Selective Estrogen Receptor Modulator Lasofoxifene Suppresses Spondyloarthritis Manifestation and Affects Characteristics of Gut Microbiota in Zymosan-induced SKG Mice

Background: Ankylosing spondylitis is a male-predominant disease and previous study revealed that estrogen has an anti-inflammatory effect on the spondyloarthritis (SpA) manifestations in zymosan-induced SKG mice. This study aimed to evaluate the effect of selective estrogen receptor (ER) modulator lasofoxifene (Laso) on disease activity of SpA. Methods: Mice were randomized into zymosan-treated, zymosan + 17β-estradiol (E2)-treated, and zymosan + Laso-treated groups. Clinical arthritis scores were measured, and 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography was performed to quantify joint inflammation. Bone mineral density (BMD) was measured. Fecal samples were collected and 16S ribosomal RNA gene sequencing was used to determine gut microbiota differences. Results: Both zymosan + E2-treated mice and zymosan + Laso-treated mice showed lower arthritis clinical scores and lower 18F-FDG uptake than zymosan-treated mice. BMD was significantly higher in zymosan + E2-treated mice and zymosan + Laso-treated mice than zymosan-treated mice, respectively. Fecal calprotectin levels were significantly elevated at 8 weeks after zymosan injection in zymosan-treated mice, but it was not significantly changed in zymosan + E2-treated mice and zymosan + Laso-treated mice. Gut microbiota diversity of zymosan-treated mice was significantly different from zymosan + E2-treated mice and zymosan + Laso-treated mice, respectively. There was no significant difference in gut microbiota diversity between zymosan + E2-treated mice and zymosan + Laso -treated mice. Conclusions: Selective ER modulator Laso inhibited joint inflammation and enhanced BMD in SKG mice, a model of SpA. Laso also affected the composition and biodiversity of gut microbiota. This study provides new knowledge regarding that selected SpA patients could benefit from selective ER modulator treatment.