The nonneuronal cholinergic system in the colon: A comprehensive review

Acetylcholine (ACh) is found not only in cholinergic nerve termini but also in the nonneuronal cholinergic system (NNCS). ACh is released from cholinergic nerves by vesicular ACh transporter (VAChT), but ACh release from the NNCS is mediated by organic cation transporter (OCT). Recent studies have suggested that components of the NNCS are located in intestinal epithelial cells (IECs), crypt-villus organoids, immune cells, intestinal stem cells (ISCs), and vascular endothelial cells (VECs). When ACh enters the interstitial space, its self-modulation or effects on adjacent tissues are part of the range of its biological functions. This review focuses on the current understanding of the mechanisms of ACh synthesis and release in the NNCS. Furthermore, studies on ACh functions in colonic disorders suggest that ACh from the NNCS contributes to immune regulation, IEC and VEC repair, ISC differentiation, colonic movement, and colonic tumor development. As indicated by the features of some colonic disorders, ACh and the NNCS have positive and negative effects on these disorders. Furthermore, the NNCS is located in multiple colonic organs, and the specific effects and cross-talk involving ACh from the NNCS in different colonic tissues are explored.