Exploring the potential mechanism of tofacitinib therapy for ankylosing spondylitis through gut microbiome and plasma metabolomics.

Objective: To explore the role of gut microbiota and plasma metabolites in the therapeutic mechanism of tofacitinib in ankylosing spondylitis (AS).

Method: Ten AS patients and ten matched healthy controls (HC) were enrolled in this study. 16S rRNA sequencing and LC-MS profiling was conducted to investigate the gut microbiota and plasma metabolite before and after tofacitinib therapy. An AS mouse model was established to validate the effect of tofacitinib in vivo via H&E staining, western blot, and ELISA.

Results: Tofacitinib improved clinical symptoms in AS patients. Microbiota analysis revealed Microbiota analysis revealed reduced α-diversity (ACE, Chao1) and altered community structure in AS patients compared to HC, which partially normalized post-treatment. LEfSe identified 84 taxa biomarkers; Barnesiella, Coprobacter, Lachnospira, and Lactobacillus tended to return to normal after tofacitinib treatment. Plasma metabolomics uncovered 3 key metabolies, including choline metabolism, glycerophospholipid metabolism, and phenylalanine metabolism. Spearman analysis revealed that the gut microbiota were closely related to the changes in differential plasma metabolites. Combinated tofacitinib and trichostatin therapy attenuated inflammation, restored metabolism caused by AS in mice in vivo.

Conclusion: AS patients suffer from dysbiosis of gut microbiota, and the mechanism of tofacitinib treatment of AS may be related to the modulation of gut microbiota and alteration of plasma metabolites. Key Points • Tofacitinib improves clinical symptoms in patients with AS. • Tofacitinib regulates gut microbiota in AS patients. • Tofacitinib regulates plasma metabolites in patients with AS. • Tofacitinib regulates the choline metabolism.