Copyright
©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 21, 2024; 30(3): 268-279
Published online Jan 21, 2024. doi: 10.3748/wjg.v30.i3.268
Calcium/calcimimetic via calcium-sensing receptor ameliorates cholera toxin-induced secretory diarrhea in mice
Lie-Qi Tang, Johnathan Fraebel, Shi Jin, Steven P Winesett, Jane Harrell, Wen-Han Chang, Sam Xianjun Cheng
Lie-Qi Tang, Johnathan Fraebel, Shi Jin, Jane Harrell, Department of Pediatrics, University of Florida, Gainesville, FL 32610, United States
Johnathan Fraebel, College of Medicine, University of Florida, Gainesville, FL 32610, United States
Steven P Winesett, Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32610, United States
Steven P Winesett, Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, Gainesville, FL 32610, United States
Wen-Han Chang, Department of Medicine, Endocrine Research Unit, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, CA 94121, United States
Sam Xianjun Cheng, Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Florida Shands Children’s Hospital, Gainesville, FL 32608, United States
Author contributions: Cheng SX conceptualized the study; Tang LQ, Fraebel J, and Cheng SX designed the study and analyzed the data; Tang LQ, Fraebel J, Jin S, and Winesett SP performed the experiments; Tang LQ and Cheng SX drafted the manuscript; Harrell J and Chang WH edited the manuscript; Cheng SX finalized the manuscript; and all authors approved the final version of the article.
Supported by Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, No. 1K08HD079674-01 and 1R41HD092133-01; National Institute of Allergy and Infectious Diseases, No. 1A21AI169282; and VA Research Career Scientist Award, No. 1IK6BX004835.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Florida (IACUC Protocol No: 201807567).
Conflict-of-interest statement: All the authors report having no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Sam Xianjun Cheng, MD, MSc, PhD, Associate Professor, Attending Doctor, Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Florida Shands Children’s Hospital, 1600 SW Archer Road, HD 600, Gainesville, FL 32608, United States. sam.cheng@ufl.edu
Received: October 2, 2023
Peer-review started: October 2, 2023
First decision: November 12, 2023
Revised: December 1, 2023
Accepted: January 2, 2024
Article in press: January 2, 2024
Published online: January 21, 2024
ARTICLE HIGHLIGHTS
Research background
Treatment of diarrhea such as cholera remains a global challenge. Cholera toxin (CTX) produces diarrhea through direct epithelial action and indirectly by activating the enteric nervous system. Calcium-sensing receptor (CaSR) is present in both tissues and, when activated, inhibits both actions. The latter has been well documented in vitro but not in vivo. Thus, the present study tested whether activating intestinal epithelial or neuronal CaSR inhibits diarrhea in vivo.
Research motivation
Acute infectious diarrhea remains among the top causes of morbidity and death in the world. Most of the morbidity and mortality is not due to infection but dehydration. Accordingly, how to effectively reduce the fluid loss from acute diarrhea offers a major opportunity for improving global health.
Research objectives
The objective of the present study was to determine whether CaSR agonists ameliorate secretory diarrhea evoked by CTX in wild type mice, epithelial-specific CaSR knockout mice (villinCre/Casrflox/flox) and neuronal-specific CaSR knockout mice (nestinCre/Casrflox/flox).
Research methods
To realize the objectives, CTX was administered orally to C57BL/6 mice to induce secretory diarrhea while calcium and calcimimetic R568 were employed to activate CaSR. To maximize their local intestinal actions, calcium was administered luminally via oral rehydration solution (ORS) whereas R568 was applied serosally using an intraperitoneal route. To verify that their actions resulted from the intestinal epithelium and enteric neurons, effects were also examined on two Cre-lox intestine-specific CaSR knockouts. Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl- or clinically by assessing stool consistency and weight loss.
Research results
CTX induced secretory diarrhea, as evidenced by increases in fecal Cl-, stool consistency, and weight loss following CTX exposure. Calcium and R568 each ameliorated CTX-induced secretory diarrhea in wild type mice but not in either knockout mouse model.
Research conclusions
Based on the present study, we propose that activating intestinal epithelial or neuronal CaSR can inhibit secretory diarrhea in vivo. Adding calcium to ORS or using calcimimetic to activate intestinal CaSR might represent a novel approach for treating secretory diarrheal diseases in humans.
Research perspectives
Future research should be directed to conduct randomized clinical trials utilizing calcium or calcimimetics to treat cholera and other secretory diarrheal diseases in humans.
