New Insights into Molecular Mechanisms of Enteric Neuro-Epithelial Pathology: From Damage to Protection

Backgrond: Functional gastrointestinal disorders (FGID) are chronic conditions characterized by symptoms for which no overt organic cause can be found. They affect up to 20% of western populations with evidence suggesting they are equally common in the Third World (Spiller 2005). Although symptoms are generally mild or moderate, a small subset of cases shows severe manifestations, i.e. nausea, vomiting, bloating, abdominal distension, intractable constipation and chronic pain, with such an intensity hampering normal feeding and compromising considerably patients’ quality of life. In addition, this subset of patients may also have recurrent intestinal sub-occlusive episodes, which occur in the absence of demonstrable mechanical causes, leading to numerous hospitalizations as well as useless and potentially harmful surgical interventions. This condition is referred to as chronic intestinal pseudo-obstruction (CIPO), a rare and intractable chronic digestive disease with symptoms and signs of intestinal obstruction without demonstrable mechanical cause. CIPO can result from derangements affecting the integrity of a variety of regulatory cells/tissues, i.e. smooth muscle cells, the interstitial cells of Cajal (ICC) (pace-makers of gut motility), and neurons (either intrinsic – the enteric nervous system- or extrinsic nerve pathways). Aims and experimental studies: The present thesis was conceived to provide a thorough account of the molecular defects underlying CIPO and highlight new strategies of neuro-epithelial protection to prevent enteric neurodegeneration. The experimental studies are based on genetic analysis of CIPO patients and characterization of RAD21 in the ENS of human and mouse intestine. Other studies are focus on 5-hydroxytryptamine-4 (5-HT4) receptor particularly studying whether the activation of colonic epithelial 5-HT4 protects against experimentally induced inflammation of the mouse colon. Conclusion: My thesis focuses on both mechanisms of neurodegeneration and neuro/epithelial protection as a paradigm to better understand both pathophysiology of severe conditions such as CIPO, and related targeted therapeutic options.