Altered Expression and Localization of Ion Transporters Contribute to Diarrhea in Mice With Salmonella-Induced Enteritis

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.D2NrampG169 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.

Correction of Ductal CFTR Activity Rescues Acinar Cell and Pancreatic and Salivary Gland Functions in Mouse Models of Autoimmune Disease

“…It should be applicable to other inflammatory diseases of organs that express CFTR, such as the intestine and the lung. In the intestine, salmonella-induced enteritis causes mislocalization of CFTR 44 and there is a strong correlation between CFTR function and asthma 45 . Treatment with CFTR correctors may offer another tool to treat these diseases.…”

Campylobacter jejuni infection suppressed Cl− secretion induced by CFTR activation in T-84 cells

“…CFTR is also highly expressed in the intestinal tract, and CFTR mutations might be associated with intestinal infections. Indeed, a previous study showed that enteropathogenic Escherichia coli and Salmonella enteritidis suppress Cl À transport activity in the intestinal tract [9,10]. These reports suggest that Cl À secretion mediated by CFTR could be critical for bacterial clearance in the intestine, and that CFTR may play a key role in the intestinal host defense mechanism.…”

Cystic Fibrosis Transmembrane Conductance Regulator Reduces Microtubule-Dependent Campylobacter jejuni Invasion

“…Recently, other bacteria causing intestinal infections, including enteropathogenic Escherichia coli (EPEC) and Salmonella enterica serovar Typhimurium, were reported to suppress CFTR ion channel activity (45,46). Moreover, in the respiratory tract, P. aeruginosa was shown to invade host cells via a microtubule-dependent pathway that is regulated by CFTR (47).…”