5-Hydroxytryptamine (serotonin) in the gastrointestinal tract
Open accessAbstract
PURPOSE OF REVIEW: Although the gut contains most of the body's 5-hydroxytryptamine (5-HT), many of its most important functions have recently been discovered. This review summarizes and directs attention to this new burst of knowledge. RECENT FINDINGS: Enteroendocrine cells have classically been regarded as pressure sensors, which secrete 5-HT to initiate peristaltic reflexes; nevertheless, recent data obtained from studies of mice that selectively lack 5-HT either in enterochromaffin cells (deletion of tryptophan hydroxylase 1 knockout; TPH1KO) or neurons (TPH2KO) imply that neuronal 5-HT is more important for constitutive gastrointestinal transit than that of enteroendocrine cells. The enteric nervous system of TPH2KO mice, however, also lacks a full complement of neurons; therefore, it is not clear whether slow transit in TPH2KO animals is due to their neuronal deficiency or absence of serotonergic neurotransmission. Neuronal 5-HT promotes the growth/maintenance of the mucosa as well as neurogenesis. Enteroendocrine cell derived 5-HT is an essential component of the gastrointestinal inflammatory response; thus, deletion of the serotonin transporter increases, whereas TPH1KO decreases the severity of intestinal inflammation. Enteroendocrine cell derived 5-HT, moreover, is also a hormone, which inhibits osteoblast proliferation and promotes hepatic regeneration. SUMMARY: New studies show that enteric 5-HT is a polyfunctional signalling molecule, acting both in developing and mature animals as a neurotransmitter paracrine factor, endocrine hormone and growth factor.
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An estimated 90% of the body's serotonin is produced by enterochromaffin (EC) cells in the digestive tract.
“An estimated 90% of the body’s serotonin is produced by enterochromaffin (EC) cells in the digestive tract [51].”
From Effect of fecal microbiota transplant on symptoms of psychiatric disorders: a systematic review (2020) · cites this paper as [51]
Serotonin and its receptors play an important role in gastrointestinal motility.
“The role of serotonin in the gastrointestinal system is very complex, but one thing is very clear: serotonin and its receptors play an important role in gastrointestinal motility.36”
From Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review (2018) · cites this paper as [36]
Blood 5-HT is synthesized in the gut, where it plays a critical role in regulating motility and inflammation.
“Blood 5-HT is synthesized in the gut, where it plays a critical role in regulating motility and inflammation (Gershon 2013).”
From Brief Report: Whole Blood Serotonin Levels and Gastrointestinal Symptoms in Autism Spectrum Disorder (2016) · cites this paper as Gershon 2013
The neuronal pool of 5-HT, rather than the majority EC-cell pool, is most critical for ENS development and motility.
“Although the vast majority of intestinal 5-HT is located in the EC cells, it is the neuronal pool of 5-HT that is most critical for ENS development and motility [26, 27].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [26]
Enteric 5-HT accounts for >90% of the body's 5-HT stores and is contained in two primary reservoirs: intestinal epithelium EC cells and neurons of the ENS.
“Enteric 5-HT, which accounts for >90% of the body’s 5-HT stores, is contained in two primary reservoirs: in the intestinal epithelium, where it is produced by enterochromaffin (EC) cells, and in neurons of the ENS [26].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [26]
Synthesis of neuronal 5-HT in both the CNS and ENS is regulated by TPH2, while EC-cell derived 5-HT is produced by TPH1.
“Synthesis of neuronal 5-HT, both in the CNS and ENS, is regulated by TPH2, while EC-cell derived 5-HT is produced by TPH1 [26].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [26]
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- [50]Erspamer V Erspamer V Occurrence of indolealkylamines in nature Handbook of experimental pharmacology: 5-hydroxytryptamine and related indolealkylamines 1966 New York Springer-Verlag 132 181
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Serotonin, tryptophan metabolism and the brain-gut-microbiome axis
O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G., & Cryan, J. F. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.027 · Cited by 2,012 · see citing works
Reigstad, C. S., Salmonson, C. E., III, J. F. R., Szurszewski, J. H., Linden, D. R., Sonnenburg, J. L., Farrugia, G., & Kashyap, P. C. (2015) · The FASEB Journal · doi:10.1096/fj.14-259598 · Cited by 1,335 · see citing works
Control of brain development, function, and behavior by the microbiome
Sampson, T. R., & Mazmanian, S. K. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.04.011 · Cited by 1,093 · see citing works
The microbiota-gut-brain axis: from motility to mood
Margolis, K. G., Cryan, J. F., & Mayer, E. A. (2021) · Gastroenterology · doi:10.1053/j.gastro.2020.10.066 · Cited by 999 · see citing works
From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways
Rogers, G. B., Keating, D. J., Young, R. L., Wong, M.-L., Licinio, J., & Wesselingh, S. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.50 · Cited by 969 · see citing works
Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways
Bellono, N. W., Bayrer, J. R., Leitch, D. B., Castro, J., Zhang, C., O’Donnell, T. A., Brierley, S. M., Ingraham, H. A., & Julius, D. (2017) · Cell · doi:10.1016/j.cell.2017.05.034 · Cited by 910 · see citing works
The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology
Rutsch, A., Kantsjö, J. B., & Ronchi, F. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.604179 · Cited by 821 · see citing works
Carvalho, A. F., Sharma, M. S., Brunoni, A. R., Vieta, E., & Fava, G. A. (2016) · Psychotherapy and Psychosomatics · doi:10.1159/000447034 · Cited by 650 · see citing works
The bowel and beyond: The enteric nervous system in neurological disorders
Rao, M., & Gershon, M. D. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.107 · Cited by 629 · see citing works
Self-citationThe serotonin system in autism spectrum disorder: From biomarker to animal models
Muller, C. L., Anacker, A. M. J., & Veenstra-VanderWeele, J. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2015.11.010 · Cited by 531 · see citing works
Enteroendocrine cells: a review of their role in brain–gut communication
Latorre, R., Sternini, C., De Giorgio, R., & Greenwood‐Van Meerveld, B. (2016) · Neurogastroenterology & Motility · doi:10.1111/nmo.12754 · Cited by 392 · see citing works
Deng, Y., Zhou, M., Wang, J., Yao, J., Yu, J., Liu, W., Wu, L., Wang, J., & Gao, R. (2021) · Gut Microbes · doi:10.1080/19490976.2020.1869501 · Cited by 362 · see citing works
Heiss, C. N., & Olofsson, L. E. (2019) · Journal of Neuroendocrinology · doi:10.1111/jne.12684 · Cited by 304 · see citing works
Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review
Wang, S.-M., Han, C., Bahk, W.-M., Lee, S.-J., Patkar, A. A., Masand, P. S., & Pae, C.-U. (2018) · Chonnam Medical Journal · doi:10.4068/cmj.2018.54.2.101 · Cited by 299 · see citing works
Ge, X., Ding, C., Zhao, W., Xu, L., Tian, H., Gong, J., Zhu, M., Li, J., & Li, N. (2017) · Journal of Translational Medicine · doi:10.1186/s12967-016-1105-4 · Cited by 274 · see citing works
Non-conventional features of peripheral serotonin signalling — the gut and beyond
Spohn, S. N., & Mawe, G. M. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.51 · Cited by 282 · see citing works
Cao, H., Liu, X., An, Y., Zhou, G., Liu, Y., Xu, M., Dong, W., Wang, S., Yan, F., Jiang, K., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-10835-8 · Cited by 253 · see citing works
Effect of fecal microbiota transplant on symptoms of psychiatric disorders: a systematic review
Chinna Meyyappan, A., Forth, E., Wallace, C. J. K., & Milev, R. (2020) · BMC Psychiatry · doi:10.1186/s12888-020-02654-5 · Cited by 254 · see citing works
Bosi, A., Banfi, D., Bistoletti, M., Giaroni, C., & Baj, A. (2020) · International Journal of Tryptophan Research · doi:10.1177/1178646920928984 · Cited by 221 · see citing works
Oliva, V., Lippi, M., Paci, R., Del Fabro, L., Delvecchio, G., Brambilla, P., De Ronchi, D., Fanelli, G., & Serretti, A. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110266 · Cited by 219 · see citing works
Regulation of gut luminal serotonin by commensal microbiota in mice
Hata, T., Asano, Y., Yoshihara, K., Kimura-Todani, T., Miyata, N., Zhang, X.-T., Takakura, S., Aiba, Y., Koga, Y., & Sudo, N. (2017) · PLOS ONE · doi:10.1371/journal.pone.0180745 · Cited by 211 · see citing works
The role of the gut microbiota in multiple sclerosis
Correale, J., Hohlfeld, R., & Baranzini, S. E. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00697-8 · Cited by 207 · see citing works
Waclawiková, B., & El Aidy, S. (2018) · Pharmaceuticals · doi:10.3390/ph11030063 · Cited by 172 · see citing works
Human-Derived Bifidobacterium dentium Modulates the Mammalian Serotonergic System and Gut–Brain Axis
Engevik, M. A., Luck, B., Visuthranukul, C., Ihekweazu, F. D., Engevik, A. C., Shi, Z., Danhof, H. A., Chang-Graham, A. L., Hall, A., Endres, B. T., et al. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.08.002 · Cited by 164 · see citing works
Heredia, D. J., Gershon, M. D., Koh, S. D., Corrigan, R. D., Okamoto, T., & Smith, T. K. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.256230 · Cited by 144 · see citing works
Margolis, K. G., Li, Z., Stevanovic, K., Saurman, V., Israelyan, N., Anderson, G. M., Snyder, I., Veenstra-VanderWeele, J., Blakely, R. D., & Gershon, M. D. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84877 · Cited by 139 · see citing works
Self-citationSerotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders
Israelyan, N., & Margolis, K. G. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.03.020 · Cited by 122 · see citing works
KUWAHARA, A., MATSUDA, K., KUWAHARA, Y., ASANO, S., INUI, T., & MARUNAKA, Y. (2020) · Biomedical Research · doi:10.2220/biomedres.41.199 · Cited by 112 · see citing works
Recent developments in the pathophysiology of irritable bowel syndrome
El-Salhy, M. (2015) · World Journal of Gastroenterology · doi:10.3748/wjg.v21.i25.7621 · Cited by 111 · see citing works
Serotonin and colonic motility
Kendig, D. M., & Grider, J. R. (2015) · Neurogastroenterology & Motility · doi:10.1111/nmo.12617 · Cited by 113 · see citing works
Prenatal environmental risk factors for autism spectrum disorder and their potential mechanisms
Love, C., Sominsky, L., O’Hely, M., Berk, M., Vuillermin, P., & Dawson, S. L. (2024) · BMC Medicine · doi:10.1186/s12916-024-03617-3 · Cited by 110 · see citing works
Complications from carcinoid syndrome: Review of the current evidence
Mota, J. M., Sousa, L. G., & Riechelmann, R. P. (2016) · ecancermedicalscience · doi:10.3332/ecancer.2016.662 · Cited by 99 · see citing works
Brief Report: Whole Blood Serotonin Levels and Gastrointestinal Symptoms in Autism Spectrum Disorder
Marler, S., Ferguson, B. J., Lee, E. B., Peters, B., Williams, K. C., McDonnell, E., Macklin, E. A., Levitt, P., Gillespie, C. H., Anderson, G. M., et al. (2016) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-015-2646-8 · Cited by 95 · see citing works
The Regulation of Peripheral Metabolism by Gut-Derived Hormones
Sun, E. W. L., Martin, A. M., Young, R. L., & Keating, D. J. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00754 · Cited by 71 · see citing works
Whitney, M. S., Shemery, A. M., Yaw, A. M., Donovan, L. J., Glass, J. D., & Deneris, E. S. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1469-16.2016 · Cited by 77 · see citing works
Rigid-compulsive behaviors are associated with mixed bowel symptoms in autism spectrum disorder
Peters, B., Williams, K. C., Gorrindo, P., Rosenberg, D., Lee, E. B., Levitt, P., & Veenstra-VanderWeele, J. (2014) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-013-2009-2 · Cited by 70 · see citing works
Phenolic Melatonin-Related Compounds: Their Role as Chemical Protectors against Oxidative Stress
Galano, A., Castañeda-Arriaga, R., Pérez-González, A., Tan, D.-X., & Reiter, R. (2016) · Molecules · doi:10.3390/molecules21111442 · Cited by 60 · see citing works
CrossTalk proposal: 5-HT is necessary for peristalsis
Smith, T. K., & Gershon, M. D. (2015) · The Journal of Physiology · doi:10.1113/jp270182 · Cited by 51 · see citing works
Self-citationLewis-Fernández, R., Lam, P., Lucak, S., Galfalvy, H., Jackson, E., Fried, J., Rosario, M., de la Cruz, A. A., Sánchez-Lacay, A., Díaz, S., et al. (2016) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000000599 · Cited by 49 · see citing works
Gross Margolis, K., Vittorio, J., Talavera, M., Gluck, K., Li, Z., Iuga, A., Stevanovic, K., Saurman, V., Israelyan, N., Welch, M. G., et al. (2017) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00215.2017 · Cited by 28 · see citing works
Self-citationBrindley, R. L., Bauer, M. B., Blakely, R. D., & Currie, K. P. M. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.08.015 · Cited by 26 · see citing works
Chan, D. G., Ventura, K., Villeneuve, A., Du Bois, P., & Holahan, M. R. (2022) · Journal of Parkinson's Disease · doi:10.3233/jpd-223461 · Cited by 24 · see citing works
Cheng, H.-W., Jiang, S., & Hu, J. (2019) · Oral Health by Using Probiotic Products · doi:10.5772/intechopen.86775 · Cited by 17 · see citing works
Tonello, L., Gashi, B., Scuotto, A., Cappello, G., Cocchi, M., Gabrielli, F., & Tuszynski, J. A. (2018) · Journal of Integrative Neuroscience · doi:10.3233/jin-170048 · Cited by 3 · see citing works
- Authors
- Gershon, M. D.
- Affiliations
- Columbia University (US)
- Corresponding author
- Gershon, Michael D.
- ORCID
- Gershon, Michael D.
- Venue
- Current Opinion in Endocrinology, Diabetes & Obesity
- Published
- 2013-02
- Volume
- 20
- Issue
- 1
- Pages
- 14-21
- ISSN
- 1752-296X (ISSN-L)
- PMC
- PMC3708472
- OpenAlex
- W2155948158
- Cited by
- 617
- References
- 88
- Citations by year
- 2026: 23 · 2025: 43 · 2024: 39 · 2023: 61 · 2022: 81 · 2021: 66 · 2020: 63 · 2019: 44 · 2018: 36 · 2017: 50 · 2016: 41 · 2015: 26 · 2014: 26 · 2013: 15
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Opinion in Endocrinology Diabetes and Obesity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ns015547-39)
- National Institute of Neurological Disorders and Stroke (R01NS012969, NS12969, R01-NS015547, 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
- serotonin, gastrointestinal tract, enteroendocrine cells, enterochromaffin cells, tryptophan hydroxylase 1, tryptophan hydroxylase 2, enteric nervous system, gastrointestinal transit, neurogenesis, intestinal inflammation, serotonin transporter, paracrine signaling, growth factors, osteoblast proliferation, liver regeneration
- MeSH terms
- Animals, Constipation, Diarrhea, Enterochromaffin Cells, Female, Gastrointestinal Motility, Humans, Intestinal Mucosa, Male, Synaptic Transmission, Serotonin, Tryptophan Hydroxylase, Mice, Knockout, Enteroendocrine Cells, Gastrointestinal Tract, Irritable Bowel Syndrome, Serotonin Plasma Membrane Transport Proteins, Mice, Serotonergic Neurons
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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