title: Secretory diarrhoea: mechanisms and emerging therapies.
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.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Thiagarajah
authors.affiliation: Departments of Physiology and Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Ross 925, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Donowitz
authors.affiliation: Departments of Medicine and Physiology, 1246 Health Sciences East Tower, University of California, 500 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000930:Antidiarrheals / Q000627:therapeutic use; D001424:Bacterial Infections; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors; D003967:Diarrhea / Q000209:etiology / Q000628:therapy*; D005759:Gastroenteritis / Q000150:complications; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D008246:Lysophospholipids / Q000627:therapeutic use; D058990:Molecular Targeted Therapy / Q000379:methods; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D019936:Probiotics / Q000627:therapeutic use; D044169:Receptors, Calcium-Sensing / Q000819:agonists; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000819:agonists; D064506:Solute Carrier Family 12, Member 2 / Q000187:drug effects; D014777:Virus Diseases
chemical_list: D000930:Antidiarrheals; C095550:CASR protein, human; C492109:CLCA1 protein, human; D018118:Chloride Channels; D008246:Lysophospholipids; D026902:Potassium Channel Blockers; D044169:Receptors, Calcium-Sensing; C578877:SLC12A2 protein, human; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D064506:Solute Carrier Family 12, Member 2; D019005:Cystic Fibrosis Transmembrane Conductance Regulator