{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:23:15Z","timestamp":1773422595925,"version":"3.50.1"},"reference-count":44,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2008,7]]},"abstract":"<jats:p>Na<jats:sup>+<\/jats:sup>\/H<jats:sup>+<\/jats:sup>exchanger 3 (NHE3) provides a major route for intestinal Na<jats:sup>+<\/jats:sup>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<jats:sup>\u2212\/\u2212<\/jats:sup>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\u2032-deoxyuridine-positive cells, diffuse neutrophilic infiltrate with concomitant 15-fold increase in matrix metalloproteinase 8 expression, an increased number of pSer<jats:sup>276<\/jats:sup>-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-\u03b1 (6-fold), macrophage inflammatory protein-2 (48-fold), and IL-18 (3-fold) in the distal colon of NHE3<jats:sup>\u2212\/\u2212<\/jats:sup>mice. NHE3<jats:sup>\u2212\/\u2212<\/jats:sup>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.<\/jats:p>","DOI":"10.1152\/ajpgi.90207.2008","type":"journal-article","created":{"date-parts":[[2008,5,9]],"date-time":"2008-05-09T01:11:26Z","timestamp":1210295486000},"page":"G63-G77","source":"Crossref","is-referenced-by-count":80,"title":["Colonic gene expression profile in NHE3-deficient mice: evidence for spontaneous distal colitis"],"prefix":"10.1152","volume":"295","author":[{"given":"Daniel","family":"Laubitz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire 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