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  • Review Article
  • Published:

Secretory diarrhoea: mechanisms and emerging therapies

Nature Reviews Gastroenterology & Hepatology volume 12, pages 446–457 (2015)Cite this article

Subjects

Key Points

  • Diarrhoeal disease remains a major global health burden

  • Secretory diarrhoea results from abnormal fluid and electrolyte absorption and/or secretion

  • Ion channels and transporters such as the cystic fibrosis transmembrane conductance regulator and sodium/hydrogen exchanger 3 are targets for antisecretory antidiarrhoeal drugs

  • New compounds targeting intestinal transporters are in development for antidiarrhoeal therapy, including small molecules, natural compounds and existing drugs

  • Antidiarrhoeal therapies might be useful as stand-alone therapy or together with oral rehydration solutions

Abstract

Diarrhoeal disease remains a major health burden worldwide. Secretory diarrhoeas are caused by certain bacterial and viral infections, inflammatory processes, drugs and genetic disorders. Fluid secretion across the intestinal epithelium in secretory diarrhoeas involves multiple ion and solute transporters, as well as activation of cyclic nucleotide and Ca2+ signalling pathways. In many secretory diarrhoeas, activation of Cl− channels in the apical membrane of enterocytes, including the cystic fibrosis transmembrane conductance regulator and Ca2+-activated Cl− channels, increases fluid secretion, while inhibition of Na+ transport reduces fluid absorption. Current treatment of diarrhoea includes replacement of fluid and electrolyte losses using oral rehydration solutions, and drugs targeting intestinal motility or fluid secretion. Therapeutics in the development pipeline target intestinal ion channels and transporters, regulatory proteins and cell surface receptors. This Review describes pathogenic mechanisms of secretory diarrhoea, current and emerging therapeutics, and the challenges in developing antidiarrhoeal therapeutics.

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Figure 1: Mechanisms of intestinal fluid absorption and secretion in secretory diarrhoeas.
Figure 2: Potential therapies for secretory diarrhoeas at various stages of development and their molecular targets.
Figure 3: Chemical structures of CFTR and CaCC inhibitors for secretory diarrhoeas.

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Acknowledgements

J.R.T. has received a grant from the National Institute of Child Health and Human Development (HD00085), M.D. has received grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK089502, DK061765, DK026532, DK072084, DK099803) and a Gates Foundation Grand Challenges award, and A.S.V. has received grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK072517, DK035124, DK101373), the National Eye Institute (EY13574) and the National Institute of Biomedical Imaging and Bioengineering (EB000415).

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Authors and Affiliations

  1. Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, 02115, MA, USA

    Jay R. Thiagarajah

  2. Departments of Physiology and Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Ross 925, 720 Rutland Avenue, Baltimore, 21205, MD, USA

    Mark Donowitz

  3. Departments of Medicine and Physiology, 1246 Health Sciences East Tower, University of California, 500 Parnassus Avenue, San Francisco, 94143, CA, USA

    Alan S. Verkman

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  1. Jay R. Thiagarajah
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The authors contributed equally to all aspects in the production of this article.

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Correspondence to Alan S. Verkman.

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Competing interests

A.S.V. is a named inventor on several CFTR and CaCC inhibitor patents owned by the University of California, San Francisco. J.R.T. and M.D. declare no competing interests.

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Thiagarajah, J., Donowitz, M. & Verkman, A. Secretory diarrhoea: mechanisms and emerging therapies. Nat Rev Gastroenterol Hepatol 12, 446–457 (2015). https://doi.org/10.1038/nrgastro.2015.111

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