Dietary GD3 Ganglioside Reduces the Incidence and Severity of Necrotizing Enterocolitis by Sustaining Regulatory Immune Responses

Xu, Jiliu*; Anderson, Virginia; Schwarz, Steven M.*

Journal of Pediatric Gastroenterology & Nutrition: November 2013 - Volume 57 - Issue 5 - p 550–556
doi: 10.1097/MPG.0b013e3182a027e1
Original Articles: Gastroenterology

Objectives: Gangliosides are glycosphingolipids, rich in colostrum and in membrane microdomains, which promote enterocyte growth and differentiation, and modulate TH1/TH2 responses. In an in vitro intestinal explant model of necrotizing enterocolitis (NEC), gangliosides have been shown to ameliorate intestinal injury; however, possible immunomodulatory mechanisms associated with this observation, as well as potential in vivo protective effects of gangliosides, remain unknown. The present study evaluates the effects of dietary GD3, the predominant ganglioside in neonatal rat intestine, both on the clinicopathologic expression of disease and on ileal Foxp3+ T regulatory cell immune responses in an experimental NEC model.

Methods: Newborn rat pups were fed gavage formula (NEC) or formula supplemented with 15 μg/mL GD3 (GD3-NEC). Dam-fed (DF) littermates served as controls. NEC was induced by asphyxia and cold stress. At 96 hours, ileal gross and histologic changes were evaluated, and ileal cytokine profiles, Foxp3 expression, and Foxp3+ cell numbers were determined.

Results: GD3 decreased the incidence and gross and histopathologic severity of NEC. Ileal Foxp3 expression and Foxp3+ cell numbers were significantly decreased in the NEC group compared with DF. GD3 increased ileal Foxp3 expression and Foxp3+ cell numbers, in association with upregulation of anti-inflammatory cytokine interleukin (IL)-10 and chemokines, tissue inhibitor of metalloproteinases 1, IL-1 receptor antagonist (IL-1ra), and suppressed proinflammatory mediators.

Conclusions: These data suggest that dietary GD3 protects newborn rats from NEC, in part, by augmenting mucosal Foxp3+ T regulatory immune responses.

*Departments of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition

Department of Pathology, SUNY-Downstate Medical Center, Brooklyn, NY.

Address correspondence and reprint requests to Jiliu Xu, MD, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital at Downstate, 445 Lenox Road, Box 49, Brooklyn, NY 11203 (e-mail: jiliu.xu@downstate.edu).

Received 23 March, 2013

Accepted 11 June, 2013

This study was financially supported by a Madu Rao Pediatric Research Award and a 2008 SUNY-Downstate Dean's Pilot Project Grant (J.X., S.M.S.).

The authors report no conflicts of interest.

© 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,