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VSL3 UP-REGULATES MUCOSAL SPHINGOMYLINASE ACTIVITY IN A MOUSE MODEL OF COLITIS: A MECHANISM THAT MAY REDUCE COLON CANCER RISK IN PATIENTS WITH IBD

I Soo, K Madsen, RS Sherbaniuk, RN Fedorak
Division of Gastroenterology, University of Alberta, Edmonton, Alberta

BACKGROUND: Sphingomyelinase produces ceramide, sphingosine and sphingosine-1-phosphate by means of hydrolyzing sphingomyelin. Three types of sphingomyelinase have been identified in humans. Both neutral and acidic sphingomyelinase are found in various tissues throughout the body. In contrast, alkaline sphingomyelinase (AlkSMase) is found exclusively in bile and the intestinal brush border. There is evidence that AlkSmase acts as a tumour suppressor in colonocytes, and reduced enzyme levels are associated with premalignant and malignant epithelia. Recent findings have demonstrated decreased AlkSMase activity in the mucosa of patients with ulcerative colitis (UC).
AIM: The aim of this study was to determine the effect of probiotic therapy with VSL3 on mucosal levels of alkaline sphingomyelinase in a mouse model of colitis and in patients with ulcerative colitis (UC).
METHODS: IL-10 gene-deficient mice (IL-10^-/- mice) were treated with VSL3 (10⁹ cfu/d) (Bifidobacterium longum, B infantis, B breve, L acidophilus, L casei, L bulgaricus, L plantarum and Streptococcus salivarius subspecies thermophilus) for 3 wks. At sacrifice, ileal and colonic tissue were removed for measurement of AlkSmase activity and histological analysis. UC patients were treated with one sachet of VSL3 2´/d for 5 weeks. Mucosal sigmoid biopsies were taken before and following treatment. AlkSmase activity was measured in biopsies and UCDAI and endoscopic grading of disease was obtained.
RESULTS: Placebo-treated IL-10^-/- mice demonstrated active inflammation in the colon, with no histological signs of inflammation in the ileum. However, AlkSmase levels were reduced in both the ileum, in the absence of any inflammation, and in the colon. Treatment of IL-10^-/- mice with VSL3 resulted in a significant attenuation of inflammation in the colon, and an upregulation of AlkSmase in both the colon and the ileum. Sixteen UC patients with quiescent disease participated. The mean age was 50.13 ± 11.58. After VSL3 treatment, mean UCDAI decreased from 1.75 ± 1.81 to 1.44 ± 3.03 and mean endoscopic grading of disease activity decreased from 0.813 ± 0.98 to 0.563 ± 0.96.
CONCLUSION: AlkSmase activity is reduced in the intestine in an animal model of colitis, even in regions that demonstrate no histological inflammation. Probiotic therapy with VSL3 reduces inflammation and upregulates AlkSmase activity.

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