Factors in breast milk (antibodies, lymphoid cells and bacterial/viral inhibitory agents) provide passive protection for the infant intestine against intraluminal micro-organisms, toxins and antigens. However, breast milk may also actively stimulate the development of the neonate's own intestinal host defenses. Accordingly, our working hypothesis for this proposal is that breast milk can actively stimulate the accelerated development of normal intestinal host defenses in the newborn including the mucosal immune response to ingested antigens. We reported that intestinal microvillus membranes (MVM) from newborn intestine have biochemical and functional differences compared to MVM from adult intestine. These differences in the """"""""intestinal mucosal barrier"""""""" may account for the increased attachment and uptake of antigens noted in the newborn (possibly leading to allergic illness) and for an increase response to bacterial toxins (toxigenic diarrhea). We can stimulate the MVM of newborn intestine to assume biochemical and functional characteristics similar to the MVM from intestine of adults by giving cortisone or thyroxin to pregnant dams or to neonates. We now plan to test whether breast milk or its """"""""growth factors"""""""" (hormones, lymphokines or epidermal growth factor) can modify the handling of antigens by neonatal enterocytes and stimulate a normal mucosal immune response to these antigens and whether these factors alter the composition of enterocyte membranes to affect bacterial adherence, toxin response and antigen uptake. Using established techniques, we will determine if colostrum and its lymphoid cells modify the response to ingested antigen in the neonate by examining if systemic priming or tolerance occurs. We will also examine antigen handling and Ia antigen expression on enterocytes in the presence of breast milk and study the role of known colostral growth factors on MVM biochemical composition and enterocyte responses to enterotoxin. We will study the effect of breast feeding on glycoslytransferases and MVM glycoprotein and glycolipid receptors. Finally, using a new human fetal transplant model and organ culture/MVM preparation of surgical specimens of intestines from premature infants, we will determine if breast milk alters the mucosal surface response to enterotoxins, antigen binding/uptake and bacteria adherence and MVM receptor expression (Fc, Sc, Ia, GM1). These studies should help define mucosal barrier defects in newborns and help explain the pathogenesis of neonatal diseases such as necrotizing enterocolitis, toxigenic diarrhea and food allergy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Unknown (R22)
Project #
5R22HD012437-11
Application #
3566277
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1979-05-01
Project End
1992-12-31
Budget Start
1990-01-01
Budget End
1990-12-31
Support Year
11
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Beck, P L; Ihara, E; Hirota, S A et al. (2010) Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and trefoil factor 3. Am J Physiol Gastrointest Liver Physiol 299:G43-53
Savidge, Tor C; Newman, Paul; Pothoulakis, Charalabos et al. (2007) Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione. Gastroenterology 132:1344-58
Bao, Yuanwu; Zhu, Libin; Newburg, David S (2007) Simultaneous quantification of sialyloligosaccharides from human milk by capillary electrophoresis. Anal Biochem 370:206-14
Meng, Di; Newburg, David S; Young, Cheryl et al. (2007) Bacterial symbionts induce a FUT2-dependent fucosylated niche on colonic epithelium via ERK and JNK signaling. Am J Physiol Gastrointest Liver Physiol 293:G780-7
Nanthakumar, N Nanda; Dai, Dingwei; Meng, Di et al. (2005) Regulation of intestinal ontogeny: effect of glucocorticoids and luminal microbes on galactosyltransferase and trehalase induction in mice. Glycobiology 15:221-32
Dai, Dingwei; Nanthakumar, N Nanda; Savidge, Tor C et al. (2002) Region-specific ontogeny of alpha-2,6-sialyltransferase during normal and cortisone-induced maturation in mouse intestine. Am J Physiol Gastrointest Liver Physiol 282:G480-90
Fernandez, I M; Silva, M; Schuch, R et al. (2001) Cadaverine prevents the escape of Shigella flexneri from the phagolysosome: a connection between bacterial dissemination and neutrophil transepithelial signaling. J Infect Dis 184:743-53
Dai, D; Nanthkumar, N N; Newburg, D S et al. (2000) Role of oligosaccharides and glycoconjugates in intestinal host defense. J Pediatr Gastroenterol Nutr 30 Suppl 2:S23-33
Siafakas, C G; Anatolitou, F; Fusunyan, R D et al. (1999) Vascular endothelial growth factor (VEGF) is present in human breast milk and its receptor is present on intestinal epithelial cells. Pediatr Res 45:652-7
Capano, G; Bloch, K J; Carter, E A et al. (1998) Polyamines in human and rat milk influence intestinal cell growth in vitro. J Pediatr Gastroenterol Nutr 27:281-6

Showing the most recent 10 out of 61 publications