Salmon proteoglycan modulates TIMP–gelatinase regulation in intestinal epithelial cells

Chondroitin sulfate (CS) and CS proteoglycans (CSPGs) are increasingly used in nutritional and biomedical applications. Although their functional benefits have traditionally been attributed to their translocation into the bloodstream after oral administration, their poor bioavailability, due to high molecular weight and strong negative charge, has prompted substantial debate. In this study, we examined the possibility that CS and CSPG act directly on intestinal epithelial cells, thereby providing an alternative explanation for their physiological effects under non-absorptive conditions. Differentiated Caco-2 cells (human enterocyte) were employed as an in vitro model of the intestinal epithelium. Administration of CS and CSPG modulated tissue inhibitor of metalloproteinase gene expression and altered gelatinase activity in the basolateral compartment. While the two glycans shared some overlapping actions, each also exerted distinct effects reflective of their structural features. These findings suggest that CS and CSPG directly modulate epithelial signaling and reshape the basement membrane microenvironment. Overall, this study suggests a mechanism by which CS/CSPG exerts physiological actions in the intestinal tract independent of systemic absorption, providing a new perspective on the functional outcomes of oral administration.