Serotonergic Control of Gastrointestinal Development, Motility, and Inflammation

Abstract

Although it is most well-known for its roles in central nervous system (CNS) function, the vast majority of serotonin, or 5-hydroxytryptamine (5-HT), is produced in the gastrointestinal (GI) tract. 5-HT is synthesized mostly by enterochromaffin (EC) cells of the GI epithelium and, in small part, by neurons of the enteric nervous system (ENS). The GI tract contains an array of broadly distributed 5-HT receptors, which participate in functions such as motility, sensation, inflammation, and neurogenesis. The roles of 5-HT in these functions are reviewed, as well as its role in the pathophysiology of disorders of gut-brain interaction (DGBIs) and inflammatory bowel diseases (IBD). © 2023 American Physiological Society. Compr Physiol 13:4851-4868, 2023.

Figure 1. Expression and distribution of serotonergic cells and axonal fibers in the colonic mucosa and the enteric nervous system (ENS).

Serotonin (5-hydroxytryptamine, 5-HT)-positive cells (green) are present in both the enterochromaffin (EC) cells of the mucosa (A) and within myenteric plexus of the ENS (B). In the mucosa, 5-HT is expressed in EC cells (starred in inset) which make up less than 1% of gut epithelial cells (stained with nuclei marker, bisbenzimide, magenta). In the myenteric plexus, 5-HT+ neurons (arrow, inset) comprise 2% to 3% of total myenteric neurons (stained with pan-neuronal marker, ANNA-1, magenta) as observed in wholemount laminar preparation of the myenteric plexus (B) and a cross-section of the colon (arrow). In the ENS, 5-HT is also present in continuous presynaptic fibers that run across the enteric ganglia and along interganglionic fiber tracts, thus providing extensive innervation to other neurons within the ganglion. Made in © BioRender - biorender.com.

Figure 2. Serotonin (5-HT) biosynthesis and metabolism in the gastrointestinal tract.

Biosynthesis of 5-HT in the gut is accomplished by two different isoforms of the rate-limiting enzyme, tryptophan hydroxylase (TPH). TPH1 is responsible for 5-HT synthesis in the mucosal enterochromaffin cells and TPH2 synthesizes 5-HT in enteric neurons. Both enzymes convert the amino acid l-tryptophan (l-Tryp) to 5-hydroxytryptophan (5-HTP). The enzyme l-amino acid decarboxylase (l-AAD) then converts 5-HTP to 5-HT where it is then released into the extracellular space (solid arrows) to act on 5-HT receptors and initiate downstream serotonergic signaling. Extracellular 5-HT is then taken back up into EC cells or enteric neurons via the 5-HT transporter, SERT (dashed arrows). Once intracellular, 5-HT is inactivated by monoamine oxidase (MAO), in the mitochondria, to 5-hydroxyindoleacetic acid (5-HIAA). Made in © BioRender - biorender.com.

Figure 3. Mucosa and neuronal 5-HT in peristaltic reflexes and intestinal motility.

Mucosal 5-HT is released from enterochromaffin (EC) cells upon chemical or mechanical stimulation of the mucosa. A subpopulation of EC cells expresses the mechanoreceptor, Piezo2, that responds to distention/mechanical force causing 5-HT release (Inset). Mucosal 5-HT release causes downstream neuronal activation where intrinsic primary afferent neurons (IPAN) signal from the mucosa to ascending and descending neural pathways in the ENS to initiate contraction and relaxation respectively. Neuronal 5-HT present in a small population of enteric neurons (2% to 3%) project extensively and innervate different functional classes of neurons that drive intestinal motility. Neuronal 5-HT can mediate slow and fast excitatory synaptic transmission as well as play critical roles in the descending inhibitory pathways which culminates to intestinal motility. (A) A bolus of food in the gut lumen stimulates both ascending (B_i and descending (B_ii) reflex pathways that work cohesively to propel the food through the gut. Ascending interneurons activate excitatory motor neurons upstream of the stimulus to initiate smooth muscle contraction (B_i, red dotted box) while descending interneurons activate inhibitory motor neurons downstream of the stimulus to initiate smooth muscle relaxation (B_ii, blue dotted box). Made in © BioRender - biorender.com.