Roles of nAChR and Wnt signaling in intestinal stem cell function and inflammation

•Wnt signaling regulates intestinal stem cells (ISCs) and inflammatory bowel disease (IBD).•Nicotinic acetylcholine receptor (nAChR) signaling regulates ISCs and IBD.•A proper balance of nAChR and Wnt signaling is required in the intestine.•A combinatorial signaling pathway may be a common theme in stem cell biology. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that signal using endogenous acetylcholine (ACh) and the agonist, nicotine. The nAChR signaling pathway is a central regulator of physiological homeostasis in the central and peripheral nervous systems. The receptors are expressed not only in the nervous system, but also play a pivotal role in regulation of epithelial cell growth, migration, differentiation, and inflammation processes in various mammalian non-neuronal cells. In the intestine, the Wnt signaling pathway plays a central role in the epithelium and is a principal regulator of intestinal stem cell (ISC) identity and proliferation. Since Wnt signaling was first described more than 40 years ago in ISCs, large amounts of scientific evidence have demonstrated remarkable long-term self-renewal capacity of ISCs. Intestinal organoids are commonly used for studying ISC biology and intestinal pathophysiology. The contribution of non-neuronal nAChR signaling to Wnt signaling in the intestine has received less attention. Experiments using cultured intestinal organoids that lack nerve and immune cells were performed. Endogenous ACh is synthesized in the intestinal epithelium and drives organoid growth and differentiation through activation of nAChR signaling. Furthermore, nAChR signaling is coordinated with Wnt signaling for regulation of ISC function. Elucidating the mechanism of the coordinated activities of nAChR and Wnt signaling in the intestine provides new insight into epithelial homeostasis, and may be of particular relevance in inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.