From Rodents to Chips: Preclinical Models of Inflammatory Bowel Disease with Emphasis on Host-Microbiome Interactions

Inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, is a chronic relapsing inflammatory disorder with steadily increasing global prevalence, significantly impairing patient quality of life. Preclinical research in IBD has traditionally relied on animal models to investigate disease etiology, immunopathogenesis, and therapeutic responses. A wide range of experimental models primarily rodents, along with limited use of larger animals such as pigs and non-human primates-have been developed to reproduce key clinical, histological, and immunological features of human IBD. These models have played a crucial role in evaluating pharmacological agents, biologics, probiotics, dietary interventions, gene-based therapies, and microbiome-targeted strategies. Notably, accumulating evidence highlights the pivotal role of gut microbiota dysbiosis in disease initiation, progression, and therapeutic responsiveness, making host-microbiome interactions a central component of contemporary IBD research. However, despite their utility, animal models exhibit important limitations related to interspecies differences, incomplete microbiome representation, and poor translational predictability. In response, increasing regulatory pressure from agencies such as the NIH and FDA to reduce animal experimentation has accelerated the development of human-relevant, non-animal platforms, including intestinal organoids, 3D in vitro co-culture systems, and gut-on-chip technologies. This review critically evaluates existing in vivo IBD models with particular emphasis on their ability to capture immune-microbiome epithelial interactions, while also discussing emerging human-derived systems as complementary translational tools. Collectively, the integration of microbiome-responsive and immune-competent advanced in vitro models represents a promising direction to bridge the gap between experimental findings and clinical application in IBD research.