In addition to its role in regulating energy homeostasis, the adipokine, leptin modifies gastrointestinal (GI) function. Indeed, leptin-resistant obese humans and leptin-deficient obese mice exhibit altered GI motility. In the functional GI disorder, irritable bowel syndrome (IBS), circulating leptin levels are reported to differ from healthy controls. Additionally, IBS patients display altered cytokine profiles, including elevated circulating levels of the pro-inflammatory cytokine, interleukin (IL)-6, which bears structural homology and similarities in intracellular signalling to leptin. This study aims to investigate interactions between leptin and IL-6 in colonic neurons and their possible contribution to IBS pathophysiology. The functional effects of leptin and IL-6 on colonic contractility and absorpto-secretory function were assessed in organ baths and Ussing chambers in Sprague Dawley rat colons. Calcium imaging and immunohistochemical techniques were employed to investigate the neural regulation of GI function by these signalling molecules. Our findings provide a neuromodulatory role for leptin in submucosal neurons, where it inhibited the stimulatory effects of IL-6. Functionally, this translated to suppression of IL-6 evoked potentiation of veratridine-induced secretory currents. Leptin also attenuated IL-6-induced colonic contractions, although it had little direct effect on myenteric neurons. Calcium responses evoked by IBS plasma in both myenteric and submucosal neurons were also suppressed by leptin, possibly through interactions with IL-6, which is elevated in IBS plasma. As leptin has the capacity to ameliorate the neurostimulatory effects of soluble mediators in IBS plasma and modulated IL-6-evoked changes in bowel function, leptin may have a role in immune-mediated bowel dysfunction in IBS patients. This article is protected by copyright. All rights reserved.