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Review
. 2015 Aug;12(8):446-57.
doi: 10.1038/nrgastro.2015.111. Epub 2015 Jun 30.

Secretory diarrhoea: mechanisms and emerging therapies

Jay R Thiagarajah  1 , Mark Donowitz  2 , Alan S Verkman  3
Affiliations
Review

Secretory diarrhoea: mechanisms and emerging therapies

Jay R Thiagarajah et al. Nat Rev Gastroenterol Hepatol. 2015 Aug.

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 Ca(2+) signalling pathways. In many secretory diarrhoeas, activation of Cl(-) channels in the apical membrane of enterocytes, including the cystic fibrosis transmembrane conductance regulator and Ca(2+)-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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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Mechanisms of intestinal fluid absorption and secretion in secretory diarrhoeas. a | Luminal and basolateral membrane transporters and intracellular signalling mechanisms are involved in intestinal fluid absorption and secretion by enterocytes. b | Some bacteria secrete enterotoxins that increase intracellular cyclic nucleotides, resulting in Cl− secretion and inhibition of NHE3 and Na+ absorption. Invasive bacteria cause a tissue inflammatory response involving recruitment of immune cells and release of cytokines, resulting in intracellular Ca2+ signalling. c | The rotaviral protein NSP4 causes elevation of cytoplasmic Ca2+ concentration by binding to integrin-α1β2, galanin and/or by activation of enteric nerves. Rotaviral NSP4 also inhibits NHE3 and SLC5A1. d | Congenital diarrhoeas result from rare inherited genetic mutations in several intestinal proteins. e | Activation of inflammatory signalling pathways such as NF-κB result in Ca2+ or cyclic nucleotide signalling and stimulation of Cl− secretion or inhibition of Na+ absorption. The release of inflammatory mediators such as TNF and IL-6 by activated T cells and neutrophils can also stimulate Cl− secretion. Abbreviations: CaCC, calcium-activated chloride channel; CaSR, calcium-sensing receptor; CFTR, cystic fibrosis transmembrane conductance regulator; CT, cholera toxin; DRA, down regulated in adenoma Cl−/HCO3− exchanger; EC, enterochromaffin; ENaC, epithelial Na+ channel; ENS, enteric nervous system; EPCAM, epithelial cell adhesion molecule; Gal, galanin; GALR1, galanin receptor 1; GUCY2C, guanylate cyclase C (heat stable enterotoxin receptor); 5-HT, 5-hydroxytryptamine; MYO5B, unconventional myosin-5b; NHE, sodium/hydrogen exchanger; NKCC, Na/K/Cl symporter; NSP4, nonstructural protein 4; RABs, Ras-related proteins; SCFA, short-chain fatty acid; SLC5A1, sodium/glucose cotransporter; STa, heat-stable toxin; TLR, toll-like receptor; VIP, vasoactive intestinal peptide.
Figure 2
Figure 2
Potential therapies for secretory diarrhoeas at various stages of development and their molecular targets. Various molecular targets including intestinal ion channels and transporters, regulatory proteins and cell surface receptors are found on epithelial cells lining the intestine, enteric nerves and enterocytes. Novel therapeutics targeting these molecules are in the development pipeline. Abbreviations: AF, antisecretory factor; BPO, benzopyrimido-pyrrolo-oxazinedione; CaCC, calcium-activated chloride channel; CaSR, calcium-sensing receptor; CFTR, cystic fibrosis transmembrane conductance regulator; EC, enterochromaffin; LPA, lysophosphatidic acid; LPAR2, LPA receptor 2; NHE, sodium/hydrogen exchanger; NKCC, Na/K/Cl symporter; PPQ, pyrimido-pyrrolo-quinoxalinedione.
Figure 3
Figure 3
Chemical structures of CFTR and CaCC inhibitors for secretory diarrhoeas. Abbreviations: CaCC, calcium-activated chloride channel; CFTR, cystic fibrosis transmembrane conductance regulator; PPQ, pyrimido-pyrrolo-quinoxalinedione.
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