Oral Exposure to Diabetes-Promoting Food or Immunomodulators in Neonates Alters Gut Cytokines and Diabetes
- Fraser W. Scott123,
- Paul Rowsell24,
- Gen-Sheng Wang1,
- Karolina Burghardt12,
- Hubert Kolb5 and
- Stefanie Flohé5
- 1Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada
- 2University of Ottawa, Ottawa, Ontario, Canada
- 3Nutrition Research Division Health Canada, Ottawa, Ontario, Canada
- 4Toxicology Research Division, Health Canada, Ottawa, Ontario, Canada
- 5German Diabetes Research Institute, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
Abstract
Disease development in diabetes-prone BB rats is modified by the type of diet fed after weaning. The aim of this investigation was to determine whether exposure during the first week of life to antigens from a known diabetes-promoting diet (NIH-07) could modify diabetes incidence and, if so, to what extent this occurs via alterations in systemic T-cell reactivity, gut cytokines, or islet infiltration. Diabetes-prone BB (BBdp) rats were hand-fed twice daily between age 4 and 7 days with vehicle, a hydrolyzed casein (HC)–based infant formula, Pregestimil (PG), PG + cereal-based NIH-07 diet, PG + lipopolysaccharides (LPS) or PG + LPS + silica. After weaning, they were fed either an NIH-07 diet or a semipurified HC (diabetes-retardant) diet until 150 days. In separate studies, 5-day-old BBdp rat pups were administered the aforementioned treatments, and expression of intestinal mRNA for γ-interferon (IFN-γ) or transforming growth factor-β (TGF-β) was quantified using reverse transcriptase–polymerase chain reaction. The effect of early oral treatment with NIH-07 or PG on systemic T-cell reactivity was evaluated using footpad swelling delayed-type hypersensitivity (DTH) and the popliteal lymph node assay. Oral exposure of neonates to a complex mixture of antigens from the diabetes-promoting diet delayed onset of diabetes (79 vs. 88 days) and prevented disease in approximately one-third of animals. A similar protective effect was seen for neonatal exposure to wheat gluten in animals subsequently weaned onto a semipurified wheat gluten diet. By contrast, LPS-treated neonates displayed more severe insulitis and developed diabetes at an increased rate, which was significantly suppressed by co-administration of silica particles. The protective effect of early exposure to diabetogenic diets was not associated with significant reduction of islet infiltration, and there was no impact on the DTH response to food antigens. However, whereas diabetes-resistant BBc rats developed systemic tolerance to NIH-07 antigens fed chronically, BBdp rats did not. The lack of effect of the early oral antigen regimen on the DTH reaction in the footpad, a classic Th1-mediated reaction, suggests little effect on systemic T-cell reactivity. However, local effects were observed in the small intestine. Oral exposure to diabetes-promoting food antigens or LPS downregulated the Th1 cytokine IFN-γ and decreased the IFN-γ/TGF-β ratio. Thus, oral exposure to diabetes-promoting food antigens and immune modulators in neonates can modify diabetes expression in association with changes in local cytokine balance in the gut.
Footnotes
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Address correspondence and reprint requests to Fraser W. Scott, Ottawa Health Research Institute, Molecular Medicine Program, Laboratory N1, Box 221, 501 Smyth Road, Ottawa, Ontario, K1H 8L6, Canada. E-mail: fscott{at}ohri.ca.
Received for publication 8 July 2001 and accepted in revised form 3 October 2001.
BLU, Boehringer light units; DTH, delayed-type hypersensitivity; HC, hydrolyzed casein diet; IFN-γ, γ-interferon; IL, interleukin; LPS, lipopolysaccharide; NIH, NIH-07 diet; PG, Pregestimil diet; PLN, popliteal lymph node; RT-PCR, reverse transcriptase–polymerase chain reaction; TGF-β, transforming growth factor-β; WG, wheat gluten diet.
