Rajashri S. Iyengar, MD, MPH; Clinical Instructor in Pediatric Allergy/Immunology, Massachusetts General Hospital for Children; Instructor in Pediatrics, Harvard Medical School
Allergic colitis: the role of breast milk factors in infant allergic disease
Childhood allergic disease has increased dramatically over the past 20 years. The basis of this increase is incompletely understood. Human breast milk contains a complex array of immune factors and can be viewed as the interface between the maternal and infant immune systems. Emerging evidence identifies the importance of intestinal mucosal responses in several pathologic conditions, including necrotizing entercolitis (NEC), Crohn’s disease, inflammatory bowel disease, and allergic colitis. In this context, the interaction of external factors such as breast milk on the gut epithelium with remains poorly understood.
My research interests center on understanding the role of breast milk in modulating gut mucosal responses in allergic disease. Allergic colitis (AC), is a poorly characterized immune reaction to food proteins, and is the most common food allergy under 2 years of age (1). It commonly causes blood-streaked stools in otherwise healthy infants, most of whom are strictly breastfed, by an unknown mechanism. Intestinal mucosal immune responses have been implicated in AC, but the molecular pathogenesis remains poorly understood.
Previous work from our group has demonstrated the immunomodulatory potential of breast milk in the gastrointestinal (GI) system. In vitro studies of human fetal epithelial cells (hFIECs) exposed to breast milk levels of TGF-b2 demonstrated attenuated inflammatory responses when treated with IL-1b(2). In addition, we have established a novel ex vivo system that utilizes human fetal intestinal xenografts transplanted into immunodeficient SCID mice to model the human infant gut lining (3). This innovative system provides a novel platform to identify specific gene expression patterns of the intestinal immune response and characterize how external factors, like breast milk, interface with gut mucosal immune responses relevant to AC.
Figure legend: Stimulation with IL-1 rapidly induced phosphorylation of ERK, which is a key signaling molecule in the IL-1 dependent pro-inflammatory cascade. This signalling cascade was inhibited by TGF- B2 as demonstrated by immunohistochemistry in fetal intestinal organ culture explants(2).
Figure legend: Hydrocortisone (HCT) induces changes in gene expression and differentiation in immature human enterocytes. This venn diagram demonstrates HCT-regulated expression of multiple genes important for intestinal epithelial cell maturation, including genes associated with the polarization of intestinal epithelial cells.
Environmental allergens in human breast milk and airway disease
Although exclusive breastfeeding is the preferred method of nutrition for all infants based on other potential benefits of breastfeeding, studies examining these issues are crucial in determining whether specific factors in the breast milk are protective against allergic disease.
No studies to date have systematically examined the transfer of aeroallergens and cytokines in human maternal breast milk and their potential role in infant allergic tolerance and incidence of allergic disease. A recent seminal study in a murine model found that aeroallergens can be efficiently transferred from mother to neonate through breast milk (4) and protect breast-fed progeny from aeroallergen sensitization and asthma. We are currently conducting a 3 year prospective, observational birth cohort study of 50 atopic mothers and their newborn children. Breastfeeding mothers with and without (controls) a history of asthma and/or allergic rhinitis will be recruited from the MGH Birthing Center. The aim of this IRB-approved study is to identify possible aeroallergens and cytokines present in the breast milk of breastfeeding mothers. We will also prospectively follow these maternal-infant cohorts from delivery and determine if infants are protected from sensitization to aeroallergens present in the maternal breast milk. In addition, we will determine if specific immune cells (antigen-specific CD4+ T cells) isolated from breast-fed infants are less reactive (i.e. tolerized) to these antigens. During follow-up, each mother will be evaluated using a questionnaire for past/current history of asthma and other allergic disease and serum IgE testing for a standard panel of aeroallergens will be obtained. In addition, serial breast milk samples will be obtained throughout the duration of breastfeeding to be analyzed for the presence of environmental allergens noted in the maternal serum.
Reprinted by permission from Macmillan Publishers Ltd: Nature Medicine; Puddington L et al. Nat Med 2008.
Figure legend: Lactating non-allergic mice were exposed to a specific inhaled allergen, OVA. OVA was then found to be present in the BM, and when accompanied by TGF-Beta, provided the breast-feeding offspring with OVA-specific protection. This was achieved through the induction of CD4+ Tcells that were thought to be T reg cells.
- Iyengar SR, Walker WA. Immune Factors In Breastmilk And The Development of Atopic Disease. J Pediatr Gastroenterol Nutr.2012 Jun8.
- Rautava S, Nanthakumar NN, Dubert-Ferrandon A, Lu L, Rautava J, Walker WA. Breast milk-transforming growth factor-beta specifically attenuates IL-1beta-induced inflammatory responses in the immature human intestine via an SMAD6- and ERK-dependent mechanism. Neonatology;99(3):192-201.
- Lu L, Li T, Williams G, Petit E, Borowsky M, Walker WA. Hydrocortisone induces changes in gene expression and differentiation in immature human enterocytes. Am J Physiol Gastrointest Liver Physiol;300(3):G425-32.
- Verhasselt V, Milcent V, Cazareth J, Kanda A, Fleury S, Dombrowicz D, et al. Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat Med 2008;14(2):170-5.