LAUSR

BACKGROUND Long-time use of pharmacological immunosuppressive agents frequently leads to metabolic disorders. Most studies have focused on islet toxicity leading to post-transplantation diabetes mellitus. In contrast, the link between intestinal dysbiosis and immunosuppressive drug-induced metabolic disorders remains unclear. METHODS We established a mouse model of metabolic abnormality via sirolimus treatment. Fecal microbiota was examined using 16S rRNA gene MiSeq sequencing. Intestinal barrier function was assessed using fluorescein isothiocyanate-dextran assay and mucus immunostaining. Systemic inflammation was determined using a multiplexed fluorescent bead-based immunoassay. RESULTS Sirolimus induced dyslipidemia and glucose intolerance in mice in a dose-dependent manner. Interestingly, the clinical-mimicking dose of sirolimus altered the intestinal microbiota community, which was characterized by the enrichment of Proteobacteria, depletion of Akkermansia, and potential function shifts to those involved in lipid metabolism and the immune system. In addition, the clinical-mimicking dose of sirolimus reduced the thickness of the intestinal mucosal layer, increased the intestinal permeability, and enriched the circulating pro-inflammatory factors, including IL-12, IL-6, MCP-1, GM-CSF, and IL-1β. Our results showed a close association between intestinal dysbiosis, intestinal barrier failure, systemic inflammation, and metabolic disorders. Furthermore, we demonstrated that oral intervention in the gut microbiota by Lactobacillus rhamnosus HN001 protected against intestinal dysbiosis, especially by depleting the LPS-producing Proteobacteria, and attenuated the sirolimus-induced systemic inflammation, dyslipidemia, and insulin resistance. CONCLUSION Our study demonstrated a potentially causative role of intestinal dysbiosis in sirolimus-induced metabolic disorders, which will provide a novel therapeutic target for transplant recipients.