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

Abstract

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.

Keywords: Disease Modeling; Genomics; Inflammatory Bowel Disease (IBD); Monogenic IBD; Precision Medicine.

Fig. 1

Genetic and immune landscape of IBD pathogenesis. Visual representation of key genes and their functional categorization in IBD. Genes are grouped based on their primary biological functions within epithelial integrity, immune regulation, and cytokine signaling. Genes associated with tight junction integrity (C1orf106, HNF4A, FERMT1, EpCAM) help maintain epithelial cohesion and prevent barrier dysfunction. ER stress-related genes (TTC7A, SLCO2A1, RNF186, ATG16L1) contribute to protein folding and cellular stress responses critical for epithelial homeostasis. Genes involved in cytosolic DNA sensing (MEFV, NLRC4 and NLRC3) activate immune responses upon detecting intracellular pathogens. Genes linked to phagocytosis and neutrophil function (CYBA, CYBB, NCF1, NCF2, NCF4, NOX1, DUOX2, SLC37A4, G6PC3) regulate ROS production and bacterial clearance. Others innate immune regulators (GUCY2C, IKBKG, TNFAIP3, TNIP1, RIPK1) play roles in NF-κB signaling and inflammatory modulation. Genes controlling T-cell and B-cell function (XIAP, FOXP3, LRBA, CARMIL2, TRIM22) are critical for immune homeostasis and tolerance. Cytokine receptors (IL-10RA, IL-10RB, IL23R, IL-12Rβ1) mediate immune signaling pathways essential for inflammation resolution and immune cell differentiation. Genes such as DKC1 and GSDMB are implicated in epithelial maintenance and tissue integrity. The depicted cells include epithelial cells, macrophages, neutrophils, APCs, T cells, and B cells, highlighting the interaction between genetic predisposition and immune dysregulation in IBD pathogenesis

Fig. 2

A The impact of tight junction aberration on gut homeostasis. In a healthy gut, tight junctions maintain intestinal barrier integrity and regulate immune responses by promoting regulatory T cell (Treg) activity and anti-inflammatory cytokines (IL-10 and TGF-β). In contrast, in the IBD gut, genetic mutations (C1orf106, HNF4A, FERMT1, TTC7A, SLCO2A1, RNF186 and ATG16L1) compromise barrier function, leading to increased permeability. This triggers immune activation, including dendritic cell stimulation and macrophage activation, as well as the recruitment of neutrophils, Th1, and Th17 cells. Consequently, pro-inflammatory cytokines (TNF, IL-6, IL-12, IL-23 and IFN-γ) are upregulated, exacerbating inflammation and contributing to disease pathology. B Pathogenic mutations in key components of the NF-κB pathway. Mutations in critical regulators of the NF-κB signaling pathway (highlighted in yellow), such as RIPK1, NEMO, TAK1, and IKB, disrupt cellular homeostasis, leading to aberrant immune responses. These mutations contribute to excessive activation of inflammatory gene expression, promoting apoptosis and necroptosis. Dysregulated NF-κB signaling plays a crucial role in driving chronic inflammation and immune dysfunction, key features of IBD

Fig. 3

Dysregulation of the immune network in monogenic IBD. Monogenic IBD is characterized by mutations in key immune regulatory genes (FOXP3, IL-10R, LRBA, XIAP, NOX1, NOX2, IL-23R), leading to immune network dysregulation. Impaired Treg function and defective IL-10 signaling contribute to uncontrolled inflammation. Dysregulated Th1, Th2 and Th17 responses, along with microbial dysbiosis, drive excessive immune activation. Increased production of pro-inflammatory cytokines (TNF, IL-6, IL-12, IL-23, IFN-γ and IL-17) exacerbates intestinal inflammation, leading to the severe phenotype observed in monogenic IBD

Fig. 4

Schematic representation of the cytosolic DNA sensor pathway. Cytosolic DNA sensing plays a crucial role in innate immune activation and inflammation. Upon detection of free nucleic acids, multiple pathways contribute to immune responses. A The cGAS-STING pathway senses cytosolic DNA, leading to type I interferon responses and NF-κB activation, promoting the production of pro-inflammatory cytokines such as IL-6 and TNF-α. B Toll-like receptors (TLR9, TLR4) recognize extracellular and endosomal nucleic acids, triggering downstream signaling cascades. C Inflammasome activation, mediated by AIM2 or NLRP inflammasomes, results in caspase-1 activation, which facilitates the maturation of pro-IL-1β and pro-IL-18 into their active forms (IL-1β and IL-18), further amplifying the inflammatory response. The pathway involves key organelles such as the ER and Golgi apparatus, emphasizing the complex regulation of nucleic acid-driven immune activation in inflammatory diseases including IBD

Fig. 5

An overview of in vitro and in vivo models in IBD research. A In vitro systems leverage patient-derived samples, transfection with mutant genes, 2D cultures, transwells, and organoid models to study epithelial barrier function, immune interactions, and drug screening. These models enable co-culture experiments to assess host–pathogen interactions, immune cell signaling, and epithelial integrity in a controlled microenvironment. B In vivo models provide a physiologically relevant context for studying intestinal inflammation and immune responses. This includes gene KO models targeting key IBD-associated genes (NOD2, DUOX2, TTC7A, etc.) and chemical induction of colitis using DSS to mimic inflammatory conditions. These models help assess the impact of genetic mutations, inflammatory triggers, and therapeutic interventions on disease progression