Diet-Induced Hyperhomocysteinaemia Increases Intestinal Inflammation in an Animal Model of Colitis.

BACKGROUND

Hyperhomocysteinaemia [HHcy] is a common phenomenon observed in patients with inflammatory bowel disease [IBD]. Homocysteine is a pro-inflammatory molecule and has been identified as a risk factor for cardiovascular and cerebral diseases. Whether HHcy contributes to the chronic inflammation of the colon in IBD has rarely been explored. The aim of this study was to investigate the effect of HHcy on dextran sulphate sodium [DSS]-induced colitis.

METHODS

Wistar rats were randomly divided into eight groups: [1] Control; [2] HHcy; [3] p38 inhibitor; [4] DSS; [5] HHcy + DSS; [6] HHcy + DSS+p38 inhibitor; [7] HHcy + DSS [21 days]; and [8] HHcy + DSS + folate [21 days]. Colitis was induced by 5% DSS. HHcy was induced by the normal rodent diet containing 1.7% methionine. The mRNA expression of interleukin 17 [IL-17] was detected by qRT-PCR. The protein expressions of IL-17, retinoid-related orphan nuclear receptor-γt [RORγt], p38 MAPK, phosphorylated-p38 MAPK, cytosolic phospolipaseA2 [cPLA2], phosphorylated-cPLA2, and cyclooxygenase 2 [COX2] were detected by immunoblot analysis.

RESULTS

The rats of the HHcy + DSS group had significantly higher myeloperoxidase [MPO] activity, DAI score, and histological score. HHcy significantly increased the plasma concentration, the colonic mRNA, and the protein levels of IL-17. HHcy also activated p38 MAPK and cPLA2, and increased the protein levels of COX2 and RORγt as well as the plasma level of prostaglandin E2 [PGE2]. Folate supplementation down-regulated homocysteine-induced IL-17 and RORγt expressions.

CONCLUSIONS

HHcy aggravated DSS-induced colitis by stimulating IL-17 expression via the p38/cPLA2/COX2/PGE2 signalling pathway. The folate supplementation may represent a novel approach to treating the chronic intestinal inflammation of IBD exacerbated by HHcy.