Gastroenterology. 2025 Mar;168(3):480-495. doi: 10.1053/j.gastro.2024.08.033.Epub 2024 Sep 3.

Madhusudan Grover ¹, Tim Vanuytsel ², Lin Chang ³

Author information

¹Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

²Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KULeuven, Leuven, Belgium.

³Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, California. Electronic address: linchang@mednet.ucla.edu.

Abstract

Intestinal barrier function lies at a critical interface of a range of peripheral and central processes that influence disorders of gut-brain interactions (DGBI). Although rigorously tested, the role of barrier dysfunction in driving clinical phenotype of DGBI remains to be fully elucidated. In vitro, in vivo, and ex vivo strategies can test various aspects of the broader permeability and barrier mechanisms in the gut. Luminal mediators of host, bacterial, and dietary origin can influence the barrier function and a disrupted barrier can also influence the luminal milieu. Critical to our understanding is how barrier dysfunction is influenced by stress and other comorbidities that associate with DGBI and the crosstalk between barrier and neural, hormonal, and immune responses. Additionally, the microbiome's significant role in the communication between the brain and gut has led to the integrative model of a microbiome gut-brain axis with reciprocal interactions between brain networks and networks composed of multiple cells in the gut, including immune cells, enterochromaffin cells, gut microbiota and the derived luminal mediators. This review highlights the techniques for assessment of barrier function, appraises evidence for barrier dysfunction in DGBI including mechanistic studies in humans, as well as provides an overview of therapeutic strategies that can be used to directly or indirectly restore barrier function in DGBI patients.