Colitis Alters Oxysterol Metabolism and is Affected by 4β-Hydroxycholesterol Administration

Abstract

Background and Aims Inflammatory bowel diseases [IBD] represent a challenging health issue with a complex aetiology involving genetic and environmental parameters. Although our understanding of the pathophysiology of IBD has improved, much remains to be explored. In this context, bioactive lipids, more specifically oxysterols, i.e. oxygenated derivatives of cholesterol, represent an interesting avenue to investigate. Indeed, oxysterols or their receptors are involved in inflammation and immune regulation. Therefore, we set out to study the oxysterome in IBD. Methods We used both high-performance liquid chromatograph/mass spectroscopy and molecular biology tools to quantify oxysterol levels and the expression of their metabolic enzymes in several models of murine colitis [both acute and chronic], as well as in colon biopsies from patients with Crohn's disease and ulcerative colitis. Results We found that the oxysterome is altered in IBD, in both acute and chronic murine models as well as in human IBD. Two of the oxysterols quantified, 4β-hydroxycholesterol and 25-hydroxycholesterol, were consistently altered in all our models and therefore could be of interest in this context. Hence, we administered them to mice with colitis. While 25-hydroxycholesterol had no effect, 4β-hydroxycholesterol worsened colon inflammation. Conclusions Our study addresses the potential involvement of oxysterols in colitis and clearly points towards an active role as well as a clinical relevance for these bioactive lipids.