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©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
BACKGROUND
Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system. Calcium-sensing receptor (CaSR) inhibits both actions. The latter has been well documented in vitro but not in vivo. The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo.
AIM
To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin (CTX) in mice.
METHODS
CTX was given orally to C57BL/6 mice to induce diarrhea. Calcium and calcimimetic R568 were used 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 intestine, effects were also examined on 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.
RESULTS
CTX induced secretory diarrhea, as evidenced by increases in fecal Cl-, stool consistency, and weight loss following CTX exposure, but did not alter CaSR, neither in content nor in function. Accordingly, calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines. Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts (villinCre/Casrflox/flox) and neuronal CaSR knockouts (nestinCre/Casrflox/flox).
CONCLUSION
Treatment of acute secretory diarrheas remains a global challenge. Despite advances in diarrhea research, few have been made in the realm of diarrhea therapeutics. ORS therapy has remained the standard of care, although it does not halt the losses of intestinal fluid and ions caused by pathogens. There is no cost-effective therapeutic for diarrhea. This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secretory diarrheal diseases.
Core Tip: Treatment of diarrhea remains a global challenge. Enterotoxins induce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system. Using in vitro models in isolated tissues, we have previously shown that calcium-sensing receptor (CaSR) inhibits both actions. In the present study, we use a mouse model of secretory diarrhea in conjunction with a tissue-specific knockout approach and demonstrate that calcium or calcimimetic via CaSR ameliorates cholera toxin-induced secretory diarrhea in vivo. This study suggests that adding calcium to oral rehydration solution or using calcimimetic to activate intestinal CaSR might represent a new approach for treating secretory diarrheal diseases.
