Atherogenic diets exacerbate colitis in mice deficient in glutathione peroxidase

Abstract Background: The proinflammatory effect of high‐fat diet has been observed beyond the cardiovascular system, but there is little evidence to support its role in triggering inflammatory bowel disease. GPx1/2‐double‐knockout (DKO) mice deficient in 2 intracellular glutathione peroxidases, GPx1 and GPx2, on a C57BL/6 (B6) background, have mild ileocolitis on a conventional chow. Methods: We fed B6 DKO mice 2 atherogenic diets to test the dietary effect on atherosclerosis and ileocolitis. Both atherogenic diets have high cholesterol—the Chol+/CA diet has cholic acid (CA), and the Chol+ diet has no CA. Results: The Chol+/CA diet induced severe colitis, but not ileitis, in the DKO mice compared with the Chol+ and the Chol− control diet. On the Chol+/CA diet, the wild‐type (WT) mice had levels of aortic lesions and hypercholesterolemia similar to those of DKO mice but had no intestinal pathology. The diet‐associated inflammatory responses in the DKO mice included increased colonic proinflammatory serum amyloid A3 expression, plasma lipopolysaccharide, and TNF‐α levels. The Chol+/CA diet lowered the expression of the unfolded protein response genes ATF6, CHOP , unspliced Xbp U , and Grp78/Bip , in WT and DKO mice compared with mice on the Chol− diet. Conclusions: We concluded that a cholesterol diet weakens the colon unfolded protein response, which can aggravate spontaneous colitis, leading to gut barrier breakdown. GPx has no impact on atherosclerosis without ultrahypercholesterolemia. Inflamm Bowel Dis 2010