Fig. 3.

States of malabsorption and diarrhea in the small intestine. A: under normal conditions, transcellular Na⁺ absorption occurs primarily via NHE3 and water is absorbed paracellularly. B: SGLT1 serves as a nutrient sensor and triggers rearrangement of the tight junction to increase paracellular fluid and nutrient absorption. C: SGLT1 also increases NHE3 activity that mediates greater Na⁺ absorption and further increases the osmotic gradient for water absorption across the tight junction. D: pathologic barrier dysfunction, i.e., paracellular permeability increases, can enhance fluid absorption when the transepithelial osmotic gradient is maintained. This occurs experimentally when mice are treated with LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry mediator on T cells) (17). E: inhibition of Na⁺ malabsorption leads to a diminished osmotic gradient and less water absorption, ultimately causing mild diarrhea. This occurs experimentally in NHE3 knockout mice (74). F: in cases where there is both a barrier defect and reduced Na⁺ malabsorption, as in mice treated with TNF (16, 17), luminal Na⁺ is retained and the osmotic gradient favors movement of fluid from the tissue into the lumen. The barrier dysfunction allows greater fluid efflux than would occur with Na⁺ malabsorption alone.