The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis

Sulfasalazine is a prodrug known to be effective for the treatment of inflammatory bowel disease (IBD)-associated peripheral spondyloarthritis (pSpA), but the mechanistic role for the gut microbiome in regulating its clinical efficacy is not well understood. Here, treatment of 22 IBD-pSpA subjects with sulfasalazine identifies clinical responders with a gut microbiome enriched in Faecalibacterium prausnitzii and the capacity for butyrate production. Sulfapyridine promotes butyrate production and transcription of the butyrate synthesis gene but in F. prausnitzii in vitro, which is suppressed by excess folate. Sulfasalazine therapy enhances fecal butyrate production and limits colitis in wild-type and gnotobiotic mice colonized with responder, but not non-responder, microbiomes. F. prausnitzii is sufficient to restore sulfasalazine protection from colitis in gnotobiotic mice colonized with non-responder microbiomes. These findings reveal a mechanistic link between the efficacy of sulfasalazine therapy and the gut microbiome with the potential to guide diagnostic and therapeutic approaches for IBD-pSpA. [Display omitted] •IBD-SpA subjects that respond to sulfasalazine therapy have a distinct gut microbiome•The responder microbiome is enriched in F. prausnitzii and butyrate•Sulfapyridine promotes butyrate production by F. prausnitzii, which limits colitis•F. prausnitzii restores response in mice with non-responder microbiomes Lima and Pires et al. identified a unique gut microbiome in patients with IBD-associated spondyloarthritis that respond to sulfasalazine therapy. Sulfasalazine therapy enhances butyrate synthesis by F. prausnitzii, a key component of this microbiome, which is sufficient to restore sulfasalazine protection from colitis in gnotobiotic mice colonized with non-responder microbiomes.