Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2015; 21(35): 10080-10090
Published online Sep 21, 2015. doi: 10.3748/wjg.v21.i35.10080
Increased catabolism and decreased unsaturation of ganglioside in patients with inflammatory bowel disease
John J Miklavcic, Tasha DL Hart, Gordon M Lees, Glen K Shoemaker, Kareena L Schnabl, Bodil MK Larsen, Oliver F Bathe, Alan BR Thomson, Vera C Mazurak, M Tom Clandinin
John J Miklavcic, Glen K Shoemaker, Vera C Mazurak, M Tom Clandinin, Alberta Institute for Human Nutrition, University of Alberta, Edmonton AB T6G 2R1, Canada
Tasha DL Hart, Kareena L Schnabl, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton AB T6G 2B7, Canada
Gordon M Lees, Division of General Surgery, University of Alberta, Edmonton AB T6G 2B7, Canada
Bodil MK Larsen, Alberta Health Services, Edmonton AB T6G 2B7, Canada
Oliver F Bathe, Alberta Health Services, Calgary AB T2N 4N2, Canada
Alan BR Thomson, Division of Gastroenterology, Western University, London ON N6A 5A5, Canada
M Tom Clandinin, Department of Medicine, University of Alberta, Edmonton AB T6G 2B7, Canada
Author contributions: Miklavcic JJ co-authored the manuscript and performed the research; Hart TDL and Shoemaker GK contributed to technical aspects of performing the research; Lees GM, Bathe OF and Thomson ABR procured surgical specimens; Schnabl KL, Mazurak VC, Larsen BMK and Clandinin MT contributed to study design, interpretation of results and writing of the manuscript; Clandinin MT obtained grants to fund the research, provided interpretation and supervision of all aspects.
Supported by The Natural Sciences and Engineering Research Council of Canada, the Broad Foundation, the Canadian Institutes of Health Research and The Alberta Livestock and Meat Agency.
Institutional review board statement: Ethics approval for this study was obtained from the Biomedical Panel of the University of Alberta Health Research Ethics Board (Pro00001371).
Institutional animal care and use committee statement: Animals were not used in the present study.
Conflict-of-interest statement: No relevant conflict of interest to declare.
Data sharing statement: In accordance with granting agency, the primary investigator holds the research data for 5 years after granting period. In further accordance with the granting agency, the data are not available in openly accessible databases as it does not comprise information related to bioinformatics, atomic or molecular coordinates. Consent for data sharing was not explicitly obtained but the presented data are anonymized of all personally identifying information.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. M Tom Clandinin, Department of AFNS, Distinguished University Professor Emeritus, Alberta Institute for Human Nutrition, Faculty of ALES, University of Alberta, 116 St. 85 Ave, Edmonton AB T6G 2R1, Canada. tclandin@ualberta.ca
Telephone: +1-780-4925188 Fax: +1-780-4929270
Received: February 1, 2015
Peer-review started: February 8, 2015
First decision: March 10, 2015
Revised: March 27, 2015
Accepted: May 2, 2015
Article in press: May 2, 2015
Published online: September 21, 2015
Abstract

AIM: To investigate whether accelerated catabolism of ganglioside and decreased ganglioside content contribute to the etiology of pro-inflammatory intestinal disease.

METHODS: Intestinal mucosa from terminal ileum or colon was obtained from patients with ulcerative colitis or inflammatory Crohn’s disease (n = 11) undergoing bowel resection and compared to control samples of normal intestine from patients with benign colon polyps (n = 6) and colorectal cancer (n = 12) in this observational case-control study. Gangliosides and phospholipids of intestinal mucosa were characterized by class and ceramide or fatty acid composition using liquid chromatography triple-quad mass spectrometry. Content and composition of ganglioside classes GM1, GM3, GD3, GD1a, GT1 and GT3 were compared among subject groups. Content and composition of phospholipid classes phosphatidylcholine (PC) and phosphatidylethanolamine were compared among subject groups. Unsaturation index of individual ganglioside and phospholipid classes was computed and compared among subject groups. Ganglioside catabolism enzymes beta-hexosaminidase A (HEXA) and sialidase-3 (NEU3) were measured in intestinal mucosa using western blot and compared among subject groups.

RESULTS: Relative GM3 ganglioside content was 2-fold higher (P < 0.05) in intestine from patients with inflammatory bowel disease (IBD) compared to control intestine. The quantity of GM3 and ratio of GM3/GD3 was also higher in IBD intestine than control tissue (P < 0.05). Control intestine exhibited 3-fold higher (P < 0.01) relative GD1a ganglioside content than IBD intestine. GD3 and GD1a species of ganglioside containing three unsaturated bonds were present in control intestine, but were not detected in IBD intestine. The relative content of PC containing more than two unsaturated bonds was 30% lower in IBD intestine than control intestine (P < 0.05). The relative content of HEXA in IBD intestine was increased 1.7-fold (P < 0.05) and NEU3 was increased 8.3-fold (P < 0.01) compared to normal intestine. Intestinal mucosa in IBD is characterized by increased GM3 content, decreased GD1a, and a reduction in polyunsaturated fatty acid constituents in GD3, GD1a and PC.

CONCLUSION: This study suggests a new paradigm by proposing that IBD occurs as a consequence of increased metabolism of specific gangliosides.

Keywords: Ganglioside, Phospholipid, Fatty acid, Lipid, Inflammatory bowel disease, Inflammation, Nutrition, Crohn disease, Ulcerative colitis

Core tip: This research suggests a new paradigm by proposing that increased metabolism of specific gangliosides is fundamental to the etiology of inflammatory bowel disease. The study demonstrates that the catabolism of gangliosides is elevated in the intestinal mucosa of patients with inflammatory bowel disease and suggests that intervention with appropriate dietary gangliosides potentially reduces intestinal permeability, improving intestinal integrity.