The role of claudins in the physiology and pathology of the digestive system

Claudins (CLDNs) are small transmembrane proteins that constitute a key component of tight junctions, playing a crucial role in maintaining epithelial barrier integrity and regulating paracellular ion flux. To date, 27 members of the CLDN family have been identified in mammals. CLDNs are expressed throughout the gastrointestinal tract, with marked regional variability along different anatomical segments. Alterations in CLDN expression have been widely observed under pathological conditions such as inflammatory bowel diseases, bacterial infections, and various malignancies. Typically - though not invariably - pathological states are associated with a reduced expression of barrier-forming CLDNs, which restrict paracellular flux of solutes and ions, and increased expression of channel-forming CLDNs that selectively permit the passage of specific ions while still limiting the permeability of larger molecules and oppositely charged ions, leading to compromised epithelial integrity and enhanced paracellular permeability. Beyond structural role of CLDNs, they have been implicated in signal transduction, regulation of cell polarity, and proliferation, which makes them important players in tumorigenesis and metastasis. Consequently, CLDNs are under extensive investigation as potential diagnostic and prognostic biomarkers, as well as therapeutic targets in gastrointestinal cancers. Notably, clinical trials are currently underway evaluating therapeutic agents targeting for instance CLDN18.2 for the treatment of gastric and gastroesophageal cancers. The aim of this work is to summarize the current knowledge about CLDNs, their presence under physiological conditions, and their role in gastrointestinal diseases.