diarrhea , caused by acute infectious or chronic diseases , may be considered as an imbalance between the approximately 7 l of fluids ingested or secreted into the gastrointestinal tract each day , and the reabsorption of almost an equivalent volume . infectious organisms such as escherichia coli or vibrio cholerae produce toxins that stimulate normal secretory pathways in the intestine , resulting in potentially life - threatening secretory diarrhea and dehydration . the gold standard of treatment is rehydration with glucose - electrolyte solution but , regrettably , there is still a high mortality from these conditions in developing countries ; hence , more effective treatments are needed . for example , v. cholerae infection induces enteroendocrine cells to secrete 5-hydroxytryptamine ( 5-ht or serotonin ) , which stimulates secretion of water and electrolytes from small intestinal epithelial cells or enterocytes . it has been shown that secretions from goblet cells include the peptides guanylin   and uroguanylin , which have similar amino acid sequences to the heat - stable enterotoxin of e. coli . these enterotoxins and endogenous peptides bind to guanylate cyclase c ( gc - c ) and stimulate the production of increased levels of intracellular cyclic guanosine monophosphate ( cgmp ) . increased levels of cgmp ultimately activate the secretion of chloride ions through the cystic fibrosis transmembrane conductance regulator ( cftr ) . when chloride reaches the intestinal lumen , its osmotic force pulls water out of the interstitial fluid through the spaces between enterocytes and this ultimately leads to dehydration . it has been demonstrated that enterotoxigenic e. coli requires the gc - c receptor to induce intestinal secretion . in addition to its presence in goblet cells , guanylin is also located in enteroendocrine cells , as well as in neuroendocrine tumors such as carcinoids . in fact , enhanced local secretion of guanylin may contribute to secretory diarrhea in these patients . the relationship of enterocytes , goblet cells and enteroendocrine cells in the lining of the intestine and the role of secretomotor mechanisms has been reviewed previously . although some of the signaling pathways involved in abnormal intestinal secretion have been identified , targeted approaches to reverse secretion are needed to complement rehydration therapy . this article highlights a recent study that identifies the molecular genetic basis of a familial diarrhea ( fd ) , illustrating a mechanism that can be pharmacologically targeted to enhance secretion in constipation or to inhibit secretion in diarrheal diseases . fiskerstrand et al .   identified a norwegian family with a rare , early onset form of chronic or intermittent fd . their investigation started with careful clinical observations of an 88-year - old admitted to hospital for acute diarrhea and dehydration . it was noted that affected members of the family started to develop symptoms in infancy , had chronic , relatively mild diarrhea , and the symptoms tended to subside by middle age in some members of the family . the fd was a dominantly inherited , fully penetrant disease in 32 ( 18 male and 14 female ) members of the family . fourteen unaffected members of the family were also evaluated . in a series of elegant studies , the authors used whole genome linkage analysis based on arrays with snps to identify a candidate region on chromosome 12 , and then sequenced gucy2c , encoding gc - c . linkage analysis was used to determine the candidate region for the mutation in samples from 11 affected members and 14 unaffected members . this analysis revealed only one shared region in the affected members , located on the short arm of chromosome 12 ( 12p ) with a maximum lod ( logarithm ( base 10 ) of odds ) score of 5.1 . a haplotype spanning approximately 2.9 megabases showed complete segregation with the disease , and the region contained 28 putative protein coding genes , including gucy2c . exome sequencing of the entire candidate region from three affected family members excluded mutations in genes other than gucy2c as possible causes of or contributors to susceptibility to the disease . in addition , fiskerstrand et al .   conducted functional studies of mutant gc - c in hek293 t cells . exposure of the mutant receptor to its ligands ( heat - stable enterotoxin , uroguanylin and guanylin ) resulted in markedly increased ( up to eightfold ) production of cgmp . these functional assays demonstrate that the mutation is capable of inducing the intracellular production of the second messenger cgmp , which results in intestinal secretion through cftr . the authors appropriately describe this familial variation as a form of ' genetic knock - in ' of the mechanism that is stimulated by enterotoxigenic e. coli , and this represents an intriguing confluence of the effects of bugs and genes . the fiskerstrand et al . study , which identified the causative gucy2c mutation , has important implications from mechanistic , diagnostic and therapeutic perspectives . first , identification of this gene mutation in fd provides evidence that the pathway is an important mechanism of chronic diarrhea in addition to infectious enterotoxic diarrhea . second , mutation in gucy2c should be considered in the differential diagnosis of chronic diarrhea , especially when there is a positive history of fd . third , understanding the pathway provides a target for the development of a new drug class to treat constipation by inducing intestinal secretion . since analogs of guanylin and uroguanylin ( linaclotide and plecanatide ) already exist , clinical translation of the science to develop secretagogue drugs for relief of constipation and associated symptoms ( bloating and abdominal pain ) had preceded the intriguing molecular genetic discovery of fiskerstrand et al . . targeting the receptor represents an alternative therapeutic approach , in lieu of targeting the gene itself . however , there are some loose ends in the story . the susceptibility of the norwegian family to inflammatory bowel disease ( ibd ) , small bowel obstruction and esophagitis in the absence of hiatal hernia can not be easily attributed to the effects of the gucy2c mutation on gc - c , based on current knowledge . in addition , there are no reports of any association of the gucy2c mutation and ibd , even with genome - wide association studies . nevertheless , the gc - c agonists plecanatide and sp-333 ( analogs of uroguanylin ) have been shown to ameliorate inflammation in murine colitis models via downregulation of certain pro - inflammatory cytokines , such as il-6 , il-17 and il-23 , and they may also have therapeutic potential in ibd and , possibly , carcinogenesis . this remarkable story may eventually have a happy ending for patients with this specific fd . the report should stimulate the development of blockers of the gc - c and cftr intestinal secretory pathways , and this will have potential for wide application to life - threatening infectious diarrheas , in addition to the chronic , mild , non - fatal diarrhea afflicting this family ; these diarrheas could then be specifically targeted with personalized or precision medicine . cgmp : cyclic guanosine monophosphate ; cftr : cystic fibrosis transmembrane conductance regulator ; fd : familial diarrhea ; gc - c : guanylate cyclase c ; ibd : inflammatory bowel disease ; il : interleukin ; snp : single - nucleotide polymorphism .