Hons IM, Burda JE, Grider JR, Mawe GM, Sharkey KA. Alterations to enteric neural signaling underlie secretory abnormalities of the ileum in experimental colitis in the guinea pig. Am J Physiol Gastrointest Liver Physiol 296: G717-G726, 2009. First published February 12, 2009 doi:10.1152/ajpgi.90472.2008.-Inflammatory bowel diseases (IBD) can involve widespread gastrointestinal dysfunction, even in cases in which inflammation is localized to a single site. The underlying pathophysiology of dysfunction in noninflamed regions is unclear. We examined whether colitis is associated with altered electrogenic ion transport in the ileal mucosa and/or changes in the properties of ileal submucosal neurons. Colitis was induced by administration of trinitrobenzene sulfonic acid (TNBS), and the uninflamed ileum from animals was examined 3, 7, and 28 days later. Electrogenic ion transport was assessed in Ussing chambers. Intracellular microelectrode recordings were used to examine the neurophysiology of the submucosal plexus of the ileum in animals with colitis. Noncholinergic secretion was reduced by 33% in the ileum from animals 7 days after the induction of colitis. The epithelial response to vasoactive intestinal peptide (VIP) was unaltered in animals with colitis, but the response to carbachol was enhanced. Slow excitatory synaptic transmission was dramatically reduced in VIP-expressing, noncholinergic secretomotor neurons. This change was detected as early as 3 days following TNBS treatment. No changes to fast synaptic transmission or the number of VIP neurons were observed. In addition, cholinergic secretomotor neurons fired more action potentials during a given stimulus, and intrinsic primary afferent neurons had broader action potentials in animals with colitis. These findings implicate changes to enteric neural circuits as contributing factors in inflammation-induced secretory dysfunction at sites proximal to a localized inflammatory insult. submucosal plexus; electrogenic secretion; ion transport; synaptic transmission; vasoactive intestinal peptide THE INTEGRATIVE NERVE CIRCUITRY of the enteric nervous system (ENS) provides regulatory control of the gastrointestinal (GI) tract (16). The output of the ENS is modulated by extrinsic autonomic influences from the sympathetic and parasympathetic nervous systems. When the gut is diseased or damaged, the nervous system attempts to adapt to maintain the essential digestive and defensive functions of the GI tract. However, in chronic disease, gut function is frequently compromised. Inflammatory bowel diseases (IBD), which include Crohn's disease and ulcerative colitis, are relapsing and remitting chronic intestinal inflammatory conditions. They are the source of considerable morbidity, arising from disturbances of motility and secretion (10,20,54). These functional alterations develop throughout the GI tract, even at sites distant from a localized region of active inflammation (2,28,47,51). Abnormalities in function also occur during periods of remission from IBD, when the...