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 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.

Chemotherapy-Induced Constipation and Diarrhea: Pathophysiology, Current and Emerging Treatments

“…Excessive fluid secretion is driven by active chloride secretion, followed by secondary movement of water and sodium into the intestine. Although there is a lack of selective potent inhibitors of voltage gated chloride channels, inhibition of calcium-activated chloride channels throughout the intestines successfully reduced secretion of chloride into the intestinal lumen (Thiagarajah and Verkman, 2013; Thiagarajah et al, 2015). In a mouse model of rotavirus-induced severe secretory diarrhea, inhibition of calcium-activated chloride channels with a red wine extract reduced intestinal fluid secretion, diminishing the symptoms of diarrhea (Ko et al, 2014).…”

A gastrointestinal anti-infectious biotherapeutic agent: the heat-treated Lactobacillus LB

“…A variety of luminally acting agents are used to treat diarrhoea by altering intestinal and/or colonic motility, or fluid secretion, but some of which have adverse effects [Menees et al 2012]. Innovative therapeutics in the pipeline target intestinal ion channels and transporters, cell surface receptors, and cell signaling regulatory proteins [Thiagarajah et al 2015]. Recommendations have been given for the use of a limited number of probiotic strains as an adjunct to rehydration therapy for the treatment of acute gastroenteritis in previously healthy infants and children [Szajewska et al 2014a].…”

Human mini-guts: new insights into intestinal physiology and host–pathogen interactions

“…Although the use of oral rehydration solution has saved many lives, no effective antidiarrhoeal drug exists 12,13 . Antibiotic use against enteric infections has proven, at best, to be useless, or at worst, to enhance virulence, making the pathogen more harmful to the host.…”

“…Antibiotic use against enteric infections has proven, at best, to be useless, or at worst, to enhance virulence, making the pathogen more harmful to the host. Diarrhoea occurs due to the imbalance between electrolyte absorption and secretion, resulting in a substantial increase in water secretion 13 . To develop effective antidiarrhoeal drugs or a general antisecretory agent, the physiology of intestinal absorption and secretion and the pathophysiological changes from specific enteric pathogens and their virulent factors or toxins must first be characterized.…”