Chapter 27 - Enteric Neural Regulation of Mucosal Secretion

Chemotherapy is the main treatment for many cancers, including colorectal cancer, a type of cancer with some of the highest prevalence and mortality rates worldwide. Although chemotherapeutic drugs have greatly improved the survival rates of cancer patients, there are many side-effects associated with their use. The gastrointestinal side-effects of chemotherapy often lead to dose reduction or even discontinuation of treatment, which in turn affects the clinical outcome. Gastrointestinal side-effects, such as chemotherapy-induced diarrhea and constipation, may persist many years after treatment, greatly reducing quality of life. Current treatments for these side-effects have many adverse effects themselves; therefore, new approaches are needed to address this problem. Changes in the enteric nervous system located within the gastrointestinal tract and controlling its functions have been implicated in many disorders. Recent studies providing insight into the association between chemotherapy-induced damage to enteric neurons and gastrointestinal dysfunction have highlighted the enteric nervous system as a potential therapeutic target to alleviate chemotherapy-induced toxicity which may improve both clinical outcomes and the quality of patients’ lives.

Co-ordinated gastrointestinal function is the result of integrated communication between the enteric nervous system (ENS) and “effector” cells in the gastrointestinal tract. Unlike smooth muscle cells, interstitial cells, and the vast majority of cell types residing in the mucosa, enteric neurons and glia are not generated within the gut. Instead, they arise from neural crest cells that migrate into and colonise the developing gastrointestinal tract. Although they are “later” arrivals into the developing gut, enteric neural crest-derived cells (ENCCs) respond to many of the same secreted signalling molecules as the “resident” epithelial and mesenchymal cells, and several factors that control the development of smooth muscle cells, interstitial cells and epithelial cells also regulate ENCCs. Much progress has been made towards understanding the migration of ENCCs along the gastrointestinal tract and their differentiation into neurons and glia. However, our understanding of how enteric neurons begin to communicate with each other and extend their neurites out of the developing plexus layers to innervate the various cell types lining the concentric layers of the gastrointestinal tract is only beginning. It is critical for postpartum survival that the gastrointestinal tract and its enteric circuitry are sufficiently mature to cope with the influx of nutrients and their absorption that occurs shortly after birth. Subsequently, colonisation of the gut by immune cells and microbiota during postnatal development has an important impact that determines the ultimate outline of the intrinsic neural networks of the gut. In this review, we describe the integrated development of the ENS and its target cells.