Monogenic forms of inflammatory bowel disease: Genetic mechanisms, models, and clinical implications

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic disease that lead to impaired quality of life, affecting individuals across diverse age groups and ethnic backgrounds. Despites extensive research, the etiology and the underlying mechanisms of IBD remain unclear. However, genetic, epigenetic, immune, and environmental factors are recognized as critical contributors to the onset, progression, and persistence of the disease. MAIN BODY: Over the last decades, genome-wide association studies (GWAS) and high-throughput sequencing have identified numerous common risk loci and rare pathogenic variants associated with IBD, while emerging multi-omics approaches are expected to refine how these genetic factors affect specific cell types and pathways involved in IBD pathogenesis. In-depth studies using distinct in vitro and in vivo models have further elucidated the impact of these variants on intestinal inflammation, enhancing our understanding of the genetic basis of certain forms of IBD. Although, the interaction of these variants with environmental triggers is yet to be investigated. These models have also opened new avenues for the development of diagnostic and therapeutic strategies. CONCLUSION: This review focuses on the genetic bases of IBD, with a particular emphasis on its monogenic forms, and highlights the role of in vitro and in vivo models in unraveling IBD pathogenesis and advancing treatment modalities.