Intestinal epithelial stem/progenitor cells are controlled by mucosal afferent nerves.

BACKGROUND: The maintenance of the intestinal epithelium is of great importance for the survival of the organism. A possible nervous control of epithelial cell renewal was studied in rats and mice. METHODS: Mucosal afferent nerves were stimulated by exposing the intestinal mucosa to capsaicin (1.6 mM), which stimulates intestinal external axons. Epithelial cell renewal was investigated in the jejunum by measuring intestinal thymidine kinase (TK) activity, intestinal (3)H-thymidine incorporation into DNA, and the number of crypt cells labeled with BrdU. The influence of the external gut innervation was minimized by severing the periarterial nerves. PRINCIPAL FINDINGS: Luminal capsaicin increased all the studied variables, an effect nervously mediated to judge from inhibitory effects on TK activity or (3)H-thymidine incorporation into DNA by exposing the mucosa to lidocaine (a local anesthetic) or by giving four different neurotransmitter receptor antagonists i.v. (muscarinic, nicotinic, neurokinin1 (NK1) or calcitonin gene related peptide (CGRP) receptors). After degeneration of the intestinal external nerves capsaicin did not increase TK activity, suggesting the involvement of an axon reflex. Intra-arterial infusion of Substance P (SP) or CGRP increased intestinal TK activity, a response abolished by muscarinic receptor blockade. Immunohistochemistry suggested presence of M3 and M5 muscarinic receptors on the intestinal stem/progenitor cells. We propose that the stem/progenitor cells are controlled by cholinergic nerves, which, in turn, are influenced by mucosal afferent neuron(s) releasing acetylcholine and/or SP and/or CGRP. In mice lacking the capsaicin receptor, thymidine incorporation into DNA and number of crypt cells labeled with BrdU was lower than in wild type animals suggesting that nerves are important also in the absence of luminal capsaicin, a conclusion also supported by the observation that atropine lowered thymidine incorporation into DNA by 60% in control rat segments. CONCLUSION: Enteric nerves are of importance in maintaining the intestinal epithelial barrier.

Effects of nicotinic receptor blockade on the colonic mucosal response to luminal bile acids in anaesthetized rats.

AIM: To test the hypothesis that nicotinic receptor mechanisms mediate the effects of bile acids on the colonic mucosa. METHODS: The epithelial transport response to 4 mm deoxycholic acid (DCA) was studied in vitro and in vivo, in rat colon. In vitro, epithelial resistance was measured by square pulse analysis, and net membrane current was calculated from the transmucosal potential difference (PD) and resistance. In vivo, we measured PD and net fluid transport. RESULTS: In vitro, DCA significantly increased membrane current and induced a progressive decrease in epithelial resistance, which in the distal colon eventually resulted in a significant PD reduction. This response was not significantly affected by hexamethonium. In vivo, DCA reduced PD with a significantly larger response in distal colon, but had no consistent effect on net fluid absorption. Nicotinic receptor blockade per se increased net fluid absorption and slightly reduced PD in proximal colon, and inhibited spontaneous net fluid secretion and markedly reduced PD in distal colon. Nicotinic receptor blockade significantly attenuated the bile-acid induced PD response. CONCLUSION: The data do not support the theory that a bile acid-activated secretory reflex exists in rat colon. The reduced PD response after hexamethonium suggests that a mechanism involving nicotinic receptors may potentiate the permeability response to luminal bile acids.