Mapping the impact of JAK 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, reduced hospital admissions, and a diminished need for surgery. In contrast to biologics that specifically target a receptor or its substrate, Janus Kinase (JAK) inhibitors (JAKis) interfere with several shared signalling pathways and therefore exert broader effects. JAK-STAT signalling 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 JAKis have greatly complicated the identification of cellular mediators of beneficial, adverse, or off-target effects, and this remains a challenge to date. This review summarises current knowledge on the mechanisms of action of JAKis for the treatment of IBD, outlined per major cell type implicated in the pathophysiology of the disease. Deeper understanding of their effects on the diverse mucosal cell types is crucial to elucidate therapeutic mechanisms and explain treatment non-response.