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Interleukin-6 (IL-6) can activate gastrointestinal submucosal neurons, with associated implications for motility and secretory function. Patients with irritable bowel syndrome (IBS) have elevated levels of circulating IL-6. Colons from the Wistar Kyoto (WKY) rat model of IBS secrete more IL-6 (12.84 pg/ml) than control Sprague Dawley (SD) colons (5.55 pg/ml) and WKY secretions stimulated calcium responses in naïve submucosal neurons of greater amplitude. Recombinant IL-6 activated more submucosal neurons in WKY tissue preparations (p < 0.05). These data demonstrate that WKY colonic supernatants activate submucosal neurons using an IL-6-dependent mechanism, thereby providing a link between gastrointestinal dysfunction and alterations in IL-6 levels.