ABSTRACT A substantial proportion of patients with X‑‐linked inhibitor of apoptosis (XIAP) deficiency develop severe and treatment‑‐refractory Crohn's disease (CD). Although hematopoietic stem cell transplantation (HSCT) remains the only curative option for these patients, its outcomes are suboptimal, with a long‑‐term survival rate of only 50%. Therefore, identifying novel therapeutic targets is crucial to bridge this unmet clinical need. Here, we demonstrate that the abundance of tuft cells is reduced in both XIAP‐deficient CD patients and Xiap knockout ( Xiap −/− ) mice. Mechanistically, XIAP deficiency reduces TLE4 ubiquitination, resulting in elevated TLE4 protein levels and consequent suppression of Wnt/β‑‐catenin–ASCL2 signaling, which is critical for secretory lineage differentiation. Tuft cell deficiency may increase susceptibility to microbial dysregulation, thereby promoting intestinal inflammation. Furthermore, we demonstrate that JAK inhibition promotes tuft cell regeneration and ameliorates mucosal inflammation in Xiap −/− mice. Consistently, in an XIAP‑‐deficient CD patient, treatment with a selective JAK1 inhibitor effectively increased tuft cell proportion and alleviated colonic symptoms. In conclusion, our study identifies tuft cell deficiency as a trigger of intestinal pathology in XIAP‑‐deficient Crohn's disease and suggests JAK inhibition as a promising therapeutic strategy.
Fang et al. (Sat,) studied this question.