Microflora trigger colitis in mice deficient in selenium-dependent glutathione peroxidase and induce Gpx2 gene expression.
Selenium-dependent glutathione peroxidase isoenzymes-1 and -2 are the major glutathione-dependent H2O2-reducing activities in the epithelium of the mid- to lower gastrointestinal tract. The two isoenzymes protect mice against ileocolitis. We have found that luminal microflora are required for colitis to develop in mice deficient in GPX-1 and GPX-2 activity (GPX-DKO). Within 7 days of association with microflora, previously asymptomatic germ-free GPX-DKO mice developed severe acute colitis while their littermates with at least one wild-type Gpx1 or Gpx2 gene remained virtually symptom-free. Microflora also affected Gpx2 gene expression. Gpx2, but not Gpx1, mRNA levels were elevated 4-5 fold in the ileum and colon in conventionally reared or microflora-associated adult mice compared with germ-free mice. Since the gastrointestinal tract microflora undergo major changes 2-3 weeks after birth, from relatively benign to a potentially stressful composition, we examined postnatal Gpx2 gene expression. The jejunal and ileal GPX-2 activity levels were low in two to three week-old mice and increased 5-7 fold during the next two weeks. GPX-2 activity levels were correlated with the mRNA levels. Colon Gpx2 mRNA levels held steady at about 50% of adult levels from 12-21 days of age but were several times higher than ileal levels. Our results suggest that ileal Gpx2 mRNA and GPX-2 activity levels are induced by luminal microflora. This response is consistent with a role for GPX as an anti-inflammatory activity.
Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
R Steven
RS
Esworthy
Scott W
SW
Binder
James H
JH
Doroshow
Fong-Fong
FF
Chu
D000375:Aging / Q000502:physiology; D000818:Animals; D000906:Antibodies / Q000032:analysis; D003092:Colitis / Q000201:enzymology* / Q000382:microbiology* / Q000473:pathology; D003106:Colon / Q000382:microbiology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005856:Germ-Free Life; D005979:Glutathione Peroxidase / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics; D007082:Ileum / Q000254:growth & development / Q000382:microbiology / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012643:Selenium / Q000378:metabolism*
D000906:Antibodies; D012333:RNA, Messenger; C492172:Gpx2 protein, mouse; D005979:Glutathione Peroxidase; D012643:Selenium