Inflammatory bowel disease (IBD), which encompasses Crohn's disease and ulcerative colitis, is a debilitating condition characterised by chronic inflammation of the gastrointestinal tract. The aetiology is complex, but a hallmark of the disease is dysregulation in the intestinal epithelium. Therefore, Emre Turer and colleagues conducted a large-scale forward genetic screen of N-ethyl-N-nitrosourea (ENU) mutagenised mice to identify genes involved in the maintenance and resilience of the intestinal epithelium. Among the 119 candidate genes found to modulate susceptibility to dextran sodium sulfate (DSS)-induced colitis in the mice, the authors chose to further investigate delta 4-desaturase, sphingolipid 2 (DEGS2). DEGS2 catalyses the production of both ceramide and phytoceramide from dihydroceramide, but its role in murine intestinal homeostasis was not previously known.
By generating mice with an independent CRISPR/Cas9-targeted mutation in the Degs2 gene, the authors confirmed that Degs2−/− mice were highly susceptible to DSS-induced colitis, as demonstrated by increased weight loss, disease activity index, and colonic shortening and inflammation, compared to Degs2+/+ mice treated with DSS. Interestingly, the authors also found decreased DEGS2 expression in colonic and small intestinal biopsies from IBD patients, by analysing publicly available transcriptome data. Delving deeper into the role of DEGS2 in the intestine, the authors performed mass spectrometry with whole colons and small intestinal enteroids isolated from Degs2−/− mice to detect normal levels of ceramide, but decreased levels of phytoceramide, alongside the accumulation of its precursor dihydroceramides. This demonstrates the role of DEGS2 in sphingolipid metabolism in the intestinal epithelium, even in untreated mice. Finally, the authors found enhanced cell death accompanied by decreased cell proliferation and stem cell markers in the colon of Degs2−/− mice exposed to DSS. Therefore, mice deficient in DEGS2 have an imbalance in phytoceramide and dihydroceramide levels that leads to defective regeneration and resilience in response to acute stress.
As altered expression of DEGS2 was also observed in human IBD patient biopsies, DEGS2 and sphingolipid metabolism may be potential targets for IBD therapy development. However, further work is needed to fully characterise the mechanism downstream of DEGS2 regulation in the intestinal epithelium.
The image shows EDU labeling in Degs2+/+ distal colon after 4 days of DSS treatment. For permission to reuse, please contact Emre Turer ([email protected]).
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