Protective Role of Dietary Short-Chain Fatty Acid Propionate against Autoimmune Responses and Pathology of Systemic Lupus Erythematosus in MRL-lpr Mice

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs, including the skin and kidneys. The etiology of SLE remains unclear but involves hormonal, environmental, and genetic factors. Environmental factors, such as diet and microbiota-derived metabolites, among which short-chain fatty acids (SCFAs) are major players, can influence autoimmune disease pathogenesis. Objectives: This study investigates the involvement of SCFAs in the pathogenesis of SLE and further investigates the effect of propionate (PA) supplementation on SLE disease outcome in MRL/MpJ-Fas^lpr (MRL-lpr) mice. Methods: Cecal SCFAs from mouse models with varying degrees of SLE disease activities (B6 (C57BL/6), MRL+/+ (Murphy Roths Large, MRL/MpJ), and MRL-lpr) were determined by liquid chromatography/MS analysis. Five-week-old MRL-lpr mice were supplemented with PA (200 mM, via drinking water) for 6 wk, and assessed for autoimmunity and disease markers. Results: Liquid chromatography/mass analysis of cecal SCFAs showed a significant decrease of PA in MRL-lpr mice (P < 0.001). PA treatment ameliorated the autoimmune response, evident from reduced serum autoantibodies (P < 0.05 for both antinuclear antibodies and anti–double-stranded deoxyribonucleic acid) and a significant alleviation of glomerulonephritis (P < 0.05). Furthermore, it restored the imbalances in gut microbiome composition and SCFAs, especially PA (P < 0.01). Additionally, PA treatment resulted in decreased splenic activated cluster of differentiation 4 (CD4) T cells (P < 0.05) and alterations in renal inflammatory signaling pathways. Conclusions: Our findings support the beneficial effects of PA in alleviating SLE and the therapeutic potential of PA or PA-producing bacteria for SLE.