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Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

A Correction to this article was published on 27 August 2013

This article has been updated

Abstract

Serotonin (5-HT) has been recognized for decades as an important signalling molecule in the gut, but it is still revealing its secrets. Novel gastrointestinal functions of 5-HT continue to be discovered, as well as distant actions of gut-derived 5-HT, and we are learning how 5-HT signalling is altered in gastrointestinal disorders. Conventional functions of 5-HT involving intrinsic reflexes include stimulation of propulsive and segmentation motility patterns, epithelial secretion and vasodilation. Activation of extrinsic vagal and spinal afferent fibres results in slowed gastric emptying, pancreatic secretion, satiation, pain and discomfort, as well as nausea and vomiting. Within the gut, 5-HT also exerts nonconventional actions such as promoting inflammation and serving as a trophic factor to promote the development and maintenance of neurons and interstitial cells of Cajal. Platelet 5-HT, originating in the gut, promotes haemostasis, influences bone development and serves many other functions. 5-HT3 receptor antagonists and 5-HT4 receptor agonists have been used to treat functional disorders with diarrhoea or constipation, respectively, and the synthetic enzyme tryptophan hydroxylase has also been targeted. Emerging evidence suggests that exploiting epithelial targets with nonabsorbable serotonergic agents could provide safe and effective therapies. We provide an overview of these serotonergic actions and treatment strategies.

Key Points

  • Serotonin (5-HT) is an important gastrointestinal signalling molecule that conveys signals from the lumen of the gut to intrinsic and extrinsic sensory neurons, and contributes to synaptic signals in the enteric nervous system

  • Fundamental properties of mucosal 5-HT signalling are altered in response to inflammation and in functional gastrointestinal disorders

  • Actions of 5-HT released from mucosal enterochromaffin cells include stimulation of intrinsic reflexes such as peristalsis, segmentation, secretion and vasodilation

  • 5-HT can also activate signals sent to the CNS that stimulate digestive reflexes and can cause abdominal pain and discomfort, satiety or nausea

  • Mucosal 5-HT can promote intestinal inflammation, and 5-HT in the muscularis propria can promote survival of neurons and interstitial cells of Cajal, and promote neural regeneration

  • As the colonic epithelium is rich in 5-HT-related targets, nonabsorbable drugs that target 5-HT3 receptors, 5-HT4 receptors and tryptophan hydroxylase could serve as safe and effective therapies

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Figure 1: 5-HT signalling in the gut.
Figure 2: Intrinsic and extrinsic afferent nerve fibres.
Figure 3: Distribution of 5-HT receptors on enteric neurons, extrinsic nerve fibres and other excitable cells in the gut.
Figure 4: The 5-HT4 receptor is expressed by virtually all epithelial cells, including enterochromaffin cells, in the mouse colon.11

Change history

  • 27 August 2013

    In the original version of this article published online and in print, the permission line for Figure 2 was omitted. The error has been corrected for the HTML and PDF versions of the article.

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Acknowledgements

This work of the authors is supported by NIH grant DK62267 (to G. M. Mawe). The authors thank Dr B. Lavoie for editorial assistance.

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Mawe, G., Hoffman, J. Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol 10, 473–486 (2013). https://doi.org/10.1038/nrgastro.2013.105

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