Intraluminal Prucalopride Increases Propulsive Motor Activities in the Human Colon

Background Luminal application of 5-HT4 receptor agonists can increase peristalsis in the guinea pig, mouse, rat and rabbit colon. Our aim in the present study was to test the effects of intraluminal prucalopride on motor patterns in the human colon. Methods Colonic motor patterns were studied in vivo in a healthy volunteer using High-Resolution Colonic Manometry (HRCM) with an 84-sensor water perfused catheter with 1cm spacing. 5-HT and 5-HT4 receptor immunohistochemistry was performed on human tissue biopsies throughout the colon. Key results Activating mucosal 5-HT4 receptors via intraluminal prucalopride enhanced propulsive motor activity in the human colon by increasing occurrence and amplitude of propulsive motor patterns including high-amplitude propagating pressure waves (HAPWs), pancolonic simultaneous pressure waves (SPWs) and HAPW-SPWs. Prucalopride-induced motor patterns had a close temporal association with a significant degree of anal sphincter relaxation and some were accompanied by a strong urge to defecate. Biopsies showed 100% colocalization of the 5-HT4 receptor to enterochromaffin cells throughout the colon and rectum. Conclusions and inferences Activating luminal 5-HT4 receptors on enterochromaffin cells by intraluminal prucalopride increased propulsive motor activity. 5-HT4 receptors were found only on enterochromaffin cells and not ubiquitous on all epithelial cells. Our data support incorporation of prucalopride in colon-specific drug delivery systems as a prokinetic to treat colonic hypomotility disorders. 50 word abstract High-resolution colonic manometry and biopsy immunohistochemistry revealed that 5-HT4 receptors in the lumen of the human colon are present exclusively on enterochromaffin cells and that the 5-HT4 agonist prucalopride evokes all major propulsive motor patterns, associated with significant anal sphincter relaxation, when given intraluminally. 250-character clinical message Activating luminal 5-HT4 receptors on enterochromaffin cells by intraluminal prucalopride increased propulsive motor activity in the human colon. Colon-specific delivery systems with a 5-HT4 agonist may become the preferred colon prokinetic. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Canadian Institute of Health Research (PJT 152942) to Jan D Huizinga and an Ontario Graduate Scholarship to Mitra Shokrollahi. Ji-Hong Chen and Xuan-Yu Wang received salary support from the Farncombe Family Digestive Health Research Institute. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Hamilton Integrated Research Ethics Board (HiREB) All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data are in the manuscript