Scientific Abstract
Proposal No. IBD-0162R
Principal Investigator: Michael T. Clandinin, Ph.D.
Applicant Organization: University of Alberta (Edmonton, Canada)
Project Title: Milk-derived gangliosides as novel anti-inflammatory therapy for inflammatory bowel disease
Period of Award: March 1, 2006 – August 31, 2008
Gangliosides (GG) are sialic acid-containing glycosphingolipids located at the surface of the cell membrane. Approximately 20% of brush border membrane lipids are glycosphingolipids. GG occur naturally in the milk fat globule membrane in human and bovine milk. We have shown that feeding dietary GG to rats alters the content and composition of phospholipids as well as the polyunsaturated fatty acid composition of phospholipids in the developing gut, implying that functions of enterocytes may be influenced by the presence and composition of constituent sphingolipids. Our animal data further suggests that physiological levels of dietary GG exert anti-inflammatory effects by increasing the ether phospholipid content of normal intestinal mucosa and by inhibiting PAF, PGE2, LTB4, IL-1β and TNF-α in inflamed mucosa and blood. This data points to a specific therapeutic role for dietary GG in the prevention and treatment of inflammatory conditions of the gut.
GG may offer an effective therapeutic option for individuals suffering from Crohn’s disease (CD) and ulcerative colitis (UC), the two most common forms of inflammatory bowel disease (IBD). Current IBD therapies are not effective in all patients and are associated with significant toxicity. Dietary GG do not have adverse side effects and may offer protection against some of the harmful side effects of other IBD therapies. GG may therefore be useful as monotherapy or as an adjunct to current therapies to augment their therapeutic benefit while minimizing harmful side effects. Evidence indicates that GG also help to maintain the integrity and function of the healthy gut and therefore dietary GG may uniquely be used to both treat and prevent the development of IBD.
Specific dietary supplementation of GG for the treatment of disease has never been attempted in a clinical setting and potential health benefits have not been fully characterized. Our objective is to conduct a small pilot clinical study to provide preliminary proof of concept that GG are an efficacious therapeutic option for individuals with IBD. Twenty individuals with mildly active CD and 20 with mild to moderate UC will be randomly assigned to treatment with conventional therapy of 5-aminosalicylic acid (5-ASA) + placebo or 5-ASA + GG for eight weeks. Change in disease activity indices will be quantified and biopsy and blood samples will be taken pre and post intervention to assess the change in plasma and mucosal levels of pro-inflammatory mediators and lipids. The influence of GG on intestinal permeability will be assessed at baseline and after eight weeks of GG supplementation. The safety of ganglioside supplementation will be assessed in CD and UC subjects and in a group of 20 healthy control subjects. We hypothesize that GG therapy will improve disease activity indices in CD and UC patients and will significantly reduce the pro-inflammatory response and intestinal permeability relative to baseline values and in comparison to the placebo group.
If favorable outcomes are obtained, this study will serve as the basis for larger clinical studies to assess the efficacy of GG supplementation and to determine the specific GG and mechanisms that account for these beneficial effects. The results of this study are expected to significantly impact the lives of individuals with IBD by providing evidence in support of the use of a novel, efficacious and non-toxic therapeutic option for those affected by IBD.