The Role of Intestinal Microbiota in Modulating Mesenchymal Stromal Cell Therapy in a Murine Model of Lupus-like Autoimmunity

Abstract

This study investigated the impact of gut microbiota on the efficacy of mesenchymal stromal cell (MSC) therapy in lupus-like autoimmunity. Using a co-housing approach to facilitate microbiota transfer between mice, we assessed lupus-like phenotypes, gut permeability, 16S rRNA sequencing, and metabolomics analyses. While MSC therapy effectively ameliorated lupus-like autoimmunity, its therapeutic benefits were significantly diminished when MSC-treated mice were co-housed with untreated R848-induced lupus-like mice. Co-housing altered therapeutic outcomes, impaired intestinal barrier function, and modulated immune cell subpopulations, which correlated with changes in gut microbiota composition and serum metabolite profiles. Two key bacterial taxa ( Bacteroides acidifaciens and a taxon from the Muribaculaceae ) and three serum metabolites (cinnamic acid, 3,4-dihydroxyhydrocinnamic acid, and pyruvic acid) were identified as correlating with T and B lymphocyte development. In vitro experiments revealed that these metabolites suppressed T cell activation, restored the Th1/Th2 and Th17/Treg balance, and exhibited an additive effect with MSC in regulating T cell responses. These findings directly link the microbiota–metabolite axis to the modulation of MSC therapeutic efficacy, emphasizing the critical role of gut microbiota and its metabolic products in determining MSC therapy outcomes for lupus-like autoimmunity.