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

• Author / Creator

  Miklavcic, John J

• 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.

• Subjects / Keywords

  • IBD
  • Gangliosides
  • Inflammation
  • Nutrition

• Graduation date

  Fall 2014

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3895B

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.