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Diet-Induced Hyperhomocysteinaemia Increases Intestinal Inflammation in an Animal Model of Colitis
Siying Zhu1, Jin Li1, Yuntao Bing2
1Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, P.R. China.
Insights
High homocysteine levels worsen inflammatory bowel disease (IBD) colitis by increasing IL-17. Folate supplementation may help reduce this intestinal inflammation.
Area of Science:
- Gastroenterology
- Immunology
- Molecular Biology
Background:
- Hyperhomocysteinemia (HHcy) is common in inflammatory bowel disease (IBD).
- Homocysteine is a pro-inflammatory molecule linked to cardiovascular and cerebral diseases.
- The role of HHcy in chronic intestinal inflammation in IBD is under-explored.
Purpose of the Study:
- To investigate the effect of HHcy on dextran sulphate sodium (DSS)-induced colitis in Wistar rats.
- To elucidate the molecular mechanisms underlying HHcy-induced aggravation of colitis.
Main Methods:
- Induction of colitis using 5% DSS and HHcy using a methionine-rich diet in Wistar rats.
- Assessment of disease activity and histological damage.
- Quantification of mRNA and protein expression for key inflammatory markers including IL-17, RORγt, p38 MAPK, cPLA2, and COX2.
Main Results:
- HHcy significantly exacerbated DSS-induced colitis, indicated by higher MPO activity, DAI, and histological scores.
- HHcy increased plasma and colonic IL-17 levels, activated the p38 MAPK/cPLA2 pathway, and elevated COX2 and PGE2 levels.
- Folate supplementation reduced homocysteine-induced IL-17 and RORγt expression.
Conclusions:
- HHcy aggravates DSS-induced colitis by promoting IL-17 expression through the p38/cPLA2/COX2/PGE2 signaling pathway.
- Folate supplementation shows potential as a novel therapeutic strategy for managing IBD-related chronic intestinal inflammation exacerbated by HHcy.
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.
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