Rapamycin treatment ameliorates HLA-B27-mediated gut inflammation and alters the microbiome in experimental spondyloarthritis

Objective To determine whether rapamycin affects HLA-B27-mediated gut inflammation in experimental spondyloarthritis (SpA). Methods HLA-B27/human β 2 -microglobulin transgenic (B27-Tg) rats with gut inflammation were treated with rapamycin (1.5 mg/kg intraperitoneally, 3 times a week) or vehicle for 5 weeks. Healthy age-matched wild type (WT) rats were treated in parallel. Gut inflammation was evaluated via stool scoring and histological assessment. Transcriptome and microbiome analyses were performed on colon tissue and cecal luminal contents, respectively. Bulk immune cells were isolated from the colonic lamina propria of B27-Tg and WT animals, treated with rapamycin ex vivo , and pro-inflammatory cytokine expression was measured using qPCR. Results Rapamycin treatment reduced stool and colon histological scores in B27-Tg rats compared to vehicle-treated B27-Tg controls. Transcriptome analysis revealed that rapamycin reduced expression of key pro-inflammatory cytokines like Il17a, Il17f , Tnf , Il1a , IL1b , and Il22 in B27-Tg colon tissue compared to vehicle-treated B27-Tg controls. Ex vivo treatment of bulk immune cells isolated from B27-Tg rat colon with rapamycin reduced expression of Il17a, Il17f , Ifng , and Il22 compared to vehicle-treated cells. Rapamycin treatment decreased the abundance of cecum microbiota associated with inflammation in B27-Tg rats. Rapamycin also altered the gut microbiome in WT rats, without associated changes in the tissue transcriptome. Conclusion Our study demonstrates that rapamycin treatment substantially reduces HLA-B27-mediated gut inflammation in experimental SpA. Results from this pre-clinical model suggest further evaluation of rapamycin as a therapeutic strategy in HLA-B27 associated diseases is warranted.