Altered expression and localization of ion transporters contribute to diarrhea in mice with Salmonella-induced enteritis

Ronald R. Marchelletta, Melanie Gareau, Declan F. McCole, Sharon Okamoto, Elise Roel, Rachel Klinkenberg, Donald G. Guiney, Joshua Fierer, Kim E. Barrett

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Background & Aims Salmonella enterica serovar Typhimurium is an enteropathogen that causes self-limiting diarrhea in healthy individuals, but poses a significant health threat to vulnerable populations. Our understanding of the pathogenesis of Salmonella-induced diarrhea has been hampered by the lack of a suitable mouse model. After a dose of oral kanamycin, Salmonella-infected congenic BALB/c.D2NrampG169 mice, which carry a wild-type Nramp1 gene, develop clear manifestations of diarrhea. We used this model to elucidate the pathophysiology of Salmonella-induced diarrhea. Methods BALB /c.D2 NrampG169 mice were treated with kanamycin and then infected with wild-type or mutant Salmonella by oral gavage. Colon tissues were isolated and Ussing chambers, quantitative polymerase chain reaction, immunoblot, and confocal microscopy analyses were used to study function and expression of ion transporters and cell proliferation. Results Studies with Ussing chambers demonstrated reduced basal and/or adenosine 3′,5′-cyclic monophosphate-mediated electrogenic ion transport in infected colonic tissues, attributable to changes in chloride or sodium transport, depending on the segment studied. The effects of infection were mediated, at least in part, by effector proteins secreted by the bacterial Salmonella pathogenicity island 1- and Salmonella pathogenicity island-2-encoded virulence systems. Infected tissue showed reduced expression of the chloride-bicarbonate exchanger down-regulated in adenoma in surface colonic epithelial cells. Cystic fibrosis transmembrane conductance regulator was internalized in colonic crypt epithelial cells without a change in overall expression levels. Confocal analyses, densitometry, and quantitative polymerase chain reaction revealed that expression of epithelial sodium channel β was reduced in distal colons of Salmonella-infected mice. The changes in transporter expression, localization, and/or function were accompanied by crypt hyperplasia in Salmonella-infected mice. Conclusions Salmonella infection induces diarrhea by altering expression and/or function of transporters that mediate water absorption in the colon, likely reflecting the fact that epithelial cells have less time to differentiate into surface cells when proliferation rates are increased by infection.

Original languageEnglish (US)
JournalGastroenterology
Volume145
Issue number6
DOIs
StatePublished - Dec 2013

Keywords

  • Colon
  • DRA
  • ENaC
  • Salmonella

ASJC Scopus subject areas

  • Gastroenterology

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    Marchelletta, R. R., Gareau, M., McCole, D. F., Okamoto, S., Roel, E., Klinkenberg, R., Guiney, D. G., Fierer, J., & Barrett, K. E. (2013). Altered expression and localization of ion transporters contribute to diarrhea in mice with Salmonella-induced enteritis. Gastroenterology, 145(6). https://doi.org/10.1053/j.gastro.2013.08.054