Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation and chronic inflammation, with increasing evidence implicating the gut microbiota in its pathogenesis. Probiotics, such as Lactobacillus rhamnosus GG (LGG), exert anti-inflammatory effects by enhancing gut barrier function and restoring microbial homeostasis, representing a promising therapeutic strategy for SLE. However, conventional probiotic therapies are hindered by poor survival and colonization in the hostile intestinal environment. Here, a polydopamine-coated LGG (LGG@PDA) with improved viability, adhesion, and resistance to oxidative stress is developed. In murine models of lupus, LGG@PDA treatment restored gut and immune homeostasis, enhanced macrophage efferocytosis, reduced autoantibody levels, and ameliorated renal pathology. Metabolomic analysis further identified L-methionine, a metabolite diminished in both lupus mice and SLE patients, as being enriched by LGG@PDA treatment. Functionally, L-methionine enhanced macrophage efferocytosis in a CX3CR1-dependent manner, thereby contributing to the restoration of immune tolerance. Collectively, these findings establish LGG@PDA as a bioengineered probiotic platform that integrates microbiota modulation with immune regulation, highlighting L-methionine as a key metabolic mediator and a promising microbiota-based therapeutic strategy for SLE.