Lactobacillus Acidophilus Supplementation Exerts A Synergistic Effect on Tacrolimus Efficacy by Restoring Th17/Treg Imbalance in Lupus-Prone Mice via the SIGNR3 Pathway

Abstract

Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterised by tissue-binding autoantibodies and immune complexes. Tacrolimus (Tac), also known as FK506, is an immunosuppressant used in the treatment of lupus; however, it induces T-cell imbalances. Lactobacillus acidophilus (LA) is reported to have therapeutic efficacy in immune-mediated diseases via T-cell regulation. This study investigated whether a combination therapy of LA and Tac improves the therapeutic efficacy of Tac by ameliorating T-cell imbalance in an animal model of SLE. Eight-week-old MRL/Mp-Faslpr (MRL/lpr) mice were orally administered with 5 mg/kg of Tac and/or 50 mg/kg of LA daily for 8 weeks. Caecal microbiota compositions, serum autoantibodies levels, the degree of proteinuria, histological changes in the kidney, and populations of various T-cell subsets in the spleen were analysed. Results: MRL/lpr mice presented with significant gut microbiota imbalances, which were subsequently recovered by the combination treatment of Tac and LA. Double negative T-cells, a pathogenic subset of T-cells, in the peripheral blood and spleens of MRL/lpr mice were significantly decreased by the combination therapy. The combination treatment also reduced serum levels of anti-double-stranded DNA antibodies and immunoglobulin G2a, and renal pathology scores were markedly alleviated. The combination therapy induced Treg cells and decreased Th17 cells both in vitro and in vivo. In vitro treatment with LA induced the production of indoleamine-2,3-dioxygenase, programmed death-ligand 1, and inerleukin-10, which was partially mediated by the induction of the specific intracellular adhesion molecule-3 grabbing non-integrin homolog-related 3 (SIGNR3) receptor. Conclusions: The present findings indicate that LA augments the therapeutic effect of Tac and restores Th17/Treg balance in a murine model of lupus. Accordingly, the combination treatment of Tac with LA could be a promising therapeutic candidate for lupus.