Paeoniflorin Modulates Gut Microbiota–Derived Lysophospholipids to Restore Th17/Treg Homeostasis in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is characterized by dysregulated immune responses. Paeoniflorin (PF), a highly purified monoterpene glycoside derived from Paeonia lactiflora, exhibits immunomodulatory activity, but its mechanisms in SLE remain unclear. This study investigated whether PF ameliorates SLE by modulating the gut microbiota–lipid metabolite axis and restoring Th17/Treg immune balance. Network pharmacology was applied to predict PF-related targets and pathways in SLE. MRL/lpr mice were treated with PF, and disease severity was assessed by clinical manifestations, autoantibody levels, renal function, and histopathology. Intestinal barrier integrity and motility were evaluated in vivo. Th17 and Treg cell populations in intestinal and peripheral immune tissues were analyzed by flow cytometry. Gut microbiota composition was profiled using 16S rRNA gene sequencing, and untargeted LC–MS/MS–based metabolomics of intestinal contents was performed to identify differential metabolites and enriched metabolic pathways. PF treatment significantly alleviated lupus-like manifestations in MRL/lpr mice, including reduced splenomegaly and lymphadenopathy, decreased serum anti-dsDNA, ANA, total IgG, and IL-17 levels, and improved renal function and histopathological injury. PF restored Th17/Treg balance by suppressing IL-17–producing CD4⁺ T cells and promoting Foxp3⁺ Treg cells across intestinal and peripheral immune compartments. PF also improved intestinal barrier integrity and reshaped gut microbial composition by reducing inflammation-associated taxa and enriching beneficial bacteria. Metabolomic analysis demonstrated that PF markedly downregulated glycerophospholipid metabolism, particularly reducing lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC), which have been reported to promote RORγt activity and Th17 differentiation. Correlation analyses linked microbial alterations with lipid metabolite changes and Th17/Treg-associated immune parameters. Paeoniflorin alleviates SLE by regulating a gut microbiota–lipid metabolite–immune axis, suppressing pro-Th17 lysophospholipid metabolism and restoring Th17/Treg immune homeostasis.