The Gdac1 locus modifies spontaneous and Salmonella-induced colitis in mice deficient in either Gpx2 or Gpx1 gene

Abstract

We previously identified the Gdac1 (Gpx-deficiency-associated colitis 1) locus, which influences the severity of spontaneous colitis in Gpx1- and Gpx2-double-knockout (Gpx1/2-DKO) mice. Congenic Gpx1/2-DKO mice in the 129S1/SvImJ (129) background but carrying the Gdac1(B6) allele have milder spontaneous colitis than 129 Gpx1/2-DKO mice carrying the Gdac1(129) allele. Here, we evaluated the effect of the Gdac1(B6) allele on 129 strain non-DKO mice that had a wild-type (WT) Gpx1 or Gpx2 allele and WT mice. We found that the congenic Gdac1(B6) Gpx2-KO, Gpx1-KO, and WT mice also had better health than the corresponding 129 mice measured by at least one of the parameters including disease signs, colon length, or weight gain. The Gdac1(B6) allele prevented loss of goblet cells and crypt epithelium exfoliation in the Gpx1/2-DKO mice, but did not affect epithelial cell apoptosis or proliferation. Because Gdac1(B6) affects gut dysbiosis in the DKO mice, we then tested its impact on bacteria-induced colitis in non-DKO mice. First, we found both Gpx1-KO and Gpx2-KO mice were susceptible to Salmonella enterica serotype typhimurium (S. Tm)-induced colitis under conditions where WT B6 and 129 mice were resistant. Second, the S. Tm-infected Gdac1(B6) Gpx1-KO mice had stronger inflammatory responses than 129 Gpx1-KO or 129 Gpx2-KO with both Gdac1 alleles and WT mice by having higher mRNA levels of Nod2, Nox2, Tnf, and Cox2. We conclude that the Gdac1 locus affects both spontaneous and S. Tm-induced colitis in 129 non-DKO mice, although in opposite directions.

Keywords: DUOX2; Free radicals; GPX-deficiency-associated-colitis locus-1; GPX1; GPX2; Gdac1; Gut dysbiosis; Metronidazole; Mouse genetics; Salmonella enterica serotype typhimurium; Selenium.