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• W2791102487 abstract "Every year, enteric infections and associated diarrhea kill millions of people. The situation is compounded by increases in the number of enteric pathogens that are acquiring resistance to antibiotics, as well as (hitherto) a relative paucity of information on host molecular targets that may contribute to diarrhea. Many forms of diarrheal disease depend on the dysregulation of intestinal ion transporters, and an associated imbalance between secretory and absorptive functions of the intestinal epithelium. A number of major transporters have been implicated in the pathogenesis of diarrheal diseases and thus an understanding of their expression, localization, and regulation after infection with various bacteria, viruses, and protozoa likely will prove critical in designing new therapies. This article surveys our understanding of transporters that are modulated by specific pathogens and the mechanism(s) involved, thereby illuminating targets that might be exploited for new therapeutic approaches. Every year, enteric infections and associated diarrhea kill millions of people. The situation is compounded by increases in the number of enteric pathogens that are acquiring resistance to antibiotics, as well as (hitherto) a relative paucity of information on host molecular targets that may contribute to diarrhea. Many forms of diarrheal disease depend on the dysregulation of intestinal ion transporters, and an associated imbalance between secretory and absorptive functions of the intestinal epithelium. A number of major transporters have been implicated in the pathogenesis of diarrheal diseases and thus an understanding of their expression, localization, and regulation after infection with various bacteria, viruses, and protozoa likely will prove critical in designing new therapies. This article surveys our understanding of transporters that are modulated by specific pathogens and the mechanism(s) involved, thereby illuminating targets that might be exploited for new therapeutic approaches. SummaryIntestinal ion transporters ensure fluid and electrolyte homeostasis. Several are modulated during enteric infections, potentially contributing to diarrhea. This review surveys changes in the abundance and/or regulation of transporters that occur in these conditions, pointing to possible novel targets for therapy. Intestinal ion transporters ensure fluid and electrolyte homeostasis. Several are modulated during enteric infections, potentially contributing to diarrhea. This review surveys changes in the abundance and/or regulation of transporters that occur in these conditions, pointing to possible novel targets for therapy. The intestinal epithelium is responsible for absorbing nutrients, such as sugars and peptides, as well as electrolytes and water.1Barrett K.E. Keely S.J. Integrative physiology and pathophysiology of intestinal electrolyte transport.in: 4th ed. Physiology of the Gastrointestinal Tract. Vol. 1 and 2. Academic Press, San Diego2006: 1931-1951Google Scholar Most water absorption occurs in the small intestine, with residual water absorption occurring in the colon. Absorptive processes are predominant in villi whereas secretory processes are predominant in the crypts. To facilitate solute and water absorption, the intestines rely on transporters that permit the movement of solutes through the cell membrane. Water then follows passively via both paracellular and transcellular routes. The transporters that mediate solute uptake or secretion are expressed differentially throughout the intestines, and have a wide range of substrates. Under normal conditions, the various transporters work together to provide an optimum balance between absorption and secretion, with absorption predominating to reclaim the 8–9 L of fluid that are used daily during digestion and absorption of meals in human beings. However, during pathologic states, such as infections with diarrheal pathogens, this balance is disrupted, with either increased secretion, loss of absorption, or both.1Barrett K.E. Keely S.J. Integrative physiology and pathophysiology of intestinal electrolyte transport.in: 4th ed. Physiology of the Gastrointestinal Tract. Vol. 1 and 2. Academic Press, San Diego2006: 1931-1951Google Scholar Although the gut has a substantial reserve capacity for absorption, ultimately this imbalance can cause diarrhea. Diarrhea is an almost ubiquitous sign of enteric infection, leading to the question of what benefit it provides for the microbe or the host. For the microbe, diarrhea presumably facilitates the colonization of additional hosts, particularly in settings in which sanitation is compromised. For the host, the diarrheal response, although potentially harmful in terms of dehydration, also may represent a primitive host defense mechanism, reducing microbial colonization and perhaps restricting cellular entry by invasive species.2Tsai P.Y. Zhang B. He W.Q. Zha J.M. Odenwald M.A. Singh G. Tamura A. Shen L. Sailer A. Yeruva S. Kuo W.T. Fu Y.X. Tsukita S. Turner J.R. IL-22 upregulates epithelial claudin-2 to drive diarrhea and enteric pathogen clearance.Cell Host Microbe. 2017; 21: 671-681 e4Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Because of its risks, diarrhea often calls for treatment in serious cases and/or particularly vulnerable hosts. However, most currently available antidiarrheal agents may have side effects, target motility rather than transport processes themselves, and often are relatively ineffective, particularly in the setting of life-threatening infectious diarrhea. There is therefore a need for new therapies, for which it is important to understand the underlying mechanism(s) of diarrhea. The transport of ions across the plasma membrane is crucial for cellular homeostasis. There are 3 major mediators of ion transport: (1) transporters (both cotransporters and exchangers), (2) ion channels, and (3) pumps. Transporters are transmembrane proteins that mediate the transport of ions and sometimes other solutes, such as glucose or amino acids. Some also may transport drugs or metabolites. Cotransporters bind to their substrates on one side of the membrane, causing a conformational change that releases the substrates on the other side of the membrane. Exchangers transfer a solute into the cell in exchange for one that is secreted out of the cell. In either case, the activity of transporters is driven by the prevailing combined electrochemical gradients for the solutes in question. Ion channels are pore-forming transmembrane proteins that open as gates in response to a variety of cellular signals, allowing high-capacity solute passage. The direction of ion movement depends on the electrochemical gradient for that solute across the membrane. Pumps expend cellular energy, in the form of adenosine triphosphate (ATP) hydrolysis, and allow for uphill transport of one or more of their substrates. An example is the Na+,K+ adenosine triphosphatase (ATPase), which exports 3 sodium ions for every 2 potassium ions taken up into the cell, maintaining a low intracellular sodium concentration and sustaining the negative membrane potential. Intestinal epithelial cells control the secretion and absorption of electrolytes through various arrangements of the ion transporters described earlier, which function together to maintain fluid balance; this fluid balance is impaired during diarrhea.1Barrett K.E. Keely S.J. Integrative physiology and pathophysiology of intestinal electrolyte transport.in: 4th ed. Physiology of the Gastrointestinal Tract. Vol. 1 and 2. Academic Press, San Diego2006: 1931-1951Google Scholar Impairments in transporter function can occur during infections and in inflammatory diseases, or may be caused by genetic mutations. Although the intestines express a large array of distinct transport proteins, only a subset have been examined for their possible contributions to infectious diarrhea (Table 1). Thus, we focus on those transporters here (Figures 1 and 2). They include the following.1.Sodium/hydrogen exchangers (NHEs): NHE3 (solute carrier [SLC]9A3) (and to a lesser extent, NHE2 [SLC9A2]) are responsible for electroneutral NaCl absorption in the small intestine and colon, by functioning in partnership with a chloride/bicarbonate exchanger.3Kato A. Romero M.F. Regulation of electroneutral NaCl absorption by the small intestine.Ann Rev Physiol. 2011; 73: 261-281Crossref PubMed Scopus (0) Google Scholar2.Sodium/glucose cotransporter (SGLT1, SLC5A1): this transporter is responsible for the absorption of both glucose and sodium ions postprandially.4Wright E.M. Loo D.D. Hirayama B.A. Biology of human sodium glucose transporters.Physiol Rev. 2011; 91: 733-794Crossref PubMed Scopus (441) Google Scholar3.Down-regulated in adenoma (DRA [SLC26A3]): this transporter is a Cl-/HCO3- exchanger, and is responsible for Cl- absorption (and also transports SO42-). DRA functions in concert with NHEs in the electroneutral absorption of NaCl.5Schweinfest C.W. Spyropoulos D.D. Henderson K.W. Kim J.H. Chapman J.M. Barone S. Worrell R.T. Wang Z. Soleimani M. slc26a3 (dra)-deficient mice display chloride-losing diarrhea, enhanced colonic proliferation, and distinct up-regulation of ion transporters in the colon.J Biol Chem. 2006; 281: 37962-37971Crossref PubMed Scopus (111) Google Scholar4.Epithelial sodium channel (ENaC): this channel mediates electrogenic Na+ absorption and is localized to the distal colon.6Kunzelmann K. Mall M. Electrolyte transport in the mammalian colon: mechanisms and implications for disease.Physiol Rev. 2002; 82: 245-289Crossref PubMed Scopus (521) Google Scholar5.Ca2+-activated chloride channels7Pauli B.U. Abdel-Ghany M. Cheng H.C. Gruber A.D. Archibald H.A. Elble R.C. Molecular characteristics and functional diversity of CLCA family members.Clin Exp Pharmacol Physiol. 2000; 27: 901-905Crossref PubMed Scopus (76) Google Scholar: these channels mediate the efflux of chloride ions and are activated by increases in intracellular Ca2+ concentration. Their precise molecular identity in the gut still is controversial, although one candidate is chloride channel accessory 1 (CLCA1).8Roussa E. Wittschen P. Wolff N.A. Torchalski B. Gruber A.D. Thevenod F. Cellular distribution and subcellular localization of mCLCA1/2 in murine gastrointestinal epithelia.J Histochem Cytochem. 2010; 58: 653-668Crossref PubMed Scopus (0) Google Scholar Other studies have implicated transmembrane protein 16A9Ousingsawat J. Mirza M. Tian Y. Roussa E. Schreiber R. Cook D.I. Kunzelman K. Rotavirus toxin NSP4 induces diarrhea by activation of TMEM16A and inhibition of Na+ absorption.Pflugers Arch. 2011; 461: 579-589Crossref PubMed Scopus (45) Google Scholar, 10Ousingsawat J. Martins J.R. Schreiber R. Rock J.R. Harfe B.D. Kunzelmann K. Loss of TMEM16A causes a defect in epithelial Ca2+-dependent chloride transport.J Biol Chem. 2009; 284: 28698-28703Crossref PubMed Scopus (0) Google Scholar (anoctamin 1), although the precise relative roles, if any, for both channels is still under investigation.6.Sodium/potassium/chloride cotransporter 1 (NKCC1 [SLC12A2]): this transporter mediates the uptake of Na+, K+, and 2Cl- ions across the basolateral membrane, and thereby supplies chloride for secretion.11D'Andrea L. Lytle C. Matthews J.B. Hofman P. Forbush 3rd, B. Madara J.L. Na:K:2Cl cotransporter (NKCC) of intestinal epithelial cells. Surface expression in response to cAMP.J Biol Chem. 1996; 271: 28969-28976Crossref PubMed Scopus (0) Google Scholar7.Cystic fibrosis transmembrane conductance regulator (CFTR): this is an adenosine 3′,5′-cyclic monophosphate (cAMP)- and guanosine 3′,5′-cyclic monophosphate–regulated chloride channel present primarily at the apical surfaces of epithelial cells, and mediates chloride efflux as part of the chloride secretory mechanism.1Barrett K.E. Keely S.J. Integrative physiology and pathophysiology of intestinal electrolyte transport.in: 4th ed. Physiology of the Gastrointestinal Tract. Vol. 1 and 2. Academic Press, San Diego2006: 1931-1951Google Scholar It also can transport bicarbonate.8.Na+,K+ ATPase: This establishes and maintains a low intracellular Na+ concentration that is a driving force for several different transport mechanisms, both secretory and absorptive.12Robinson J.D. Flashner M.S. The (Na+ + K+)-activated ATPase. Enzymatic and transport properties.Biochim Biophys Acta. 1979; 549: 145-176Crossref PubMed Scopus (0) Google ScholarTable 1Major Ion Transporters Targeted by Enteric InfectionsTransport functionTransporterLocationExamples of regulation by enteric pathogensAbsorptionNHEsApical membrane of small intestinal villus and surface epithelial cells in colonFunction of NHE2 and NHE3 decreased in response to cholera toxin29Viswanathan V.K. Hodges K. Hecht G. Enteric infection meets intestinal function: how bacterial pathogens cause diarrhoea.Nat Rev Microbiol. 2009; 7: 110-119Crossref PubMed Scopus (87) Google Scholar, 50Subramanya S.B. Rajendran V.M. Srinivasan P. Nanda Kumar N.S. Ramakrishna B.S. Binder H.J. Differential regulation of cholera toxin-inhibited Na-H exchange isoforms by butyrate in rat ileum.Am J Physiol Gastrointest Liver Physiol. 2007; 293: G857-G863Crossref PubMed Scopus (0) Google ScholarEHEC toxin Stx2 shown to prevent trafficking of NHE2 to the apical membrane40Laiko M. Murtazina R. Malyukova I. Zhu C. Boedeker E.C. Gutsal O. O'Malley R. Cole R.N. Tarr P.I. Murray K.F. Kane A. Donowitz M. Kovbasnjuk O. Shiga toxin 1 interaction with enterocytes causes apical protein mistargeting through the depletion of intracellular galectin-3.Exp Cell Res. 2010; 316: 657-666Crossref PubMed Scopus (0) Google ScholarRotavirus decreases NHE334Hodges K. Gill R. Infectious diarrhea: cellular and molecular mechanisms.Gut Microbes. 2010; 1: 4-21Crossref PubMed Scopus (0) Google Scholar, 61Halaihel N. Lievin V. Ball J.M. Estes M.K. Alvarado F. Vasseur M. Direct inhibitory effect of rotavirus NSP4(114-135) peptide on the Na+-D-glucose symporter of rabbit intestinal brush border membrane.J Virol. 2000; 74: 9464-9470Crossref PubMed Scopus (0) Google ScholarEPEC increases NHE2 activity24Gawenis L.R. Stien X. Shull G.E. Schultheis P.J. Woo A.L. Walker N.M. Clarke L.L. Intestinal NaCl transport in NHE2 and NHE3 knockout mice.Am J Physiol Gastrointest Liver Physiol. 2002; 282: G776-G784Crossref PubMed Google Scholar, 25Hecht G. Hodges K. Gill R.K. Kear F. Tyagi S. Malakooti J. Ramaswamy K. Dudeja P.K. Differential regulation of Na+/H+ exchange isoform activities by enteropathogenic E. coli in human intestinal epithelial cells.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G370-G378Crossref PubMed Scopus (0) Google ScholarC difficile TcdB decreases NHE3 activity57Hayashi H. Szaszi K. Coady-Osberg N. Furuya W. Bretscher A.P. Orlowski J. Grinstein S. Inhibition and redistribution of NHE3, the apical Na+/H+ exchanger, by Clostridium difficile toxin B.J Gen Physiol. 2004; 123: 491-504Crossref PubMed Scopus (0) Google Scholar, 58Engevik M.A. Engevik K.A. Yacyshyn M.B. Wang J. Hassett D.J. Darien B. Yacyshyn B.R. Worrell R.T. Human Clostridium difficile infection: inhibition of NHE3 and microbiota profile.Am J Physiol Gastrointest Liver Physiol. 2015; 308: G497-G509Crossref PubMed Scopus (0) Google ScholarSGLT1Apical membrane of small intestinal villi108Wood I.S. Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins.Br J Nutr. 2003; 89: 3-9Crossref PubMed Scopus (502) Google ScholarFunction decreased by EPEC infection29Viswanathan V.K. Hodges K. Hecht G. Enteric infection meets intestinal function: how bacterial pathogens cause diarrhoea.Nat Rev Microbiol. 2009; 7: 110-119Crossref PubMed Scopus (87) Google Scholar, 30Dean P. Maresca M. Schuller S. Phillips A.D. Kenny B. Potent diarrheagenic mechanism mediated by the cooperative action of three enteropathogenic Escherichia coli-injected effector proteins.Proc Natl Acad Sci U S A. 2006; 103: 1876-1881Crossref PubMed Scopus (0) Google ScholarRotavirus decreases SGLT134Hodges K. Gill R. Infectious diarrhea: cellular and molecular mechanisms.Gut Microbes. 2010; 1: 4-21Crossref PubMed Scopus (0) Google Scholar, 61Halaihel N. Lievin V. Ball J.M. Estes M.K. Alvarado F. Vasseur M. Direct inhibitory effect of rotavirus NSP4(114-135) peptide on the Na+-D-glucose symporter of rabbit intestinal brush border membrane.J Virol. 2000; 74: 9464-9470Crossref PubMed Scopus (0) Google ScholarENaCApical membrane of surface cells in distal colonDecreased by Salmonella infection in mice17Marchelletta R.R. Gareau M.G. McCole D.F. Okamoto S. Roel E. Klinkenberg R. Guiney D.G. Fierer J. Barrett K.E. Altered expression and localization of ion transporters contribute to diarrhea in mice with Salmonella-induced enteritis.Gastroenterology. 2013; 145: 1358-1368Abstract Full Text Full Text PDF PubMed Scopus (23) Google ScholarDRAApical membrane of small intestinal villous cells and surface cells in colon109Field M. Intestinal ion transport and the pathophysiology of diarrhea.J Clin Invest. 2003; 111: 931-943Crossref PubMed Scopus (315) Google Scholar, 110Silberg D.G. Wang W. Moseley R.H. Traber P.G. The down regulated in adenoma (dra) gene encodes an intestine-specific membrane sulfate transport protein.J Biol Chem. 1995; 270: 11897-11902Crossref PubMed Scopus (0) Google Scholar, 111Jacob P. Rossmann H. Lamprecht G. Kretz A. Neff C. Lin-Wu E. Gregor M. Groneberg D.A. Kere J. Seidler U. Down-regulated in adenoma mediates apical Cl-/HCO3- exchange in rabbit, rat, and human duodenum.Gastroenterology. 2002; 122: 709-724Abstract Full Text Full Text PDF PubMed Google ScholarDecreased by EPEC, C rodentium, and Salmonella infection19Gill R.K. Borthakur A. Hodges K. Turner J.R. Clayburgh D.R. Saksena S. Zaheer A. Ramaswamy K. Hecht G.A. Dudeja P.K. Mechanism underlying inhibition of intestinal apical Cl/OH exchange following infection with enteropathogenic E. coli.J Clin Invest. 2007; 117: 428-437Crossref PubMed Scopus (0) Google Scholar, 21Gujral T. Kumar A. Priyamvada S. Saksena S. Gill R.K. Hodges K. Alrefai W.A. Hecht G.A. Dudeja P.K. Mechanisms of DRA recycling in intestinal epithelial cells: effect of enteropathogenic E. coli.Am J Physiol Cell Physiol. 2015; 309: C835-C846Crossref PubMed Scopus (5) Google Scholar, 29Viswanathan V.K. Hodges K. Hecht G. Enteric infection meets intestinal function: how bacterial pathogens cause diarrhoea.Nat Rev Microbiol. 2009; 7: 110-119Crossref PubMed Scopus (87) Google Scholar, 34Hodges K. Gill R. Infectious diarrhea: cellular and molecular mechanisms.Gut Microbes. 2010; 1: 4-21Crossref PubMed Scopus (0) Google Scholar, 112Petri Jr., W.A. Miller M. Binder H.J. Levine M.M. Dillingham R. Guerrant R.L. Enteric infections, diarrhea, and their impact on function and development.J Clin Invest. 2008; 118: 1277-1290Crossref PubMed Scopus (198) Google ScholarSecretionCaCCFor CLCA1 in human beings, apical membrane of small intestinal and colonic crypt epithelial cells (and goblet cells)113Gruber A.D. Elble R.C. Ji H.L. Schreur K.D. Fuller C.M. Pauli B.U. Genomic cloning, molecular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca2+-activated Cl- channel proteins.Genomics. 1998; 54: 200-214Crossref PubMed Scopus (174) Google ScholarPossibly stimulated by E histolytica, G lamblia, cholera (ACE toxin), V parahaemolyticus, and rotavirus34Hodges K. Gill R. Infectious diarrhea: cellular and molecular mechanisms.Gut Microbes. 2010; 1: 4-21Crossref PubMed Scopus (0) Google Scholar, 53Takahashi A. Sato Y. Shiomi Y. Cantarelli V.V. Iida T. Lee M. Honda T. Mechanisms of chloride secretion induced by thermostable direct haemolysin of Vibrio parahaemolyticus in human colonic tissue and a human intestinal epithelial cell line.J Med Microbiol. 2000; 49: 801-810Crossref PubMed Scopus (29) Google ScholarNKCC1Basolateral membrane of small intestinal and colonic crypt epithelial cells114Jakab R.L. Collaco A.M. Ameen N.A. Physiological relevance of cell-specific distribution patterns of CFTR, NKCC1, NBCe1, and NHE3 along the crypt-villus axis in the intestine.Am J Physiol Gastrointest Liver Physiol. 2011; 300: G82-G98Crossref PubMed Scopus (59) Google ScholarIn cell lines and tissue ex vivo, expression increased by enteroinvasive E coli and Salmonella Dublin43Resta-Lenert S. Barrett K.E. Enteroinvasive bacteria alter barrier and transport properties of human intestinal epithelium: role of iNOS and COX-2.Gastroenterology. 2002; 122: 1070-1087Abstract Full Text Full Text PDF PubMed Google ScholarCFTRApical membrane of small intestinal and colonic epithelial cells with expression decreasing from crypt to villus115Strong T.V. Boehm K. Collins F.S. Localization of cystic fibrosis transmembrane conductance regulator mRNA in the human gastrointestinal tract by in situ hybridization.J Clin Invest. 1994; 93: 347-354Crossref PubMed Google ScholarIncreased activity after infection with ETEC, enteroinvasive E coli, or Salmonella Dublin; the latter also may increase expression in cell lines8Roussa E. Wittschen P. Wolff N.A. Torchalski B. Gruber A.D. Thevenod F. Cellular distribution and subcellular localization of mCLCA1/2 in murine gastrointestinal epithelia.J Histochem Cytochem. 2010; 58: 653-668Crossref PubMed Scopus (0) Google Scholar, 32Golin-Bisello F. Bradbury N. Ameen N. STa and cGMP stimulate CFTR translocation to the surface of villus enterocytes in rat jejunum and is regulated by protein kinase G.Am J Physiol Cell Physiol. 2005; 289: C708-C716Crossref PubMed Scopus (0) Google ScholarRedistributed into epithelial cytosol without a change in expression after Salmonella infection in mice17Marchelletta R.R. Gareau M.G. McCole D.F. Okamoto S. Roel E. Klinkenberg R. Guiney D.G. Fierer J. Barrett K.E. Altered expression and localization of ion transporters contribute to diarrhea in mice with Salmonella-induced enteritis.Gastroenterology. 2013; 145: 1358-1368Abstract Full Text Full Text PDF PubMed Scopus (23) Google ScholarE histolytica and norovirus increase chloride secretion34Hodges K. Gill R. Infectious diarrhea: cellular and molecular mechanisms.Gut Microbes. 2010; 1: 4-21Crossref PubMed Scopus (0) Google Scholar, 116Lejeune M. Moreau F. Chadee K. Prostaglandin E2 produced by Entamoeba histolytica signals via EP4 receptor and alters claudin-4 to increase ion permeability of tight junctions.Am J Pathol. 2011; 179: 807-818Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 117Troeger H. Loddenkemper C. Schneider T. Schreier E. Epple H.J. Zeitz M. Fromm M. Schulzke J.D. Structural and functional changes of the duodenum in human norovirus infection.Gut. 2009; 58: 1070-1077Crossref PubMed Scopus (0) Google ScholarAbsorption and secretionNa+, K+ ATPaseBasolateral membrane of epithelial cells throughout the small intestine and colonSalmonella infection in mice accompanied by redistribution from basolateral to apical membrane17Marchelletta R.R. Gareau M.G. McCole D.F. Okamoto S. Roel E. Klinkenberg R. Guiney D.G. Fierer J. Barrett K.E. Altered expression and localization of ion transporters contribute to diarrhea in mice with Salmonella-induced enteritis.Gastroenterology. 2013; 145: 1358-1368Abstract Full Text Full Text PDF PubMed Scopus (23) Google ScholarActivated by the magnesium transporter C (MgtC) virulence factor of Salmonella118Gunzel D. Kucharski L.M. Kehres D.G. Romero M.F. Maguire M.E. The MgtC virulence factor of Salmonella enterica serovar Typhimurium activates Na+, K+-ATPase.J Bacteriol. 2006; 188: 5586-5594Crossref PubMed Scopus (0) Google ScholarACE, accessory cholera enterotoxin; CaCC, Ca2+-activated chloride channel; CLCA1, chloride channel accessory 1; EHEC, enterohemorrhagic E coli; Stx2, Shiga toxin 2. Open table in a new tab Figure 2Chloride secretory mechanism in the small intestine and colon, and regulation of its constituent transporters by pathogens or their secreted toxins. The green arrows and red bars represent stimulatory and inhibitory effects, respectively. CaCC, calcium-activated chloride channel; ACE, accessory cholera enterotoxin; TDH, thermostable direct hemolysin of V parahemolyticus; NSP4, rotavirus nonstructural protein-4; KCNN4, calcium-activated potassium channel; KvLQT1/KCNE3, cAMP-activated potassium channel.View Large Image Figure ViewerDownload Hi-res image Download (PPT) ACE, accessory cholera enterotoxin; CaCC, Ca2+-activated chloride channel; CLCA1, chloride channel accessory 1; EHEC, enterohemorrhagic E coli; Stx2, Shiga toxin 2. The transporters discussed earlier can be regulated in 3 main ways to effect changes in overall levels of epithelial transport.1Barrett K.E. Keely S.J. Integrative physiology and pathophysiology of intestinal electrolyte transport.in: 4th ed. Physiology of the Gastrointestinal Tract. Vol. 1 and 2. Academic Press, San Diego2006: 1931-1951Google Scholar First, changes in transcription/translation of a given transporter will result in changes in its abundance, and associated changes in the capacity of the epithelium for transport function. Second, transport activity may be controlled by trafficking of a given transporter into or out of the plasma membrane. Finally, transporter activity may be acutely regulated by post-translational modifications, such as phosphorylation by various kinases, or may be modulated directly by intracellular second messengers such as free cytosolic calcium. Each of these mechanisms has been implicated in dysregulated transport in the setting of infection. Intestinal epithelial cells play the key role in diarrheal pathogenesis. The epithelium is the first line of defense and host-microbe interactions are crucial in the development of infectious diarrhea. In addition to its transport functions, moreover, the epithelium also forms a barrier that may protect the host from the intrusion of microbial pathogens or toxins. Intestinal barrier dysfunction also may play a significant role in diarrheal disease (so-called leak-flux diarrhea).13Camilleri M. Sellin J.H. Barrett K.E. Pathophysiology, evaluation, and management of chronic watery diarrhea.Gastroenterology. 2017; 152: 515-532 e2Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 14Guttman J.A. Finlay B.B. Tight junctions as targets of infectious agents.Biochim Biophys Acta. 2009; 1788: 832-841Crossref PubMed Scopus (169) Google Scholar, 15Turner J.R. Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application.Am J Pathol. 2006; 169: 1901-1909Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar However, in this review, we have focused mostly on the role of ion transporters in infectious diarrhea. A classic view of infectious diarrhea implicated direct stimulation of epithelial chloride secretion, with associated loss of fluid, as the primary driving force for diarrheal symptoms (eg, in the setting of infection with Vibrio cholerae or enterotoxigenic strains of Escherichia coli [ETEC]). However, it has become increasingly obvious that changes in electrolyte absorptive processes also are involved in disease pathogenesis. For example, an increase in epithelial cAMP not only activates chloride secretion, but also inhibits electroneutral NaCl absorption.16Clarke L.L. Harline M.C. CFTR is required for cAMP inhibition of intestinal Na+ absorption in a cystic fibrosis mouse model.Am J Physiol. 1996; 270: G259-G267Crossref PubMed Google Scholar Furthermore, studies with invasive pathogens such as nontyphoidal Salmonella species or enteropathogenic E coli (EPEC) have failed to uncover any evidence of active anion secretion in the setting of infection.17Marchelletta R.R. Gareau M.G. McCole D.F. Okamoto S. Roel E. Klinkenberg R. Guiney D.G. Fierer J. Barrett K.E. Altered expression and localization of ion transporters contribute to diarrhea in mice with Salmonella-induced enteritis.Gastroenterology. 2013; 145: 1358-1368Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 18Hecht G. Koutsouris A. Enteropathogenic E. coli attenuates secretagogue-induced net intestinal ion transport but not Cl- secretion.Am J Physiol. 1999; 276: G781-G788PubMed Google Scholar Rather, diarrheal disease may result from the specific suppression of absorptive transport mechanisms.17Marchelletta R.R. Gareau M.G. McCole D.F. Okamoto S. Roel E. Klinkenberg R. Guiney D.G. Fierer J. Barrett K.E. Altered expression and localization of ion transporters contribute to diarrhea in mice with Salmonella-induced enteritis.Gastroenterology. 2013; 145: 1358-1368Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 19Gill R.K. Borthakur A. Hodges K. Turner J.R. Clayburgh D.R. Saksena S. Zaheer A. Ramaswamy K. Hecht G.A. Dudeja P.K. Mechanism underlying inhibition of intestinal apical Cl/OH exchange following infection with enteropathogenic E. coli.J Clin Invest. 2007; 117: 428-437Crossref PubMed Scopus (0) Google Scholar In this section, we summarize evidence for the modulation of transporters by selected bacteria, protozoa, and viruses that cause diarrheal illness. Of note, studies to date have used a variety of models, including colon cancer cell lines, tissue explants, xenografts, and whole animals (typically mice), which raises questions about the extent to which all conclusions can be extrapolated to human patients. The recent introduction of organoid models, as well as monolayers derived from these, should offer benefits in developing an enhanced understanding of diarrheal mechanisms.20Singh V. Yang J. Chen T.E. Zachos N.C. Kovbasnjuk O. Verkman A.S. Donowitz M. Translating molecular physiology of intestinal transport into pharmac" @default.
• W2791102487 created "2018-03-29" @default.
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• W2791102487 date "2018-01-01" @default.
• W2791102487 modified "2023-09-25" @default.
• W2791102487 title "The Role of Ion Transporters in the Pathophysiology of Infectious Diarrhea" @default.
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