# Rethinking Celiac Disease Management: Treatment Approaches Beyond the Gluten-Free Diet

## TL;DR

This paper reviews new treatment strategies for celiac disease beyond the gluten-free diet, aiming to address persistent symptoms and improve patient outcomes.

## Contribution

The paper synthesizes emerging therapies and technologies for celiac disease, highlighting novel approaches targeting immune pathways and intestinal function.

## Key findings

- Up to 30–40% of celiac patients experience ongoing symptoms despite gluten-free diet compliance.
- Novel therapies target pathways like IL-15 signaling and aim to modulate immune responses and intestinal barrier function.
- Technologies like organoids and machine learning are being used to advance precision medicine for celiac disease.

## Abstract

Celiac disease (CeD) is a chronic, immune-mediated enteropathy triggered by dietary gluten in genetically susceptible individuals, with environmental and epigenetic factors also contributing to its pathogenesis. Once considered a rare pediatric malabsorptive disorder, CeD is now recognized as a systemic condition that can manifest with both gastrointestinal and extraintestinal symptoms across the lifespan. Although strict adherence to a gluten-free diet (GFD) remains the cornerstone of treatment, up to 30–40% of patients experience persistent symptoms and/or ongoing mucosal injury despite reported compliance. This therapeutic gap, combined with advances in molecular understanding of disease mechanisms, has driven the development of novel strategies targeting key pathogenic pathways. Intraluminal interventions include gluten-degrading enzymes and gluten-sequestering agents, while other approaches target tissue transglutaminase 2, induce antigen-specific immune tolerance, or modulate cytokine-driven inflammation, with particular emphasis on interleukin-15 (IL-15) signaling. Additional strategies aim to inhibit lymphocyte trafficking to the intestinal mucosa and enhance intestinal barrier function through zonulin modulation. Adjunctive therapies under investigation include nutraceuticals, microbiota-targeted interventions, and vaccine-based approaches. More recently, advanced experimental and computational platforms, such as human intestinal organoids, organ-on-chip systems, and machine learning–driven analytics, are being leveraged in efforts to accelerate translational research and support the rational design of precision medicine approaches. This narrative review synthesizes current evidence for therapies beyond the GFD, examines challenges in clinical implementation, and discusses how technological innovations may reshape the future therapeutic landscape of CeD.