Evidence for a direct effect of the autonomic nervous system on intestinal epithelial stem cell proliferation

The sympathetic (SNS) and parasympathetic (PNS) branches of the autonomic nervous system have been implicated in the modulation of the renewal of many tissues, including the intestinal epithelium. However, it is not known whether these mechanisms are direct, requiring an interaction between autonomic neurotransmitters and receptors on proliferating epithelial cells. To evaluate the existence of a molecular framework for a direct effect of the SNS or PNS on intestinal epithelial renewal, we measured gene expression for the main autonomic neurotransmitter receptors in this tissue. We separately evaluated intestinal epithelial regions comprised of the stem, progenitor, and mature cells, which allowed us to investigate the distinct contributions of each cell population to this proposed autonomic effect. Notably, we found that the stem cells expressed the receptors for the SNS-associated alpha2A adrenoreceptor and the PNS-associated muscarinic acetylcholine receptors (M1 and M3). In a separate experiment, we found that the application of norepinephrine or acetylcholine decreases the expression of cyclin D1, a gene necessary for cell cycle progression, in intestinal epithelial organoids compared with controls (P < 0.05). Together, these results provide evidence of a direct mechanism for the autonomic nervous system influence on intestinal epithelial stem cell proliferation.