Inborn errors of immunity (IEI) are systemic disorders that can affect multiple organs, with gastrointestinal manifestations often representing the initial presentation and serving as a critical clue for early diagnosis. In this lecture, I will provide an overview of the relationship between IEI and gastrointestinal diseases, with a particular focus on very early-onset inflammatory bowel disease (VEO-IBD) and monogenic IBD.
VEO-IBD is defined as IBD with onset before 6 years of age, and its incidence has been increasing worldwide, including in both Western and Asian populations. Among these patients, especially those with infantile onset, a substantial proportion is attributed to monogenic IBD caused by single-gene defects involving approximately 75–80 genes. These conditions often exhibit distinct clinical phenotypes and treatment responses compared to conventional ulcerative colitis and Crohn’s disease. Clinically, they are characterized by severe enterocolitis, refractory perianal disease, early onset, recurrent infections, and autoimmune manifestations, all of which should prompt strong suspicion of an underlying genetic disorder.
In this lecture, I will present representative cases of monogenic IBD with severe enterocolitis, including endoscopic findings, inflammatory features, and clinical courses achieving remission following hematopoietic stem cell transplantation (HSCT), accompanied by illustrative images. I will also discuss the clinical aspects of intestinal inflammation in IEI.
Furthermore, I will outline current diagnostic strategies, ranging from targeted gene panels for IEI and monogenic IBD to comprehensive approaches such as whole-exome sequencing (WES) and whole-genome sequencing (WGS), highlighting practical considerations in clinical settings. Finally, I will introduce recent advances in research, including multi-omics approaches such as epigenetic analysis, microbiome profiling, and single-cell and spatial transcriptomics. Drawing on my research experience in Germany, I will discuss future perspectives for elucidating the molecular pathogenesis of monogenic IBD.
