Inflammatory bowel diseases 2026: Form, Function and Therapeutic Considerations for the Epithelial Barrier

Abstract

Inflammatory bowel disease (IBD) has long been conceptualized as a disorder of dysregulated immunity, yet growing evidence highlights the intestinal epithelium as an active determinant of disease behavior and therapeutic response. This editorial synthesizes contributions in the current issue that collectively redefine IBD through a tissue-centric lens, emphasizing barrier integrity, epithelial lineage specialization, antigen sampling, innate immune amplification, and environmental modulation. While epithelial-targeted and gut-directed therapies are biologically compelling, their successful translation into clinical practice presents significant challenges related to disease selection, trial design, endpoint sensitivity, and expected effect size. Emerging approaches—including combination strategies, maintenance therapy, and enriched populations—offer pragmatic paths forward. Importantly, advances in non-invasive, localized monitoring and functional biomarkers may be as critical as the therapies themselves, enabling detection of incremental tissue-level responses that traditional endpoints often miss. Together, these themes underscore the need for context-aware therapeutic strategies and dynamic disease assessment to advance epithelial-focused innovation in IBD.

Context matters: redefining inflammatory bowel disease through epithelial biology, immune modulation, and dynamic monitoring

Inflammatory bowel disease (IBD) has traditionally been framed as a disorder of dysregulated immunity. This paradigm has produced highly effective therapies, yet important gaps remain. Many patients fail to achieve durable remission, mucosal healing does not consistently translate into long-term disease control, and substantial heterogeneity persists in therapeutic response. These limitations increasingly suggest that immune suppression alone is insufficient to fully explain—or treat—IBD.

The themes highlighted in this issue were shaped in part by scientific discussions emerging from a recent FASEB Science Research Conference on gastrointestinal epithelial plasticity and pathways to disease, which emphasized epithelial barrier function, immune–epithelial interactions, regeneration, and translational approaches to IBD. Consistent with recent Crohn’s & Colitis Foundation–led priorities to advance human-relevant mechanisms and translational endpoints in IBD, several of the reviews assembled here focus on epithelial pathways and quantitative measures of gut function, including emerging approaches to directly assess intestinal permeability in patients.^{1, 2} Together, these contributions argue for a tissue-centric framework in which context determines outcome.

The epithelium as an active immune interface

Turner provides a critical reassessment of intestinal barrier dysfunction, moving beyond the nonspecific notion of a “leaky gut” to define discrete permeability pathways—pore, leak, and unrestricted—each with distinct mechanistic and inflammatory consequences.³ This framework clarifies why barrier failure is not monolithic and why restoring epithelial integrity requires pathway-specific strategies rather than global reinforcement. Importantly, it reframes the barrier not as a passive casualty of inflammation, but as an active determinant of inflammatory tone.

Lau extends this concept by emphasizing epithelial lineage specialization as a core regulator of mucosal immunity.⁴ Goblet, Paneth, and tuft cells are shown to actively coordinate microbial containment, immune signaling, and tissue repair. Rather than epithelial loss alone, altered differentiation and plasticity often define disease persistence or resolution. Together, these reviews reposition the epithelium as a dynamic immune organ whose structural and functional states shape disease biology.

Regulated antigen sampling and immune education

Newberry further expands epithelial function through goblet cell–associated antigen passages (GAPs), illustrating a mechanism by which the epithelium directly educates the immune system.⁵ GAPs are tightly regulated antigen delivery portals whose activity varies across homeostasis, early life, infection, and dysbiosis. When appropriately controlled, GAPs promote immune tolerance; when dysregulated, the same pathway permits inappropriate inflammation or microbial translocation. Immune outcomes in the gut, therefore, are determined not simply by antigen exposure, but by how and when antigens are sampled by epithelial cells.

Taken together, Turner, Lau, and Newberry describe an integrated epithelial framework in which permeability, lineage specialization, and antigen handling converge to govern mucosal immune balance.

Context-dependent innate immune amplification

Kulkarni details new insight on the complement system — historically viewed as a nonspecific inflammatory amplifier — and redefines it as a context-dependent regulator of mucosal defense and injury.⁶ Advances in genetics, transcriptomics, and functional studies demonstrate that complement components are synthesized locally within the intestinal mucosa and can exert either protective or pathogenic effects depending on timing, localization, and degree of activation. Genetic variants affecting complement function further underscore this dichotomy, linking impaired complement activity to severe disease phenotypes even as excessive activation exacerbates inflammation.

These findings challenge reductionist strategies aimed at global complement inhibition and instead support selective, spatially restricted modulation that preserves host defense while limiting inflammatory amplification.

Environmental modulation of epithelial–immune balance

Montrose examines dietary protein as a biologically active modulator of intestinal inflammation and repair.⁷ Protein quantity, source, and amino acid composition shape microbial metabolism, epithelial stress responses, and immune activation. Importantly, these effects are phase-dependent: adequate protein intake supports epithelial repair, whereas excess—particularly from animal sources—can worsen inflammation. These observations reinforce a recurring principle across this issue: interventions divorced from disease context risk unintended consequences (Figure 1).

Figure 1: Context-dependent epithelial-immune interactions in inflammatory bowel disease.

IBD arises from context-dependent interactions at the epithelial-immune interface, where barrier integrity, epithelial specialization, antigen handling, innate immune amplification, and environmental inputs converge. Effective therapy requires targeting this local context rather than global immune suppression. Image generated in Gemini AI.

Translating epithelial biology into gut-directed therapy

The therapeutic implications of this tissue-centric biology are articulated through the framework of gut-directed therapeutics. In the 2025 issue, Kratschmer and colleagues outlined how tissue-restricted monoclonal antibodies, small molecules, microbiome-based therapies, and engineered delivery systems can concentrate activity at the epithelial–immune interface while minimizing systemic toxicity.⁸ This strategy aligns naturally with emerging insights into epithelial specialization, antigen handling, innate immune modulation, and environmental inputs.

Despite strong mechanistic rationale, demonstrating clinical efficacy for epithelial-targeted therapies poses real—but increasingly navigable—challenges. Trial design is shaped by the disease context in which these agents may provide the greatest benefit. In mild-to-moderate disease, epithelial-directed approaches may be biologically well suited, yet the clinical imperative is less compelling given the established safety and effectiveness of existing integrin- and IL-23–targeted therapies. Conversely, in severe disease, ongoing inflammation may overwhelm epithelial repair mechanisms, limiting the apparent efficacy of barrier-focused interventions when used in isolation. These realities have shifted attention toward more pragmatic strategies, including use as add-on therapy in patients with incomplete response to anti-cytokine, anti-integrin, or small-molecule inflammatory pathway inhibitors, as well as potential roles in maintenance of remission. In all settings, anticipated effect sizes are likely to be modest, reinforcing the importance of careful patient selection and appropriately powered studies.

Disease selection and response assessment further complicate trial design but also present opportunities for innovation. Crohn’s disease carries a higher unmet need yet remains heterogeneous and difficult to monitor, whereas ulcerative colitis offers clearer endpoints and more accessible tissue-based assessments despite a higher bar for clinical relevance. Special populations, such as pouchitis or Crohn’s disease of the pouch, may represent biologically enriched but logistically challenging populations for early testing. While fecal calprotectin, endoscopy, and histology will remain central outcome measures, epithelial-targeted therapies highlight the need for more sensitive and functionally relevant biomarkers of epithelial health. Emerging stool-based transcriptomic assays, markers of tight-junction integrity, and functional measures such as intestinal permeability or bacterial translocation offer promising complements to traditional endpoints.⁹ As these tools mature, they will be critical not only for evaluating epithelial-focused therapies, but also for mitigating potential risks—such as dysregulated proliferation or microbial imbalance—through earlier detection and longitudinal monitoring. These are conceptually mapped out in Figure 2 and explicitly described in Table 1.

Figure 2: Challenges and opportunities in testing epithelial targeted therapies in IBD.

Image generated in Gemini AI.

Table 1:

Key challenges and opportunities in testing epithelial-targeted therapies in IBD

Domain	Challenge	Implication for trials	Opportunities / strategies
Disease severity	Mild disease has limited urgency; severe inflammation overwhelms repair	Difficult to demonstrate benefit at extremes	Focus on enriched populations; add-on or maintenance settings
Therapeutic positioning	Modest expected effect sizes	Underpowered or inconclusive trials	Combination therapy with anti-cytokine, anti-integrin, or small-molecule agents
Disease selection	Crohn’s disease has high unmet need but is heterogeneous; UC easier to monitor	Trade-off between need and assessability	Disease- and phase-specific trial design
Special populations	Pouchitis and Crohn’s disease of the pouch are biologically relevant	Logistically complex	Early proof-of-concept studies
Traditional endpoints	Calprotectin, endoscopy, histology are blunt tools for epithelial repair	Signal dilution	Supplement with epithelial-specific and functional measures
Monitoring resolution	Local barrier healing may be missed	Underestimation of efficacy	Ultrasound, permeability assays, stool-based transcriptomics
Safety considerations	Dysregulated proliferation or microbial imbalance	Long-term risk concerns	Longitudinal, non-invasive monitoring

Against this backdrop, early human data provide encouraging evidence that epithelial-targeted therapies can translate into measurable clinical benefit when aligned with appropriate disease context and trial design. Emerging epithelial-targeted metabolic therapies further reinforce this paradigm. Recent first-in-human data demonstrate that tauroursodeoxycholic acid (TUDCA), a bile acid functioning as a chemical chaperone, reduces epithelial endoplasmic reticulum stress, promotes mucosal restitution, and significantly improves clinical, endoscopic, and histologic disease activity in ulcerative colitis.¹⁰ These findings provide direct human evidence that modulating epithelial stress responses can translate into meaningful disease control, supporting therapeutic approaches that act locally on epithelial biology rather than systemically suppressing immune pathways.

Importantly, advances in non-invasive, real-time monitoring—such as intestinal ultrasound—may be as critical as the therapies themselves, enabling epithelial-targeted trials by detecting localized, incremental tissue-level responses that are easily missed by conventional endpoints.

Measuring disease where it happens

Mechanistic precision must be matched by equally precise tools for disease assessment. Gergely reviews intestinal ultrasound as a noninvasive, real-time modality capable of capturing transmural inflammation and healing.¹¹ Unlike symptom-based indices, static biomarkers, or endoscopy alone, ultrasound provides dynamic, localized assessment that more closely reflects underlying tissue biology. As gut-directed and epithelial-focused therapies advance, such monitoring tools will be essential for aligning treatment decisions with mucosal and transmural disease activity and for defining meaningful translational endpoints.

Toward an integrated, context-aware model of IBD

Viewed collectively, the reviews in this issue converge on a coherent model of IBD pathogenesis and management. Barrier function, epithelial lineage state, antigen sampling, innate immune amplification, dietary inputs, therapeutic targeting, and disease monitoring do not operate in isolation. Instead, they intersect at the epithelial–immune interface to determine whether inflammation escalates, resolves, or becomes chronic.

This integrated framework carries clear clinical implications. It supports therapeutic strategies that modulate (rather than abolish) innate immune pathways, nutritional interventions tailored to disease phase, and the thoughtful deployment of epithelial-focused therapies within an appropriate inflammatory context. More fundamentally, it challenges one-size-fits-all approaches to IBD and reinforces the need for precision strategies grounded in epithelial and mucosal biology.

As the field moves forward, durable success in IBD will depend not only on restoring balance at the epithelial–immune interface, but also on measuring that balance accurately and dynamically over time. The contributions in this issue collectively illuminate that path.