Grider JR, Piland BE. The peristaltic reflex induced by shortchain fatty acids is mediated by sequential release of 5-HT and neuronal CGRP but not BDNF. Am J Physiol Gastrointest Liver Physiol 292: G429 -G437, 2007. First published September 14, 2006; doi:10.1152/ajpgi.00376.2006.-Short-chain fatty acids (SCFAs) accelerate colonic transit. This study examined whether this action was mediated by activation of the peristaltic reflex. SCFAs (acetate, butyrate, or propionate) were applied to the central compartment of a three-compartment flat-sheet preparation of the rat middle to distal colon. The release of serotonin (5-HT), brain-derived neurotrophic factor (BDNF), and CGRP was measured in all three compartments. Ascending contraction and descending relaxation were measured in the orad and caudad compartments. The addition of SCFAs at physiological to supraphysiological concentrations (0.5-100 mM) to the central compartment elicited concentration-dependent ascending contraction and descending relaxation (EC 50 ϳ5 mM). At this concentration, SCFAs induced an 8-to 11-fold increase in 5-HT release and a 2-to 3-fold increase in CGRP release in the central compartment only. They had no effect on BDNF release. CGRP release was inhibited by a 5-HT 4 but not a 5-HT3 receptor antagonist. Ascending contraction and descending relaxation were also inhibited by 5-HT4 and by CGRP receptor antagonists added to the central compartment. 5-HT and CGRP release, as well as ascending contraction and descending relaxation induced by mechanical stimulation of the mucosa (2-8 strokes), were significantly augmented by 1 mM acetate. Acetate (1 mM) also doubled propulsive velocity in isolated whole segments of the guinea pig colon. In conclusion, chemical stimulation of the mucosa by SCFAs triggers a peristaltic reflex mediated by the release of 5-HT from mucosal cells and activation of 5-HT 4 receptors on sensory CGRP-containing nerve terminals. This SCFA-induced peristaltic pathway augments the peristaltic reflex elicited by mechanical stimulation of the mucosa. enteric nervous system; neurotrophins; neuropeptides; colon; gastrointestinal motility; calcitonin gene-related peptide; brain-derived neurotrophic factor; serotonin THE SHORT-CHAIN FATTY ACIDS (SCFA), acetate, propionate, and butyrate, produced by a bacterial fermentation of dietary fiber in the colon, are an important source of energy for colonic epithelial cells (4,8,9,34). These anions regulate various colonic functions, including colonic electrolyte transport and motor activity and the growth, proliferation, and differentiation of colonic mucosal cells (4,6,7,9,18,24,35,36,39). Their concentration in the colon of most mammals, including humans, varies with the nature and availability of the substrate, the type and amount of microflora present in the colon, the pH, the rate of transit of luminal contents, and the site of measurement within the colon (1, 4, 10, 37, 38). In general, the molar ratio for acetate, propionate, and butyrate is 60:20:20. In the rat, concentrations a...