Disorder ENS involvement Clinical feature(s) Therapeutic targets† Gut inflammation Proinflammatory cytokine-mediated alteration of afferent nerves and enteric glia [49 , 50 ] Specific to inflammatory disorder (Crohn’s, ulcerative colitis, or infectious diarrhea) IL-1β , TNF-α , mast cell products, 5-HT3 agonists, substance P, and CGRP [49 ] Hirschsprung’s disease Aganglionosis of myenteric and submucosal plexuses due to defective migration of neural crest cells, disruption of ICC network [52 , 53 ] Chronic constipation, obstruction, failure to thrive, toxic megacolon [37 ] Neuronal stem cell therapy; exploitation of proliferative ICC signaling pathways [53 –56 ] Infectious secretory diarrhea Prostanoid- and 5HT-mediated stimulation of secretomotor neurons triggered by inflammatory mediators released by mast cells and neutrophils [57 –59 ] Loose and watery stools, +/- blood, abdominal pain, dehydration, nutrient loss, sepsis [60 ] Neural blockade, Loperamide [57 –59 , 61 ] Diabetic diarrhea Diabetic autonomic neuropathy resulting in vagal and sympathetic nerve damage [62 ] Nocturnal watery and painless stools, +/- incontinence [63 ] Unclear, codeine phosphate [63 ]NCT04313088 ) Short bowel syndrome Intestinotrophic effects mediated by presence of GLP-2 receptor on submucosal neurons and endocrine cells [64 –66 ] Intestinal failure resulting in malabsorption and malnutrition [67 ] GLP-2 analogs such as Teduglutide [65 , 67 –69 ] Chronic intestinal pseudoobstruction (CIPO) Hyperactive but disorganized excitatory motor neurons due to dysfunctional or damaged inhibitory motor neurons and loss of ICC [53 , 70 –72 ] Nausea, vomiting, abdominal pain, distention, constipation, diarrhea, malnutrition [71 , 72 ] Metoclopramide, erythromycin, octreotide, and neostigmine; proliferative ICC pathways [53 , 72 , 73 ] Postoperative ileus Increased sympathetic activity resulting from inhibitory neural reflexes from the spinal cord; release of inhibitory neurotransmitters and ICC loss (NO, VIP, substance P) [74 –76 ] Nausea, vomiting, abdominal distention, obstipation [77 ] Octreotide and CGRP as potential therapies; proliferative ICC pathways [53 , 73 , 75 , 76 ] Parkinson’s disease (PD) and Creutzfeldt-Jakob disease Deposits of alpha-synuclein and misfolded proteins found in enteric neurons/glia [78 , 79 ] GI dysfunction, constipation, reservoir of prions [79 ] Explore ENS role as a biomarker in these diseases
