AbstractBackground and AimsCrohn’s disease [CD] is a major subtype of inflammatory bowel diseases [IBD] with increasing incidence and prevalence. Results of studies using available small and large animal models are often poorly translatable to patients, and few CD models show small intestinal pathology. Due to its similarities to humans, the pig has emerged as a highly suitable translational disease model, particularly for testing novel nutritional and technological interventions. Our goal was to develop a physiologically relevant porcine CD model to facilitate translation of findings and interventions towards the clinic.MethodsWe generated pigs bearing a 93-bp deletion of the adenosine–uracil-rich element [ARE] and a constitutive-decay element within the 3ʹ untranslated region of theTNFgene. Comparative analysis of physiological, molecular, histological and microbial characteristics was performed between wild-type,TNFΔARE/+andTNFΔARE/ΔAREanimals. Alterations in the microbiome were compared to theTNFΔAREmouse model and IBD patients.ResultsTNFΔAREpigs recapitulate major characteristics of human CD, including ulcerative transmural ileocolitis, increased abundance of proinflammatory cytokines, immune cell infiltration and dysbiotic microbial communities. 16S rRNA gene amplicon sequencing revealed enrichment in members belonging toMegasphaera,Campylobacter,Desulfovibrio,AlistipesandLachnoclostridumin faecal or mucosa-associated bacteria compared to wild-type littermates. Principal components analysis clustering with a subset ofTNFΔARE/+mice and human IBD patients suggests microbial similarity based on disease severity.ConclusionsWe demonstrate that theTNFΔAREpig resembles a CD-like ileocolitis pathophenotype recapitulating human disease. The ability to conduct long-term studies and test novel surgical procedures and dietary interventions in a physiologically relevant model will benefit future translational IBD research studies.