Large quantities of water are secreted into the lumen of the small intestine during the digestive process. Almost all of this water is also reabsorbed in the small intestine. Regardless of whether it is being secreted or absorbed, water flows across the mucosa in response to osmotic gradients. In the case of secretion, two distinct processes establish an osmotic gradient that pulls water into the lumen of the intestine:
1. Increases in luminal osmotic pressure resulting from influx and digestion of foodstuffs: The chyme that floods into the intestine from the stomach typically is not terribly hyperosmotic, but as its macromolecular components are digested, osmolarlity of that solution increases dramatically.
Starch, for example, is a huge molecule that contributes only a small amount to osmotic pressure, but as it is digested, thousands of molecules of maltose are generated, each of which is as osmotically active as the original starch molecule.
Thus, as digestion proceeds lumenal osmolarity increases dramatically and water is pulled into the lumen. Then, as the osmotically active molecules (maltose, glucose, amino acids) are absorbed, osmolarity of the intestinal contents decreases and water can be absorbed.
2. Crypt cells actively secrete electrolytes, leading to water secretion: The apical or lumenal membrane of crypt epithelial cells contain a ion channel of immense medical significance - a cyclic AMP-dependent chloride channel known also as the cystic fibrosis transmembrane conductance regulator or CFTR. Mutations in the gene for this ion channel result in the disease cystic fibrosis. This channel is responsible for secretion of water by the following steps:
- Chloride ions enter the crypt epithelial cell by cotransport with sodium and potassium; sodium is pumped back out via sodium pumps, and potassium is exported via a number of channels.
- Activation of adenylyl cyclase by a number of so-called secretagogues leads to generation of cyclic AMP.
- Elevated intracellular concentrations of cAMP in crypt cells activate the CFTR, resulting in secretion of chloride ions into the lumen.
- Accumulation of negatively-charged chloride anions in the crypt creates an electric potential that attracts sodium, pulling it into the lumen, apparently across tight junctions - the net result is secretion of NaCl.
- Secretion of NaCl into the crypt creates an osmotic gradient across the tight junction and water is drawn into the lumen.
Abnormal activation of the cAMP-dependent chloride channel (CFTR) in crypt cells has resulted in the deaths of millions upon millions of people. Several types of bacteria produce toxins that strongly, often permanently, activate the adenylate cyclase in crypt enterocytes. This leads to elevated levels of cAMP, causing the chloride channels to essentially become stuck in the "open" position". The result is massive secretion of water that is manifest as severe diarrhea. Cholera toxin, produced by cholera bacteria, is the best known example of this phenomenon, but several other bacteria produce toxins that act similarly.