HIGH ADHERENCE TO THE MEDITERRANEAN DIET DELAYS SURGERY AND REPROGRAMS INTESTINAL CELLULAR STATES IN CROHN'S DISEASE

Introduction: Fibrostenotic Crohn’s disease (CD) leads to intestinal obstruction and surgery, yet determinants of fibrogenesis remain poorly defined. While dietary patterns influence inflammation, their role in fibrotic progression remains unclear. We investigated whether Mediterranean diet (MD) adherence influences disease progression. Aims & Methods: We conducted a retrospective cohort study including 1,092 patients with Crohn’s disease from two tertiary referral centers (mean age at diagnosis 33.6 years, SD 15.3; 54% male), with B1 disease in 67%, B2 in 27%, and B3 in 6%. MD adherence was quantified using a validated food frequency questionnaire and a 0–9-point score. The primary outcome was intestinal surgery for fibrostenotic CD, and the secondary outcome was de novo intestinal stenosis. Time-to-event analyses were performed using Kaplan–Meier estimates and multivariable Cox regression, with time zero defined as first clinical assessment. Patients were censored at last clinical follow-up for surgery and at last colonoscopy for stenosis, reflecting routine clinical practice with variable follow-up intervals. Mechanistic studies were performed in SAMP1/YitFc mice fed a Mediterranean or control diet for 12 weeks. Disease severity, fibrosis, and ileal remodeling were assessed. Spatial transcriptomics was performed in murine tissue, while bulk RNA sequencing was conducted on fibroblasts from 10 CD patients stratified by diet adherence. Results: Over a median follow-up of 2.54 years (3,772 person-years), 313 patients (28.7%) underwent surgery, corresponding to an incidence rate of 8.3 per 100 person-years. The 5-year cumulative incidence of surgery decreased progressively across MD adherence levels (39.2% low, 31.8% moderate, 25.0% high; p < 0.001). For de novo stenosis, the 5-year cumulative incidence was 49.6% (95% CI 45.6–53.2%), with a graded reduction across adherence levels (56.4%, 51.2%, 35.8%). Multivariable models confirmed an independent protective association between higher MD adherence and both outcomes. In mice, MD attenuated intestinal inflammation and collagen deposition compared with the control diet (p<0.001). Spatial transcriptomics revealed diet-dependent remodeling of the intestinal microenvironment, characterized by expansion of goblet cells and RGS5+ structural myofibroblasts, with reduced SPP1+ pro-fibrotic and CD74+ inflammatory fibroblasts. In contrast, the control diet promoted inflammatory and metabolically dysregulated stromal states. Similarly, in human samples, high MD adherence was associated with enrichment of RGS5+ structural myofibroblasts in the intestinal mucosa. Conclusion: Higher MD adherence is associated with reduced risk of stenosis-associated intestinal surgery and de-novo stenosis in CD. Integrated human and experimental data suggest that the MD may modulate fibrostenotic progression by directly reshaping epithelial and stromal cellular states, beyond anti-inflammatory effects, providing a potential strategy to influence intestinal tissue remodeling.