Barrier restoration as a therapeutic strategy for disorders of gut-brain interaction

Disorders of gut-brain interaction, such as irritable bowel syndrome and functional dyspepsia, are increasingly linked to defects in gut barrier function. Mucosal disruption, encompassing alterations in the epithelial and mucus layers, leads to enhanced intestinal permeability, microbial translocation, and aberrant immune and neuronal signalling, potentially contributing to symptom severity. Despite growing recognition of barrier dysfunction in disorders of gut-brain interaction, clinical interventions remain largely symptom-based, with few therapies designed to directly restore epithelial integrity. In this Review, we examine the cellular and molecular pathways underpinning gut barrier function and highlight evidence supporting the role of diet, microbiome-targeted interventions, stress modulation, and pharmacological agents in maintaining or restoring intestinal permeability. Mechanistic insights reveal that short-chain fatty acids, amino acids (glutamine and tryptophan), and targeted probiotics can enhance tight junction integrity and mucin secretion, whereas psychological stress, low-fibre diets, and high-fat diets disrupt these pathways. We also discuss novel therapeutics, including antihistamines, mast cell stabilisers, protease inhibitors, secretagogues, and guanylate cyclase C agonists, and emerging technologies, such as vagal nerve stimulation and barrier-protective hydrogel delivery systems. Although promising, these strategies require validation in well designed clinical trials with targeted endpoints, and patient stratification based on microbial and immune phenotypes. By integrating advances in molecular biology with translational therapeutics, interventions targeting intestinal permeability could shift the treatment paradigm for disorders of gut-brain interaction from general symptom management to personalised disease modification.