Mucosal serotonin (5-HT) is a key paracrine signaling molecule in the integrated physiology of enterochromaffin
cells, enteric mast cells, spinal afferent nerves and the enteric nervous system (ENS). Enterochromaffin
cells release 5-HT as a paracrine signal to enteric mast cells, spinal afferents and neurons in the ENS. Enteric
mast cells release multiple mediators of paracrine signaling, among which are histamine and the serine proteases,
chymase and tryptase, as well as serotonin. Some of these mediators diffuse to receptors on afferent nociceptive
and mechanosensitive terminals and sensitize the terminals in a manner that may underlie abdominal pain and
distension induced pain in the irritable bowel syndrome. Substance P and calcitonin gene-related peptide (CGRP),
released by spinal afferent innervation, degranulate enteric mast cells. Substance P and CGRP are significant
factors in mucosal inflammation evoked by bacteria in the colonic microbiome. Binding of immunoglobulin
antibodies to FcεRI receptors, on enteric mast cells, degranulate the mast cells and release paracrine mediators
that overlay integrative microcircuitry in the ENS. An overlay of histamine “calls up” from the ENS library of
programed gut behaviors, a defensive program consisting of a sequence of copious mucosal secretions, increased
blood flow and powerful orthograde propulsion organized to move threats out of the colonic lumen. Symptoms of
acute watery diarrhea, cramping abdominal pain and incontinence are associated with “running” of the defense
program. Intestinal behavioral programs stored in the ENS library are described as working like digital “apps”.
Interplay between mast cells, enterochromaffin cells, and sensory signaling in the aging human bowel
