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Enteric Nervous System and GI Motility
Gfra1 Underexpression Causes Hirschsprung’s Disease and Associated Enterocolitis in Mice
RET, the receptor for the glial cell line–derived neurotrophic factor (GDNF) family ligands, is the most frequently mutated gene in congenital aganglionic megacolon or Hirschsprung’s disease (HSCR). The leading cause of mortality in HSCR is HSCR-associated enterocolitis (HAEC), which is characterized by altered mucin composition, mucin retention, bacterial adhesion to enterocytes, and epithelial damage, although the order of these events is obscure. In mice, loss of GDNF signaling leads to a severely underdeveloped enteric nervous system and neonatally fatal kidney agenesis, thereby precluding the use of these mice for modeling postnatal HSCR and HAEC.Enteric Glia: A New Player in Abdominal Pain
Chronic abdominal pain is the most common gastrointestinal issue and contributes to the pathophysiology of functional bowel disorders and inflammatory bowel disease. Current theories suggest that neuronal plasticity and broad alterations along the brain-gut axis contribute to the development of chronic abdominal pain, but the specific mechanisms involved in chronic abdominal pain remain incompletely understood. Accumulating evidence implicates glial cells in the development and maintenance of chronic pain.Age-Related Changes in Gut Microbiota Alter Phenotype of Muscularis Macrophages and Disrupt Gastrointestinal Motility
Macrophages are classified as proinflammatory M1 (classically activated) or anti-inflammatory M2 (alternatively activated),1 but binary classification fails to distinguish macrophage expression profiles.2 Tissue resident muscularis macrophages (MMs) in the gut muscularis externa modulate gut homeostasis including neuromuscular function.3,4 Through neuroimmune cross-talk, MMs may sense cues in the microenvironment from the microbiota or extrinsic sympathetic neurons and relay this information to enteric neurons.Communication Between Enteric Neurons, Glia, and Nociceptors Underlies the Effects of Tachykinins on Neuroinflammation
Tachykinins are involved in physiological and pathophysiological mechanisms in the gastrointestinal tract. The major sources of tachykinins in the gut are intrinsic enteric neurons in the enteric nervous system and extrinsic nerve fibers from the dorsal root and vagal ganglia. Although tachykinins are important mediators in the enteric nervous system, how they contribute to neuroinflammation through effects on neurons and glia is not fully understood. Here, we tested the hypothesis that tachykinins contribute to enteric neuroinflammation through mechanisms that involve intercellular neuron-glia signaling.Intrinsic Gastrointestinal Macrophages: Their Phenotype and Role in Gastrointestinal Motility
There is an increasing awareness of the role of macrophages in the regulation and maintenance of gastrointestinal function in health and disease. This work has proceeded in the context of an increased understanding of the complex phenotypic variation in macrophages throughout the body and has shown previously unidentified roles for macrophages in diseases such as gastroparesis, postoperative ileus, and inflammatory bowel disease. Opportunities for exploiting the phenotypic modulation of tissue resident macrophages have been identified as possible therapies for some of these diseases.Enteric Neuron Imbalance and Proximal Dysmotility in Ganglionated Intestine of the Sox10Dom/+ Hirschsprung Mouse Model
In Hirschsprung disease (HSCR), neural crest-derived progenitors (NCPs) fail to completely colonize the intestine so that the enteric nervous system is absent from distal bowel. Despite removal of the aganglionic region, many HSCR patients suffer from residual intestinal dysmotility. To test the hypothesis that inappropriate lineage segregation of NCPs in proximal ganglionated regions of the bowel could contribute to such postoperative disease, we investigated neural crest (NC)-derived lineages and motility in ganglionated, postnatal intestine of the Sox10Dom/+ HSCR mouse model.
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