Review Article: Intestinal Serotonin Signalling in Irritable Bowel Syndrome

G. M. Mawe; M. D. Coates; P. L. Moses


Aliment Pharmacol Ther. 2006;23(8):1067-1076. 

In This Article

The Roles of Serotonin as a Signalling Molecule in the Gut

The ENS is by far the most vast and complex component of our peripheral nervous system.[4] Distinguishing features of the ENS include the quantity of neurones, the variety of neurotransmitters and associated receptors, and the existence of intrinsic reflex circuitry. The number of neurones in the human small intestines alone (~100 000 000) approximates the number of neurones in the entire spinal cord. Almost every known neurotransmitter can be found in the ENS, and most receptors associated with these neurotransmitters are also found in the ENS. The GI tract is the only part of the body with neural reflexes that are housed entirely within the organ. Unlike reflexes associated with neural control of other organ systems or smooth muscle, complete neural circuits that include sensory neurones, interneurones, and motor neurones are contained within the wall of the intestines, and these circuits are responsible for motility, secretion and vascular tone in the gut.

One of the signalling molecules with an unambiguous physiological role in the ENS is 5-HT.[5] 5-HT is often thought of as a neurotransmitter exclusive to the central nervous system (CNS), because of its well-defined roles in depression, arousal, pain pathways and other CNS functions. However, the major source of bioavailable 5-HT in the human body is located in the bowel, primarily in a subset of epithelial cells called enterochromaffin (EC) cells.[6] EC cells express the enzymatic machinery, including the rate limiting enzyme, tryptophan hydroxylase (TpH), to synthesize 5-HT which is then stored in secretory granules. 5-HT is released from EC cells in response to luminal stimuli, including mechanical forces. Once released, 5-HT acts on receptors located on the processes of sensory neurones that pass into the lamina propria. These include branches of intrinsic sensory neurones whose cell bodies are located in submucosal and myenteric ganglia, as well as sensory neurones located in spinal (dorsal root) ganglia and vagal (nodose) ganglia (see Figure 1). As a result, release of 5-HT from EC cells initiates activation of motor, secretory and vasodilatory reflexes, as well as stimulation of afferent signals to the brain and spinal cord.

Figure 1.

Schematic diagram depicting the branch patterns of intrinsic and extrinsic primary afferent neurones that innervate the intestinal mucosa. Intrinsic primary afferent nerve fibres originate from neurones with cell bodies located in the myenteric and submucosal plexuses. These neurones are involved in local activities such as motility, secretion and vasodilation within the intestines. Extrinsic primary afferent nerves arise from neurones with cell bodies located in the nodose ganglia (vagal afferents) and dorsal root ganglia (spinal afferents). Extrinsic afferents transmit signals related to digestive reflexes, satiety, pain and discomfort from the gut to the central nervous system. As all these types of primary afferent neurones extend processes into the lamina propria of the intestines, they can be activated by serotonin (5-HT) released from enterochromaffin (EC) cells that are located in the crypt epithelium.

An important facet of efficient intercellular signalling is the termination of the signal. In the case of 5-HT signalling in the brain, nerve terminals that release 5-HT express a serotonin-selective reuptake transporter (SERT), so they are uniquely capable of terminating the signals that they initiate.[7,8] 5-HT neurotransmission in the brain can be augmented by compounds that function as selective serotonin reuptake inhibitors (SSRIs). These drugs, fluoxetine (Prozac), citalopram (Celexa) and paroxetine (Paxil) and related compounds, increase 5-HT availability in the synaptic cleft by inhibiting SERT.

The intestinal mucosa has an enormous capacity to remove 5-HT from the interstitial space because all of the epithelial cells that line the luminal surface of the gut express SERT.[5,9] Therefore, once 5-HT is released from EC cells and acts on local receptors, it is transported into epithelial cells by SERT. Postprandially, 5-HT also enters the bloodstream where it is rapidly taken up by platelets, which also express SERT.[10] In fact, 5-HT found in platelets arises primarily from 5-HT released from EC cells.[11,12]


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