Assessing the effects of tofacitinib on the gut microbiome in inflammatory bowel disease

Gut microbiota dysbiosis and impaired epithelial barrier function play a key role in inflammatory bowel disease (IBD). Tofacitinib citrate, a Janus kinase (JAK) inhibitor approved for IBD, modulates immune responses via the JAK-STAT (Janus kinase–signal transducer and activator of transcription) pathway, yet its effects on the gut microbiome remain unclear. Here, we employed the short-term colon model (ProDigest, BE) containing human microbiota from three Crohn's Disease donors to assess fermentative and metabolic activities and microbial composition following 48 h of tofacitinib treatment. A Caco-2/THP1 co-culture system was used to assess the impact of tofacitinib on epithelial immunomodulation and barrier integrity. Tofacitinib did not significantly affect microbiota composition and fermentative or metabolic activity. However, it consistently reduced pro-inflammatory chemokines motif chemokine ligand 10 (CXCL10) and monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in specific donors, indicating targeted immunomodulatory effects. These findings suggest that while tofacitinib may have a minimal impact on microbiota function, it may exert anti-inflammatory effects via microbiota-derived metabolites. The short-term colon model represents a robust platform for investigating microbiome-drug interactions relevant to IBD.