Calcium-sensing receptor: A new target for therapy of diarrhea

Table 1 Current antidiarrheal therapies and their mechanisms of action

Therapies	Mechanisms of action	Comments	Ref.
Proabsorptive
ORS/RS-ORS	↑glucose/SCFA absorption	Limited efficacy to reduce diarrhea	[98-100]
Antisecretory
Crofelemer	↓CFTR and CaCC→↓ secretion	Less efficacious as anticipated	[15]
Cholestyramine resin	↓bile salt in lumen→↓secretion	Concerns for vitamin malabsorption	[101]
Bismuth subsalicylate	↓PG synthesis→↓secretion	Safety concerns in children (Reye syndrome)	[102,103]
Antimotility/ENS modulatory
Loperamide/Diphenoxylate	↑μ opioid receptor →↓motility	Safety concerns in children (ileus)	[13,14]
Hyoscyamine/Dicyclomine	↓Ach action→↓muscle contraction	Safety concerns in children (seizure)
Alosetron	↓5-HT3R →↓motility and secretion	Safety concerns in children (ischemic colitis)	[104]
Racecadotril	↑encephalin→↓secretion	Not widely available	[105,106]
Clonidine	↑α2 adrenoceptor→↑absorption	No efficacy and safety study in children
Anti-inflammatory
TEN	Unknown mechanism of action	Slow action	[107]
Corticosteroids	Immunosuppression (↓PGs, ↑IL-10)	Concerns for adverse effects
Anti-TNFα	↓blood and tissue TNFα	Limited by expenses and adverse effects

ACh: Acetylcholine; CaCC: Ca²⁺ activated chloride channels; CFTR: Cystic fibrosis transmembrane conductance regulator; ORS: Oral rehydration solution; PG: Prostaglandins; RS-ORS: Resistant starch-based oral rehydration solution; SCFA: Short-chain fatty acids; VIP: Vasoactive intestinal polypeptide; TEN: Total enteral nutrition.

Table 2 Clinical evidence for dietary calcium-sensing receptor activators as antidiarrheals in animals and humans¹

CaSR agonists	Antidiarrheal efficacy	Ref.
Calcium	↑intestinal resistance, ↓bacterial colonization and translocation to Salmonella infection in rats	[81-84]
	↓intestinal permeability in rats	[108]
	↓diarrhea severity in Salmonella enterocolitis in rats	[82]
	↓diarrhea onset, ↓severity, ↑ recovery in DSS colitis in rodents	[73,74]
	↓gut permeability and diarrhea in immune-mediated colitis in HLA-B27 transgenic rats	[85]
	↓induced intestinal inflammation in mice	[35,72]
	↓stool volume and duration of diarrheas by viruses or parasites in humans (children)	[36]
	↓stool weight and duration of diarrhea by ETEC in humans (adults)	[87]
	↓diarrhea frequency in patients with calcitonin-secreting medullary thyroid cancer	[88]
Calcium and magnesium	↓intestinal motility and diarrhea symptoms of morphine withdrawal in mice	[62]
Polyamines	↓intestinal motility in mice	[63,64]
	↓gastrointestinal transit and diarrhea of irritable bowel syndrome in mice	[65-67]
	↓DSS colitis in rodents	[73]
Tryptophan	↓intestinal inflammation in mice	[109]
	↓DSS colitis in rodents	[73]

¹The naturally occurring calcium-sensing receptor (CaSR) activators described are all friendly minerals or nutrients and generally safe. Except for chemically synthesized polyamines, no adverse events other than mild GI discomforts (e.g., constipation[36,88], flatulence[88] and bloating[88]) were reported. DSS: Dextran sodium sulfate; ETEC: Enterotoxigenic Escherichia coli.