Cholinergically-mediated intestinal epithelial ion transport in the dextran sodium sulphate model of colitis in mice

Active movement of ions across the intestinal epithelium is one of the major mechanisms controlling water movement across the body surface---acetylcholine is a major regulator of this process. Acetylcholine release leads to an increase in Cl- and, thus, water secretion into the intestinal lumen. Too much Cl- secretion can lead to excess water (i.e. diarrhea). Paradoxically, in the dextran sodium sulfate (DSS) model of colitis in mice, a model characterized by diarrhea, we observe an antisecretory or proabsorptive pattern of colonic ion transport in response to the nonselective cholinergic agonist carbachol.; Using the ex vivo Ussing chamber technique, my studies have shown that this altered ion transport phenomenon is due to the activation of nicotinic, rather than muscarinic, ACh receptors. Furthermore, nitric oxide (NO) release, likely from glial cells of the myenteric plexus, is also required for this altered pattern of cholinergically-mediated ion transport, which, interestingly, could also be observed in control colonic tissue pretreated with a muscarinic receptor antagonist.; I also studied the role of M3 muscarinic receptors in normal intestinal epithelial ion transport by using mice engineered to lack this receptor. Surprisingly, intestinal tissue from these mice still exhibited robust ion transport responses to the muscarinic receptor agonist bethanechol, which was partially due to the presence of M1 muscarinic receptors. Furthermore, M3 knockout mice were more sensitive to DSS-induced colitis.; Finally, the lack of colonic epithelial ion transport responses to muscarinic receptor stimulation during DSS-induced colitis applied to other pro-secretory compounds that act via a rise in intracellular calcium concentrations. This could be due to functional inhibition of basolateral calcium-activated potassium channels that are required for intestinal epithelial calcium-activated chloride secretion.; Collectively, I hypothesize that downregulation of cholinergically-mediated colonic secretion represents a protective strategy to combat the excessive water loss associated with the DSS model of colitis.