Introduction
Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), represents a global health challenge characterized by chronic intestinal inflammation arising from complex interactions among genetic susceptibility, environmental triggers, immune dysregulation, and microbial dysbiosis44. Over 200 genetic loci have been associated with IBD susceptibility, affecting pathways including pattern recognition, autophagy, cytokine signaling, and barrier function44. Despite substantial therapeutic advances, significant proportions of patients experience treatment-refractory disease requiring surgery30, underscoring the urgent need to translate mechanistic insights into precision medicine approaches. This review synthesizes key pathogenesis advances from 2021–2026 and critically examines current treatment challenges and forward-looking directions.
Recent Advances in IBD Pathogenesis
Multi-Omics Integration and Molecular Endotyping
A paradigm shift toward systems-level understanding of disease heterogeneity has emerged through multi-omics integration. A landmark 2025 study identified a four-gene signature (CDC14A, PDK2, CHAD, UGT2A3) achieving diagnostic AUC 0.86–0.97 across multiple algorithms, with an integrated nomogram reaching AUC 0.9521. Single-cell RNA sequencing revealed cell-type-specific expression patterns: PDK2 showed widespread distribution across epithelial cycling cells and stem cells, while UGT2A3 demonstrated epithelial-restricted localization1. Critically, consensus clustering stratified patients into two distinct molecular subtypes with divergent immune landscapes: Cluster 1 exhibited elevated M1 macrophages, activated dendritic cells, and enhanced glycolysis signaling, while Cluster 2 showed higher signature gene expression, enhanced oxidative phosphorylation, and enrichment in regulatory immune populations including Tregs and M2 macrophages1.
The largest inter-patient differences in IBD occur within the myeloid compartment of the colonic mucosa, particularly among macrophages and neutrophils43. Integrated single-cell RNA sequencing and CosMx Spatial Molecular Imaging revealed that macrophage states define patient-specific endotypes: inflammation-associated macrophages include M1-like states (M1 ACOD1, M1 CXCL5) and IDA macrophages expressing EGFR ligands including neuregulin 1 (NRG1), with proportions varying markedly across CD and UC patients43. Spatial co-localization analyses demonstrated that IDA macrophages populate specific tissue neighborhoods and granulomas, while inflammatory fibroblasts produce GM-CSF and prostaglandin-associated signaling that sustains macrophage activation43.
Disease-Specific Immune Dysregulation
Recent mechanistic studies reveal UC and CD as distinct immunologic entities. UC-derived monocytes exhibit impaired IFN-γ-dependent STAT3 activation compared with controls and CD monocytes, resulting in STAT1/STAT3 imbalance that coincides with decreased IL-10 and CD39 levels, diminished Treg induction, and increased IL-12/IL-23 secretion3. This finding provides mechanistic rationale for the selective approval of tofacitinib (a JAK/STAT inhibitor) in UC but not CD3. Conversely, comparative transcriptomic analyses indicate that type 2 immune responses are induced across both CD and UC and widely used mouse models of IBD, suggesting that type 2 signatures represent a common inflammatory state rather than disease-specific pathomechanism8.
IL-22 has emerged as a critical mediator of epithelial regeneration and mucosal healing. Human intestinal organoid studies demonstrated that IL-22 promotes epithelial stem cell expansion, anti-microbial peptide production, and membrane mucus production, with similar effects in healthy and IBD samples5. However, IL-22-associated epithelial phenotypes differ substantially when treatments are performed in the presence of butyrate or immune cell co-cultures, indicating context-dependent effects5. IL-27, another emerging cytokine, restores permeability regulation following inflammatory insult through differential tight junction modulator expression and induces epithelial barrier wound healing13.
Microbiome-Metabolome Axis and Environmental Factors
The microbiome-metabolome axis has been comprehensively mapped as a central driver of IBD pathogenesis. IBD patients exhibit dysregulation of three major metabolite classes: short-chain fatty acids (SCFAs), amino acids/derivatives, and bile acids39. Reduced fecal SCFA concentrations, particularly butyrate, associate with reduced abundances of SCFA-producing bacteria and impair intestinal barrier maintenance through histone deacetylase inhibition, tight junction protein expression, and Treg differentiation39. Dysbiosis-associated reductions in bile salt hydrolase-producing bacteria impair secondary bile acid production, disrupting signaling through farnesoid X receptor and TGR5 that modulates barrier function and immune tolerance39.
Early-life environmental exposures critically shape IBD risk through permanent microbiota alterations. Systematic review and meta-analysis of 114 studies identified prenatal antibiotic exposure as significantly associated with IBD development (OR 1.75; 95% CI 1.22–2.51), with risk particularly elevated following third-trimester exposure (aHR 2.57; 95% CI 1.10–6.01)34. Maternal smoking during pregnancy increased IBD odds by 49% (pOR 1.49; 95% CI 1.17–1.90)34. Conversely, breastfeeding demonstrated protective effects, with greater protection observed with duration exceeding 12 months34. A population-based inception cohort study (n=1,229 adults) demonstrated that baseline microbiome profiles outperformed biochemical markers in predicting severe disease course in UC (AUC 0.72 vs 0.65, P<0.0001), suggesting prognostic utility independent of initial clinical severity35.
Organoid-Based Systems Biology Platforms
Human intestinal organoids derived from adult stem cells or induced pluripotent stem cells have emerged as robust platforms for mechanistic studies and precision medicine applications. IBD organoids maintain disease-specific characteristics including altered gene expression profiles, though the acute transcriptional inflammatory phenotype is lost during culture but can be re-induced after inflammatory stimulation2. Organoid-based systems enable patient-specific investigation of host-microbiota interactions through advanced microfluidic organ-on-chip platforms integrating epithelial, endothelial, and immune cells with structured polymeric scaffolds mimicking crypt-villi architecture244.
Clinical Insights: Therapeutic Landscape and Response Prediction
Comparative Therapeutic Efficacy and Persistence
Recent evidence demonstrates that modern IBD therapies achieve comparable efficacy across drug classes but with important disease-specific distinctions. Meta-analysis of five head-to-head RCTs (n=2,506) comparing IL-23p19 antagonists with ustekinumab in moderate-to-severe CD revealed superior clinical remission (RR 1.31, 95% CI 1.16–1.48) and endoscopic remission (RR 1.61, 95% CI 1.27–2.05) specifically in patients with prior TNF antagonist exposure, but no significant difference in biologic-naive patients19. The VARSITY trial demonstrated that vedolizumab induced significantly greater histologic remission than adalimumab in UC at week 52 (Geboes: 29.2% vs. 8.3%; RHI: 37.6% vs. 19.9%), with benefits observed in both anti-TNF-naive and anti-TNF-failure subgroups26.
Treatment persistence analysis of 2,499 Australian IBD patients revealed disease-specific patterns: in CD, ustekinumab demonstrated superior persistence compared to anti-TNF agents (HR 1.79, 95% CI 1.32–2.38), with 12-month persistence rates of 80.0% versus 64.2–68.1%28. In UC, vedolizumab showed superior persistence versus anti-TNF agents (HR 1.67, 95% CI 1.27–2.18), with 12-month persistence of 73.4% versus 45.5–61.1%28. Importantly, first-line therapy demonstrated superior persistence compared to non-first-line therapy across all drug classes28.
Precision Medicine Approaches
Nomogram-based risk stratification effectively predicted biologic treatment responses: low-risk patients demonstrated superior response rates to golimumab (63.3%), infliximab (54.8%), and vedolizumab (29% vs. 15% in high-risk group)1. Connectivity Map analysis identified MS.275 (HDAC inhibitor) as a top therapeutic enhancer; experimental validation in DSS-induced colitis confirmed synergistic anti-inflammatory effects with TNF-α inhibitors1. Real-world studies demonstrate that risankizumab achieves comparable effectiveness in both ustekinumab-naive and ustekinumab-experienced CD patients, with clinical remission rates of 69%, 64%, and 54% at weeks 12, 26, and 52, respectively33.
Critical Analysis: Treatment Challenges
Heterogeneity and Variable Response
Despite therapeutic advances, significant challenges persist. The most critical barrier is inter-patient heterogeneity at molecular and cellular levels. Macrophage and neutrophil transcriptional states vary substantially across patients, with spatial organization patterns differing between CD and UC4345. Imaging mass cytometry of intestinal sections revealed that regulatory T cell spatial interactions with macrophages, CD4+ T cells, and plasma cells differ between disease subtypes: activated lysozyme C+ macrophages were preferred Treg neighbors in CD but not UC45. This spatial heterogeneity provides mechanistic basis for understanding why CD and UC respond differently to immune-targeted therapies.
Loss of response represents a major clinical challenge. Prospective monitoring of 103 IBD patients in clinical remission on infliximab maintenance therapy demonstrated pharmacokinetic relapse (two consecutive trough levels <3 μg/mL) in 18.5% of patients, with higher rates in those with baseline levels 3–5 μg/mL (26.7%) versus ≥5 μg/mL (7.0%)15. Annual therapeutic drug monitoring may maintain therapeutic levels ≥3 μg/mL in 85% of maintenance patients15.
Safety and Complication Risks
Safety concerns remain paramount. Real-world comparative studies demonstrate that infliximab causes significantly more adverse events than adalimumab (16.6% vs. 6.2%, P<0.001)22. Vedolizumab-treated patients exhibited higher gut infection rates (3.0% overall, significantly elevated versus other biologics, P=0.0001), attributed to its gut-selective mechanism of action32. Dual biologic therapy in refractory pediatric IBD achieved 75% steroid-free remission at 6 months but was complicated by one case of septic arthritis and deep vein thrombosis in a patient on vedolizumab/tofacitinib with concurrent prednisone, highlighting thrombotic and infectious risks18.
Pregnancy considerations require careful therapeutic selection. Most anti-TNF agents (except certolizumab), vedolizumab, ustekinumab, and tofacitinib actively cross the placenta, potentially affecting fetal development20. Certolizumab undergoes only passive placental transfer, resulting in markedly lower cord blood levels and likely representing the safest biologic for infants20. Maternal IBD-associated antibodies (anti-CBir1, ANCA, anti-OmpC, ASCA) cross the placental barrier and correlate with neonatal fecal calprotectin and reduced microbiota diversity, suggesting potential intergenerational effects on intestinal inflammation and microbiota colonization11.
Refractory Disease and Complications
CD complications including fistulas and strictures represent treatment-refractory phenotypes with distinct immune landscapes. Spatial single-cell profiling demonstrated significant increases in neutrophils, effector cytotoxic T cells, and inflammatory macrophages in CD fistula samples, with decreased regulatory T cells53. Neutrophils in CD fistulas expressed significantly more matrix metalloproteinase 9 (MMP9), correlating with extracellular matrix remodeling53. These findings identify MMP9+ neutrophils and their spatial interaction with effector T cells as potential therapeutic targets for CD complications.
Forward-Looking Directions
AI-Driven Precision Medicine
Artificial intelligence is emerging as a transformative tool enabling standardized disease assessment and outcome prediction. Graph neural networks such as SORBET directly analyze complete spatial profiling data without requiring pre-defined cell type annotations, demonstrating superior accuracy in clinical endpoint prediction over leading spatial and non-spatial methods55. The future paradigm of IBD care lies in AI-enabled "endo-histo-omics" integrative approaches harmoniously fusing endoscopic, histologic, and molecular data54. However, practical challenges in implementing precision medicine approaches remain, including prediction of individual treatment responses with machine learning58.
Microbiome Engineering and Metabolite Restoration
Metabolome-based adjunctive treatments targeting restoration of SCFA, bile acid, and tryptophan metabolite production represent promising therapeutic avenues39. Fecal microbiota transplantation with extended regimens demonstrates endoscopic and clinical signals, with enhanced efficacy in UC44. Probiotic strains such as Lactobacillus paracasei R3 ameliorate colitis via Th17/Treg balance regulation9, while targeted microbial interventions can modulate tryptophan and bile acid metabolism pathways implicated in IBD pathogenesis37.
Novel Therapeutic Targets
Emerging mechanistic insights identify multiple therapeutic concepts: macrophage–fibroblast crosstalk through GM-CSF and prostaglandin signaling43, NRG1-ERBB signaling modulation affecting epithelial repair43, and CXCL8/CXCR1 axis inhibition in UC organoid models44. However, high inter-patient variability in myeloid and stromal compartments implies single targets may benefit only patient subsets, necessitating precision stratification43.
Conclusion
The past five years have witnessed a paradigm shift from disease-level categorization toward patient-level molecular endotyping through integrated single-cell, spatial, and multi-omics technologies. Myeloid-centric pathogenesis emerges as a central driver of heterogeneity, with disease-specific immune circuit dysregulation (STAT1/STAT3 imbalance in UC) and microbiome-metabolome disruptions providing mechanistic rationale for therapeutic stratification. Treatment persistence favors ustekinumab in CD and vedolizumab in UC over anti-TNF agents, while IL-23p19 antagonists outperform ustekinumab specifically in biologic-experienced CD patients. Major forward-looking challenges include translating molecular endotypes into robust clinical biomarkers in larger cohorts, integrating immune-stromal-microbial-neural components into physiologically faithful models, overcoming practical barriers to AI adoption in clinical workflows, and standardizing protocols to enable precision medicine at scale. The convergence of organoid platforms, spatial profiling, and AI-driven analysis promises to advance personalized interventions, though significant translational gaps remain between methodological advances and routine clinical implementation.