Colonic Cell Proliferation and Aberrant Crypt Foci Formation Are Inhibited by Dairy Glycosphingolipids in 1,2-Dimethylhydrazine-Treated CF1 Mice

Abstract

Dietary sphingomyelin (SM) inhibits early stages of colon cancer (appearance of aberrant crypt foci, ACF) and decreases the proportion of adenocarcinomas vs. adenomas in 1,2-dimethylhydrazine (DMH)-treated CF1 mice. To elucidate the structural specificity of this inhibition, the effects of the other major sphingolipids in milk (glycosphingolipids) were determined. Glucosylceramide (GluCer), lactosylceramide (LacCer) and ganglioside G(D3) were fed individually to DMH-treated (six doses of 30 mg/kg body weight) female CF1 mice at 0.025 or 0.1 g/100 g of the diet for 4 wk. All reduced the number of ACF by > 40% (P < 0.001), which is comparable to the reduction by SM in earlier studies. Immunohistochemical analysis of the colons revealed that sphingolipid feeding also reduced proliferation, with the most profound effect (up to 80%; P < 0.001) in the upper half of the crypts. Since the bioactive backbones of the glycosphingolipids (i.e., ceramide and other metabolites) are the likely mediators of these effects, the susceptibility of these complex sphingolipids to digestion in the colon was examined by incubating 500 microgram of each sphingolipid with colonic segments from mice and analysis of substrate disappearance and product formation by tandem mass spectrometry. All of the sphingolipids (including SM) disappeared over time with a substantial portion appearing as ceramide. Partially hydrolyzed intermediates (such as GluCer from LacCer or G(D3)) were not detected, which suggests that the cleavage involves colonic (or microflora) endoglycosidases. In summary, consumption of dairy SM and glycosphingolipids suppresses colonic cell proliferation and ACF formation in DMH-treated mice; hence, many categories of sphingolipids affect these key events in colon carcinogenesis.

Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer

“…However, we find that SPL is down-regulated in human CRC and early adenomatous lesions of Min mice. Dietary sphingolipids protect against intestinal tumorigenesis through conversion to growth-inhibitory sphingosines in the intestinal lumen (27)(28)(29). However, our finding suggests that sphingolipid metabolism may be blocked in CRC, leading to intracellular S1P accumulation.…”

Quantities of Phospholipid Molecular Classes in Japanese Meals and Prediction of Their Sources by Multiple Regression Analysis

“…Growing evidence indicates that dietary PLs have beneficial effects compared with dietary triacylglycerols (TAGs), including prevention of dyslipidemia (6)(7)(8)(9) and fatty liver disease (10)(11)(12)(13). In addition, dietary sphingomyelin (SM), classified together with glycerophospholipids (glyceroPLs) as PL, has beneficial effects such as prevention of early-stage colon cancer (14) and improvement of skin barrier function (15). GlyceroPLs are composed of hydrophobic (e.g.…”

Gangliosides in dairy products: Milk sphingolipids

“…Gangliosides are strongly associated with neural functioning. Numerous studies clearly demonstrate the importance of sphingolipid rich foods or supplements as it could be an important mediator in the prevention of colon cancer and bowel-related disease (SCHMELZ et al, 2000). Few observational fi ndings suggest that dairy food intake may be positively related to cognitive function (CRICHTON et al, 2012).…”

“…Although there is emerging evidence suggesting that dietary sphingolipids may prevent development of disease (VESPER et al, 1999;SCHMELZ et al, 2000;POSSEMIERS et al, 2005;CASTRO-GOMEZ et al, 2015), the knowledge of their concentrations in food is limited. The aim of this study was to determine the concentrations of total gangliosides in dairy products and to determine whether there is a signifi cant difference in comparison to concentration of gangliosides in cow's milk.…”