Evolving pathophysiologic models of functional gastrointestinal disorders.

In contrast to most other disorders of the digestive system, functional disorders of the gut continue to be defined by symptom criteria rather than by biological markers. At the same time, animal models of functional gastrointestinal disorders in which to test pathophysiologic hypotheses are lacking. The aim of this report is to critically review recently proposed conceptual as well as animal models of functional gastrointestinal disorders. Converging disease models have been proposed that postulate an enhanced responsiveness of neural, immune, or neuroimmune circuits in the central nervous system or in the gut to exteroceptive (psychosocial) or interoceptive (tissue irritation, inflammation, infection) perturbations of the organism's homeostasis. The enhanced responsiveness results in dysregulation of gut motility, epithelial function (immune, permeability), and visceral hypersensitivity, which in turn produce irritable bowel syndrome symptoms. These conceptual models provide plausible mechanisms for irritable bowel syndrome symptom generation and are consistent with extensive epidemiologic and pathophysiologic data. Several animal models have recently been proposed that mimic key features of these conceptual disease models. They fall into models triggered by centrally targeted stimuli (neonatal stress, post-traumatic stress disorder) or those triggered by peripherally targeted stimuli (infection, inflammation). Depending on the timing of the trigger (neonatal vs. adult), the changes induced in the animal may be permanent or transient. Future development of existing and novel models involves the use of transgenic and knockout animals, as well as the demonstration of predictive validity in terms of responsiveness to candidate drugs.