Nerves, Reflexes, and the Enteric Nervous System: Pathogenesis of the Irritable Bowel Syndrome
Abstract
The bowel exhibits reflexes in the absence of CNS input. To do so, epithelial sensory transducers, such as enterochromaffin (EC) cells, activate the mucosal processes of intrinsic (IPANs) and extrinsic primary afferent (sensory) neurons. EC cells secrete serotonin (5-HT) in response to mucosal stimuli. Submucosal IPANs, which secrete acetylcholine and calcitonin gene-related peptide, initiate peristaltic and secretory reflexes and are activated via "5-HT1P" receptors. Release of neurotransmitters is enhanced by 5-HT4 receptors, which are presynaptic and strengthen neurotransmission in prokinetic pathways. 5-HT3 receptors mediate signaling to the CNS and thus ameliorate cancer chemotherapy-associated nausea and the visceral hypersensitivity of diarrhea-predominant irritable bowel syndrome (IBS-D); however, because 5-HT3 receptors also mediate fast ENS neurotransmission and activate myenteric IPANs, they may be constipating. 5-HT4 agonists are prokinetic and relieve discomfort and constipation in IBS-C and chronic constipation. 5-HT4 agonists do not initiate peristaltic and secretory reflexes but strengthen pathways that are naturally activated. Serotonergic signaling in the mucosa and the ENS is terminated by a transmembrane 5-HT transporter, SERT. Mucosal SERT and tryptophan hydroxylase-1 expression are decreased in experimental inflammation, IBS-C, IBS-D, and ulcerative colitis. Potentiation of 5-HT due to the SERT decrease could account for the discomfort and diarrhea of IBS-D, while receptor desensitization may cause constipation. Similar symptoms are seen in transgenic mice that lack SERT. The loss of mucosal SERT may thus contribute to IBS pathogenesis.
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Enterochromaffin cells secrete serotonin and signaling peptides in response to various physiological and pathological luminal stimuli, such as microbial factors or bacterial toxins, as well as central stimuli.
“Enterochromaffin cells secrete serotonin and signaling peptides (for example, corticotropin-releasing hormone, cholecystokinin and somatostatin) in response to various physiological and pathological luminal stimuli,53-55 such as microbial factors or bacterial toxins,56-58 as well as central stimuli (see discussion above).31,32”
From Principles and clinical implications of the brain-gut-enteric microbiota axis (2009) · cites this paper as [55]
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The functional gastrointestinal disorders and the Rome III process
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Maternal serotonin is crucial for murine embryonic development
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Serotonin Type 3 Receptor Genes: <i>HTR3A, B, C, D, E</i>
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- Authors
- Gershon, M. D.
- Affiliations
- Columbia University (US)
- Corresponding author
- Gershon, Michael D
- ORCID
- Gershon, Michael D
- Venue
- Journal of Clinical Gastroenterology
- Published
- 2005-05
- Volume
- 39
- Issue
- 5
- Pages
- S184-S193
- ISSN
- 0192-0790 (ISSN-L)
- OpenAlex
- W2014814979
- Cited by
- 271
- References
- 131
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 9 · 2023: 12 · 2022: 4 · 2021: 9 · 2020: 7 · 2019: 4 · 2018: 10 · 2017: 14 · 2016: 15 · 2015: 10 · 2014: 15 · 2013: 13 · 2012: 11
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns015547-39)
- National Institute of Neurological Disorders and Stroke (R01NS012969, NS12969, NS 15547)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Keywords
- enteric nervous system, enterochromaffin cells, serotonin, serotonin receptors, 5-HT4 receptor agonist, 5-HT3 receptor, serotonin transporter, tryptophan hydroxylase 1, intrinsic primary afferent neurons, peristaltic reflex, irritable bowel syndrome, constipation, diarrhea, visceral hypersensitivity, ulcerative colitis, inflammation, neurotransmission
- MeSH terms
- Animals, Colon, Gastrointestinal Motility, Humans, Reflex, Enteric Nervous System, Irritable Bowel Syndrome
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