ERA

Download the full-sized PDF of Altered ganglioside metabolism in inflammatory bowel disease and the impact of dietary ganglioside intakeDownload the full-sized PDF

Analytics

Share

Permanent link (DOI): https://doi.org/10.7939/R3895B

Download

Export to: EndNote  |  Zotero  |  Mendeley

Communities

This file is in the following communities:

Graduate Studies and Research, Faculty of

Collections

This file is in the following collections:

Theses and Dissertations

Altered ganglioside metabolism in inflammatory bowel disease and the impact of dietary ganglioside intake Open Access

Descriptions

Other title
Subject/Keyword
nutrition
IBD
inflammation
ganglioside
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Miklavcic, John J
Supervisor and department
Clandinin, M Tom
McCargar, Linda J
Examining committee member and department
Vine, Donna (AFNS)
Schnabl, Kareena L (MLS)
McCargar, Linda J (AFNS)
Thomson, Alan BR (Gastroenterology)
Zello, Gordon A (Pharmacy and Nutrition)
Clandinin, M Tom (AFNS)
Mazurak, Vera C (AFNS)
Department
Department of Agricultural, Food, and Nutritional Science
Specialization
Nutrition and Metabolism
Date accepted
2014-09-29T11:22:46Z
Graduation date
2014-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Gangliosides are integral to the structure and function of the plasma membrane. Ganglioside composition of the small intestinal brush border membrane and apical surface of the colon influence numerous cell processes including microbial attachment, cell division, differentiation, and signaling. Accelerated catabolism of ganglioside in intestinal disease results in increased pro-inflammatory signaling. Restoring proper structure and function to the diseased intestine can resolve inflammation, increase resistance to infection and improve gut integrity to induce remission of conditions like necrotizing enterocolitis and Crohn disease. Pre-clinical studies indicate that the amount of ganglioside GD3 in intestinal mucosa is decreased with inflammation, low level of ganglioside is associated with higher production of pro-inflammatory signals, and ganglioside content of intestinal mucosa can be increased by intake of dietary ganglioside. Inducing inactive state of inflammatory bowel disease may be achieved by reducing the rate that gangliosides are degraded or by increasing the intake of specific dietary gangliosides. Sections of intestinal mucosa from terminal ileum or colon were obtained from patients with ulcerative colitis or active inflammatory Crohn disease undergoing surgical bowel resection. Control samples of normal intestine were obtained from participants with benign colon polyps and from participants with colorectal cancer. Gangliosides and phospholipids of intestinal mucosa were characterized using reverse-phase liquid chromatography-QQQ mass spectrometry. Ganglioside catabolism enzymes beta-hexosaminidase A and sialidase-3 were measured in intestinal mucosa by western blot. A cohort of healthy participants and patients with inflammatory bowel disease completed an eight-week feeding study to determine the safety and efficacy of ganglioside consumption. Participants consumed a milk fat fraction containing 43 mg ganglioside daily or the equivalent milk fat fraction without ganglioside. Plasma gangliosides were characterized using reverse-phase liquid chromatography-QQQ mass spectrometry, quality of life was assessed by quality of life inflammatory bowel disease questionnaire, intestinal permeability was assessed by oral lactulose/mannitol challenge and inflammatory markers LTB4, PGE2 and TNF-α were measured by ELISA in participants in the intervention study. Ganglioside GM3 was 2-fold higher (P<0.05) in inflammatory bowel disease intestine compared to control intestine. Control intestine exhibited 3-fold higher (P<0.001) ganglioside GD1a content than intestine from patients with inflammatory bowel disease. Intestine from patients with inflammatory bowel disease exhibited 1.7-fold increase (P<0.05) in beta-hexosaminidase A content in comparison to control intestine. The level of sialidase-3 in intestine from patients with inflammatory bowel disease was increased 8.3-fold (P<0.001) compared to normal intestine. The level of gangliosides GD3 and GD1a with two and three unsaturated bonds in the ceramide component was lower (P<0.001) in intestine from patients with inflammatory bowel disease than control intestine. In addition, polyunsaturated constituents of phosphatidylcholine were significantly reduced (P<0.05) in intestine from patients with inflammatory bowel disease versus control intestine. There were no serious or other adverse events associated with dietary ganglioside intake. Ganglioside consumption increased (P<0.05) plasma content of total GD3 by 35% over eight weeks. Consumption of ganglioside increased (P<0.01) emotional health by 39% and improved (P<0.02) systemic symptoms in patients with inflammatory bowel disease by 36% over eight weeks. Participants consuming ganglioside exhibited 19% decrease in intestinal permeability (P=0.04). Consuming ganglioside did not change the plasma concentration of acute systemic inflammatory mediators LTB4, PGE2 or TNF-α. This study suggests a new paradigm by proposing that inflammatory bowel disease occurs as a consequence of increased catabolism of specific gangliosides. Impaired intestinal integrity characteristic of inflammatory bowel disease may be overcome by dietary treatment with specific species of ganglioside shown to be deficient in inflammatory bowel disease. Ganglioside is a bioavailable dietary compound that can be consumed to improve quality of life in patients with inflammatory bowel disease and potentially treat other disorders involving altered ganglioside metabolism.
Language
English
DOI
doi:10.7939/R3895B
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
“Dietary Ganglioside Reduces Proinflammatory Signaling in the Intestine.” Miklavcic JJ, Schnabl KL, Mazurak VC, Thomson ABR, Clandinin MT. 2012. JNUME. DOI:10.1155/2012/280286

File Details

Date Uploaded
Date Modified
2014-11-15T08:22:42.768+00:00
Audit Status
Audits have not yet been run on this file.
Characterization
File format: pdf (PDF/A)
Mime type: application/pdf
File size: 1772891
Last modified: 2015:10:12 12:09:40-06:00
Filename: Miklavcic_John_J_201409_PhD.pdf
Original checksum: ecd8a065260a99a5b2060181c5702e81
Activity of users you follow
User Activity Date