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Objective: The role of muscarinic acetylcholine signaling in small intestinal mucosal homeostasis is under active investigation. Using both in-vitro and in-vivo approaches, data suggest a role for cholinergic signaling in mucosal homeostasis and proliferation. We have demonstrated the presence of the muscarinic acetylcholine receptor subtype M1 (M1-mAChR) within the intestinal crypt base in the intestinal stem cell niche. We therefore hypothesized that in-vivo stimulation of this receptor using a specific M1-mAChR agonist would result in intestinal mucosal growth.
Design: With institutional approval, wild-type C57Bl/6 mice were treated with the M1-mAChR-specific agonist McN-A-343. Intestinal segments were then procured and used to make H&E-stained histologic sections. Villus height (VH), crypt depth (CD), villus width (VW) and crypt width (CW) were measured and used to calculate mucosal surface area (MSA). Student’s t-test with p<0.05 was considered significant.
Interventions: McN-A-343 was delivered via subcutaneous mini-osmotic pump for seven days. Control mice received saline-filled pumps.
Main Outcome Measures: Morphometric parameters VH, CD, VW and CW were measured and used to determine MSA per mm² serosa using a previously described mathematical model.
Results: McN-A-343 treatment resulted in significant increases in morphometric parameters and MSA. Values for wild-type vs. McN-A-343-treated mice were as follows: VH - 205±4µm vs. 248±3µm^*, CD - 46±1µm vs. 79±2µm^*, VW - 60±2µm vs. 65±2µm, CW - 33±1µm vs. 36±1µm^*, and MSA - 39±2mm² vs. 48±2mm^{2 *}. Asterisk = p<0.05.
Conclusions: Stimulation of the M1-mAChR results in intestinal epithelial growth with a corresponding increase in mucosal surface area in the murine intestine. Given the presence of the M1-mAChR in the intestinal stem cell niche, this pathway may mediate proliferative signals between enteric nerves and intestinal stem cells.