Background: The sphingolipid sphingomyelin is a constituent in food derived from animals. Digestive breakdown of sphingomyelin results in ceramide, recently suggested to be involved in activation of cathepsin D as a novel mediator of apoptosis. Damage of the epithelial barrier was detected in patients with inflammatory bowel disease (IBD) due to increased rates of intestinal epithelial cell (IEC) apoptosis.
Methods: Acute colitis was induced in C57-BL/6 mice with 2.0% dextran sulfate sodium (DSS) over 7 days. Spontaneous colitis was developed in B6-IL10tm1Cgn (interleukin 10-negative (IL-10(-/-))) mice. Mice received 4 or 8 mg sphingomyelin/day by oral gavage. IECs were isolated ex vivo. Apoptosis was determined by propidium iodide (PI) and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. Execution of apoptosis was confirmed by analysis of active cathepsin D, caspase-3 and caspase-9 with western blot and immunohistochemistry (IHC).
Results: Following DSS-mediated colitis, fluorescence-activated cell sorting (FACS) analysis indicated increased apoptosis of IECs under dietary sphingomyelin. The mean sub-G(1) portion increased from 8.7±2.5% under a normal diet to 14.0±3.1% under dietary sphingomyelin. Cathepsin activity was significantly increased in isolated IECs after gavage of 4 mg of sphingomyelin per day. Western blot and IHC revealed execution of the apoptotic cascade via activated caspase-3 and caspase-9. Dietary sphingomyelin in the IL-10(-/-) model confirmed aggravation of mucosal inflammation.
Conclusion: Apoptosis of IEC induced by dietary sphingomyelin is mediated via ceramide and cathepsin D activation. This shortens the physiological life cycle of IECs and impairs crucial functions of the intestinal mucosa: barrier, defence and nutrient absorption. The findings provide evidence that dietary sphingomyelin may increase intestinal inflammation.
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