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

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.

Figure 1

In the intestinal epithelium, 5-HT is synthesized and released by a small subset of cells called enterochromaffin (EC) cells, and the 5-HT is then removed from the interstitial space by the serotonin-selective reuptake transporter (SERT), which is expressed by essentially all epithelial cells. a. Immunstaining for 5-HT in a biopsy from the transverse colon of one of the authors (GMM). 5-HT is stained blue, and the section is counterstained with the nucleic acid stain, yoyo. Note that there are no mast cells stained for 5-HT in this micrograph; 5-HT-immunoreactive mast cells are common in mouse and rat, but not in human. b. Immunostaining for SERT in a human rectal biopsy specimen demonstrating that essentially all cells in the colonic glands are SERT-immunoreactive. c. Schematic diagram illustrating the sequence of events involved in 5-HT signaling in the gut. At rest, 5-HT is synthesized by EC cell. Upon mechanical or chemical stimulation, 5-HT is released into the interstitial space of the lamina propria and binds to receptors on nearby nerve fibers. The 5-HT signaling is terminated during the recovery phase. 5-HT is transported by SERT into epithelial cells where it is enzymatically degraded, or it enters the blood stream where it is transported into platelets where it is stored for future use.

Figure 2

Most of the intrinsic and extrinsic primary afferent neurons that innervate the gut extend processes into the lamina propria of the mucosal layer where they can become exposed to 5-HT released by EC cells. These include vagal afferent fibers arising from the nodose ganglion, spinal afferent fibers arising from dorsal root ganglia, and intrinsic AH neurons located in submucosal and myenteric ganglia. There is also a class of mechanosensative S neurons in the myenteric ganglia that do not project to the mucosal layer.

Figure 3

Distribution of 5-HT receptors on enteric neurons, extrinsic nerve fibers and other excitable cells in the gut. At least 6 subtypes of 5-HT receptors are expressed in the wall of the gut, and they can exert excitatory and/or inhibitory influences depending on their location and on the target cell type. a. intrinsic circuits for epithelial secretion and vasodilation. The motor neuron may be the same neuron, but it promotes epithelial secretion and relaxes vascular smooth muscle. b. Intrinsic circuit for propulsive motility. c. extrinsic vagal and spinal afferent fibers. The “+” and “-“ symbols indicate excitatory and inhibitory actions, respectively. References: 5-HT_1A^{, –}; 5-HT_1P^{, , , , , –}; 5-HT₂^{, , –}; 5-HT₃^{, , , , , , , , , , ,} ; 5-HT₄^{, , , , , , , ,} ; 5-HT₇^, .

Figure 4

The 5-HT₄ receptor is expressed by virtually all epithelial cells, including EC cells, in the murine colon. This is a photomicrograph from a section of the distal colon of a 5-HT₄R(BAC)-eGFP mouse in which cells that express the 5-HT₄ receptor fluoresce green. Green fluorescence is present in all of the epithelial cells, as well as a layer of cells in the muscularis mucosa, and in a myenteric ganglion (block arrow). This section was also processed for 5-HT-immunoreactivity to label EC cells, shown in red (arrows).