Rebuttal from Nick J. Spencer, Tiong Cheng Sia, Simon J Brookes, Marcello Costa and Damien J. Keating.

Abstract

We absolutely agree that 5-HT has multiple roles and that gut-derived 5-HT is an important hormone. However, this CrossTalk is about whether 5-HT is necessary for the colonic motor patterns usually called ‘peristalsis’. Drs Smith and Gershon’s rebuttal states that we ‘highlight common misunderstandings about peristaltic reflexes’. CMMCs are commonly studied in mice, where they occur spontaneously. Peristalsis is often studied using propulsion of pellets in guinea pig colon. Both CMMCs and peristalsis persist after the removal of the mucosa. Thus, it is hard to argue that anything produced or released from mucosal cells, including serotonin from enterochromaffin cells, is necessary for CMMCs or peristalsis. Drs Smith and Gershon state that ‘mucosal pressure/distortion or chemical stimuli release 5-HT from EC cells and evoke peristaltic reflexes’ citing Bulbring & Lin (1958) and Bertrand et al. (2008). In fact, Bulbring & Lin only suggested that mucosal pressure was the stimulus for peristalsis. They could not distinguish effects on mucosal cells from distension of the entire wall. The latter would, of course, activate mechanosensitive enteric neurons, thereby triggering peristalsis. Bertrand et al. (2008) only measured the ability of mucosal distortion to release serotonin from the mucosa, not its role in peristalsis. Probably the best way to test if enterochromaffin cell 5-HT is essential for CMMCs would be to genetically ablate enterochromaffin cell 5-HT and test if CMMCs are abolished. The Smith lab did exactly this and showed that CMMCs remain in the absence of enterochromaffin cell 5-HT (Heredia et al. 2013). Furthermore, the Gershon lab demonstrated no decrease in transit time in conscious TPH1–/– mice (Li et al. 2011). That these authors still support their original hypothesis, in the face of their own contradictory data, is surprising. The second issue is whether serotonin in enteric neurons is necessary for peristalsis. Drs Smith and Gershon raise the thorny issue of terminology, i.e. the difference between ‘peristalsis’ and the ‘peristaltic reflex’. Whether peristalsis is a reflex or a more complex behaviour, it still involves enteric neuronal circuits. The subject of this CrossTalk is whether enteric neural pathways that generate neural peristalsis require 5HT as a neurotransmitter. There is simply no direct evidence to support a role of colonic neuronal 5-HT acting as a neurotransmitter that regulates motility. TPH2–/– mice, lacking neuronal 5-HT, have major gut development problems. Therefore, changes in transit in TPH2–/– mice provide no evidence that endogenous neuronal 5-HT modulates motility.