Mapping the Impact of Janus Kinase Inhibitors at a Cellular Resolution in Inflammatory Bowel Disease

The advent of biologics and targeted oral small molecules has transformed the management of patients with inflammatory bowel disease, leading to increased rates of mucosal healing, fewer hospital admissions, and reduced need for surgery. In contrast to biologics that specifically target a receptor or its substrate, Janus kinase inhibitors interfere with several shared signaling pathways and therefore exert broader effects. Janus kinase-signal transducer and activator of transcription signaling occupies a central position in multiple pro-inflammatory pathways and plays a pivotal role in the pathophysiology of autoimmune and inflammatory diseases. However, the pleiotropic effects of Janus kinase inhibitors have greatly complicated the identification of cellular mediators of beneficial, adverse, or off-target effects, and this remains a challenge to date. This review summarizes current knowledge on the mechanisms of action of Janus kinase inhibitors for the treatment of inflammatory bowel disease, outlined by major cell types implicated in the pathophysiology of the disease. A deeper understanding of their effects on the diverse mucosal cell types is crucial to elucidate therapeutic mechanisms and explain treatment nonresponse.