Gut microbiota functional remodeling and butyrate depletion amplify anti-Ro/La antibody-driven type I interferon activation in neonatal lupus

The early-life gut microbiome may influence susceptibility to antibody-mediated neonatal autoimmunity, but the underlying mechanisms remain poorly understood. We investigated whether gut microbial functional capacity and metabolites influence autoantibody-dependent immune activation in 90 neonates, including healthy controls, anti-Ro/La-exposed neonates without neonatal lupus erythematosus (No-NLE), and neonates with NLE (n = 30 per group). Shotgun metagenomic profiling demonstrated progressive remodeling of the neonatal gut microbiome across the three groups, with anti-Ro/La exposure associated with depletion of early-life commensal-associated taxa, including Bifidobacterium, Rothia, and Clostridium, and enrichment of taxa with opportunistic potential, including Klebsiella and Enterococcus, with greatest ecological divergence in neonates with NLE. Functional profiling identified altered microbial carbohydrate-processing capacity, marked by enrichment of glycosyltransferase family 4 (GT4) and depletion of GT2 in NLE. These alterations coincided with broad reductions in plasma short-chain fatty acid metabolites, most prominently butyrate, together with increased serum immunoglobulin G (IgG) and interferon-α (IFN-α) and decreased complement component 4 (C4). A GT4–Klebsiella–Rothia–IFN-α signature distinguished NLE from No-NLE (AUC = 0.883; 95% CI, 0.799–0.967). In functional assays, pooled bacteria-depleted fecal filtrates from neonates with NLE potentiated IFN-α production by neonatal peripheral blood mononuclear cells in the presence of anti-Ro/La-positive plasma. Conversely, sodium butyrate suppressed anti-Ro/La-associated IFN-α production and reduced 28 inflammation-related proteins, including CXCL10, ADA, and PD-L1, involved in cytokine, IL-17, and TNF signaling. Together, these findings provide functional evidence supporting a microbiota-associated butyrate–type I interferon pathway that may amplify maternal autoantibody-dependent immune activation and contribute to the clinical manifestation of NLE.