The human Enteric Nervous System in health and disease

      Gastrointestinal (GI) functions are controlled by a dynamic interplay among different cell types that interact through a variety of signaling molecules in communication with the central nervous system. The enteric nervous system (ENS) exerts a major regulatory role on gut function via functionally distinct classes of neurons (e.g., intrinsic primary afferent neurons, interneurons, motorneurons). Smooth muscle cells form an electrical syncytium within the gut and are innervated, directly or indirectly through interstitial cells of Cajal (ICCs), by neurons. ICCs have an active role in the control of motility as pace-makers and through mechanosensitive ion channels. Also, the immune system and enteric glia, are now increasingly understood to be actively involved in the modulation of GI function. Any noxa affecting the integrity of these cell types, alone or in combination, may evoke dysfunction as identified in a number of clinically recognized conditions characterized by severe impairment of GI motility and transit (e.g., chronic intestinal pseudo-obstruction - CIPO). Pathological abnormalities underlying severe GI dysmotility can be classified into three major entities: neuropathies, “mesenchymopathies” (i.e., changes in ICCs), and myopathies. Although rare, enteric neuro-ICC-myopathies are of primary importance for gastroenterologists and clinicians because they markedly affect the patient’s quality of life and they may be so severe to be life-threatening. Genetic, environmental and inflammatory mechanisms are now recognized to play a role in neuro-ICC-myopathies underlying severe GI dysfunction. This translational knowledge may help to develop effective and targeted therapeutic strategies for patients suffering from CIPO or other severe chronic bowel disorders.
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