Author: Lauren Jones
Jones, Lauren, 2022 The Role of Enterochromaffin Cells in Gut Motility and their Interactions with Extrinsic Sensory Nerves, Flinders University, College of Medicine and Public Health
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Enterochromaffin (EC) cells are a specialised enteroendocrine cell (EEC) type scattered throughout the gastrointestinal (GI) epithelium, responsible for the production of 90-95% of the body’s serotonin. Serotonin is a pleiotropic bioamine, with a wide range of functions throughout the body, both centrally and peripherally. Serotonin is important in the sleep-wake cycle, control of mood, anxiety and depression, GI motility, platelet aggregation, bone density regulation, and throughout many aspects of metabolism.
Within the GI tract, serotonin has long been known to play a role in GI motility, although the importance of serotonin in gut motility has been argued within the field for years. Initial evidence suggested that serotonin was essential in driving gut motility, however more recent studies demonstrate that GI motility still occurs in mice lacking EC cell serotonin ex vivo. EC cell knockout mice were created, however, come with complications, including developmental changes in GI tract morphology. As such, the field has been lacking an adequate conditional knockout model to conclusively define the importance of EC cell-derived serotonin in GI motility.
EC cells are important luminal sensory cells that can detect mechanical stimuli within the GI tract, a function of EC cells which has long been known, however the mechanisms involved are not well understood. The most recent evidence suggests the newly identified mechanosensory ion channel, Piezo2, is important in mouse mechanobiology, however this has not yet been characterized in human.
To facilitate the sensory functions of EECs, including EC cells, it has recently been demonstrated that EECs form functional synaptic-like connections with enteric neurons. These connections are thought to be facilitated by basal projections, termed neuropods, although neither the connections, nor neuropods, have been investigated of EC cells as yet.
The aims of this work were to conclusively define whether EC cell serotonin is essential in gut motility, and to investigate the mechanosensing capabilities of both mouse and human EC cells and whether EC cell mechanotransduction is facilitated through the mechanosensitive ion channel, Piezo2. This work also aimed to determine whether colonic EC cells make direct contact with sensory nerves in the intestinal wall, and contain basal projections, termed neuropods. Finally, this work aimed to investigate the role for extrinsic afferents in driving the formation of EC cell neuropods in mouse colon.
This study utilized a specific, conditional knockdown mouse model approach, in which EC cells were specifically ablated post-development. As such, we have conclusively demonstrated that EC cell serotonin is not essential, but modulatory, in GI motility both ex vivo and in vivo. Further, we have provided significant evidence for the importance of Piezo2, the mechanosensing ion channel, in mouse and human EC cell mechanobiology. We provide novel evidence that cell Piezo2 is important in GI motility and demonstrate the novel finding that EC cell mechanosensitivity is lost with age in the human colon. We also characterize EC cell neuropods and establish for the first time the connection between EC cells and sensory innervating nerves to the mouse colon, also providing preliminary evidence for human EC cell neuropods and neuronal connections. As such, these findings increase the validity of work completed in mice for human applications and progress our understanding of the EEC-neuronal connections thought to underpin the gut-brain axis. Furthermore, we find that the removal of extrinsic spinal afferents to the mouse colon in vivo significantly reduces EC cell neuropod number and length, as well as EC cell numbers within a short timeframe, which replenish over time. As such we identify 13 protein:receptors pairs of interest from the bioinformatic analysis of genes coded for by CGRP nerve fibres and EC cells respectively.
Overall, this study has demonstrated the role for EC cell mechanosensitivity and serotonin release in GI motility, and the connections EC cells form with sensory afferents which might underpin the gut-brain axis, all of which has significant implications in regulating human health.
Keywords: serotonin, Enterochromaffin cells, gut motility, mechanosensation, gut-brain axis
Subject: Medical Science thesis
Thesis type: Doctor of Philosophy
Completed: 2022
School: College of Medicine and Public Health
Supervisor: Damien Keating