Targeting JAK/STAT Signaling Attenuates Postoperative Recurrence in an HLA-B27 Transgenic Rat Model of Crohn’s Disease

Postoperative recurrence (POR) remains a common complication following ileocecal resection (ICR) in patients with Crohn’s disease (CD), and no therapy is currently approved. This study aimed to study the benefits of JAK/STAT pathway inhibition in preventing POR using an ICR model in HLA-B27 transgenic (Tg) rats. Twenty-nine Tg rats underwent ICR at 12 weeks of age (W12). TOFA (15 mg/Kg/day) or placebo was administered at W10 as a preventive intervention. Disease extent and severity were assessed by monitoring body weight, stool consistency, performing endoscopy (W15) and evaluating macroscopic and histologic scores (W18). Ileal STATs phosphorylation was assessed by Western blotting and immunohistochemistry, while inflammatory cytokine expression was quantified by qRT-PCR and ELISA. In the placebo-treated Tg group, 57% of rats exhibited mucosal ulcerations in at least 20% of the anastomotic area (macroscopic score ≥2), which correlated with an endoscopic score ≥9. In contrast, only 13% of TOFA-treated Tg rats had a macroscopic score ≥2 and all had endoscopic scores ≤9. TOFA reduced mucosal inflammation and decreased ilealSTAT3 phosphorylation and pro-inflammatory cytokine expression. These findings provide a preclinical rationale for further investigating JAK inhibition as a potential preventive strategy against POR in CD.