title: Colonic gene expression profile in NHE3-deficient mice: evidence for spontaneous distal colitis.
abstract: Na+/H+ exchanger 3 (NHE3) provides a major route for intestinal Na+ absorption. NHE3 has been considered a target of proinflammatory cytokines and enteropathogenic bacteria, and impaired NHE3 expression and/or activity may be responsible for inflammation-associated diarrhea. However, the possibility of loss of NHE3 function reciprocally affecting gut immune homeostasis has not been investigated. In this report, we describe that NHE3-deficient mice spontaneously develop colitis restricted to distal colonic mucosa. NHE3(-/-) mice housed in a conventional facility exhibited phenotypic features such as mild diarrhea, occasional rectal prolapse, and reduced body weight. Genomewide microarray analysis identified not only a large group of transport genes that potentially represent an adaptive response, but also a considerable number of genes consistent with an inflammatory response. Histological examination demonstrated changes in the distal colon consistent with active inflammation, including crypt hyperplasia with an increased number of 5-bromo-2'-deoxyuridine-positive cells, diffuse neutrophilic infiltrate with concomitant 15-fold increase in matrix metalloproteinase 8 expression, an increased number of pSer276-RelA-positive cells, and a significant decrease in periodic acid-Schiff-positive goblet cells. Real-time PCR demonstrated elevated expression of inducible nitric oxide synthase (38-fold), TNF-alpha (6-fold), macrophage inflammatory protein-2 (48-fold), and IL-18 (3-fold) in the distal colon of NHE3(-/-) mice. NHE3(-/-) mice showed enhanced bacterial adhesion and translocation in the distal colon. Colitis was ameliorated by oral administration of broad-spectrum antibiotics. In conclusion, NHE3 deficiency leads to an exacerbated innate immune response, an observation suggesting a potentially novel role of NHE3 as a modifier gene, which when downregulated during infectious or chronic colitis may modulate the extent and severity of colonic inflammation.
authors.affiliation: Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Laubitz
authors.forename: Claire B
authors.initials: CB
authors.lastname: Larmonier
authors.forename: Aiping
authors.initials: A
authors.lastname: Bai
authors.forename: Monica T
authors.initials: MT
authors.lastname: Midura-Kiela
authors.forename: Maciej A
authors.initials: MA
authors.lastname: Lipko
authors.forename: Robert D
authors.initials: RD
authors.lastname: Thurston
authors.forename: Pawel R
authors.initials: PR
authors.lastname: Kiela
authors.forename: Fayez K
authors.initials: FK
authors.lastname: Ghishan
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use; D002939:Ciprofloxacin / Q000627:therapeutic use; D003092:Colitis / Q000188:drug therapy / Q000378:metabolism*; D003106:Colon / Q000473:pathology; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D008795:Metronidazole / Q000627:therapeutic use; D051379:Mice; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000378:metabolism*; D015430:Weight Gain
chemical_list: D000890:Anti-Infective Agents; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D008795:Metronidazole; D002939:Ciprofloxacin