metabolomic signature, particularly involving dysregulation of amino acid, cholesterol, bile acid, sphingolipid, and glyceride metabolism. • These shared metabolic features define three cross-disease subtypes, primarily separated by the extent of sphingolipid metabolic disturbance. • Metabolite-clinical associations differed across the three subtypes, indicating biologically distinct clinical-metabolic patterns beyond conventional diagnostic categories.