A working theoretical model for irritable bowel syndrome (IBS) and other functional gastrointestinal disorders (FGIDs) does not exist, hampered by the lack of any clear cut invention that address all symptom and signs of the disease. Reports of cessation of symptom and signs of both major types of IBS have been published using a non-systemic, topically active agent-high potency polymerized cross-linked sucralfate (HPPCLS). The unique clinical effect of this non-systemic agent restricted to the luminal surface of the gut provides opportunity to elaborate on an alternative working model for the pathogenesis of IBS and FGIDs. While the chemical determinants of HPPCLS and the mucosal lining contribute to the clinical effects, the sequence of events resides in the functional interplay among elements within the mucosa itself. The proposed model assumes that failure of a pre-existing genomic-controlled surveillance of the epithelium localized to the luminal surface triggers primary and secondary immune activation of inflammation intent on restoring epithelial homeostasis. Delayed restoration of homeostasis results in all the symptoms, signs and likely molecular events that characterize IBS and FGIDs.