Maternal and pregnancy-related factors affecting human milk cytokines among Peruvian mothers bearing low-birth-weight neonates
Introduction
Human milk is regarded as the premier source of nutrition for infants until at least 6 months of age (AAP, 2012, WHO, 2003). It contains the nutrients necessary to promote adequate growth and bioactive substances essential for maturation of the neonatal immune system and intestinal function (Agarwal et al., 2011). Animal and in vitro studies suggest that cytokines may have an important role in the proliferation and migration of intestinal epithelial cells and in modulation of the mucosal immune system (Nguyen et al., 2014, Parigi et al., 2015, Rautava et al., 2012). Their effect could be especially important in low birth weight (LBW) infants (birth weight equal to or below 2500 g), a population at increased risk of mortality and complications like sepsis or necrotizing enterocolitis (Neu and Walker, 2011, Stoll et al., 2002). Among small infants, the intake of human milk is directly associated with decreased mortality and morbidity but the underlying mechanisms are unclear (Corpeleijn et al., 2012, Meinzen-Derr et al., 2009, Sisk et al., 2007).
This study is an exploratory analysis conducted on samples and data from a large randomized controlled trial evaluating supplemental lactoferrin for the prevention of late onset sepsis in neonates. The aim of this analysis was to characterize the cytokine profile of human milk in a cohort of mothers of LBW neonates from poor neighborhoods of Lima, Peru. These women are exposed to a high burden of infectious diseases throughout their lives and have a low intake of animal foods and high quality proteins, with potentially significant effects on their immune systems. As many obstetrical complications leading to intrauterine growth restriction and/or preterm birth may be associated with perturbations of the maternal immune system, we hypothesized that specific pregnancy disorders would be associated with distinctive human milk cytokine profiles and affect the newborn’s growth even after birth.
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Study participants
Participants were recruited at Hospital Nacional Cayetano Heredia, Hospital Nacional Almenara, and Hospital Nacional Sabogal in Lima, Peru. Infants were eligible if they weighed between 500 and 2,000 g and were admitted to the Neonatal Intensive Care Unit within the first 72 h of life. Exclusion criteria included severe underlying problems preventing oral feeding, family history of cow milk allergy or chronic conditions potentially affecting growth (for example chromosomal abnormalities, anatomic
Clinical and demographic information
Demographic and clinical data were available on 300 of the 301 mothers with milk samples available for cytokine analysis (Table 1). The median maternal age was 30 years (IQR 24, 34). The median monthly household income was 1000 Peruvian Soles (approximately US $300), with a median of 4 people (IQR 3, 6) per household. Median gestational age, assessed either by obstetrical ultrasounds, Ballard clinical score or reliable date of last menstrual period was 31 weeks (IQR 29, 33). Only 4/300 (1.3%)
Discussion
Despite the changes in human milk throughout lactation, the function of its immunological constituents, drivers of inter-individual differences and the implications for the neonate remain unclear. In this population of women living in a resource-limited setting who delivered LBW babies, we found that: 1) A core of 12 cytokines (TGF-β1-3, IL-1β, IL-6, IL-7 and TNF) and chemokines (MCP-1, MIP-1β, IP-10, IL-8, RANTES) was present in virtually all colostrum and mature human milk samples; 2)
Conclusion
Complications of pregnancy influence the concentration of cytokines and chemokines in human milk, potentially affecting the initial priming of the neonatal immune system. In depth understanding of the interplay between human milk immune components and the intestinal mucosa system could open the way for innovative approaches to neonatal health.
Funding
This work was funded by the Grand Challenges Explorations Grant from Bill & Melinda Gates Foundation, Grant OPP1015669 (T.J.O.), by the Public Health Service award R01-HD067694-01A1 from the National Institute of Child Health and Human Development (NICHD), USA (T.J.O.), and by the Center for Tropical Diseases-Institute for Human Infections and Immunity at the University of Texas Medical Branch at Galveston (N.S.U.). The content is solely the responsibility of the authors and does not
References (34)
- et al.
Premature delivery influences the immunological composition of colostrum and transitional and mature human milk
J. Nutr.
(2011) - et al.
Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns
Int. J. Biochem. Cell Biol.
(2013) - et al.
Ontogeny of early life immunity
Trends Immunol.
(2014) - et al.
Effects of interleukin-8 on the developing human intestine
Cytokine
(2002) Breastfeeding and the use of human milk
Pediatrics
(2012)Neonatal immunology: responses to pathogenic microorganisms and epigenetics reveal an immunodiverse developmental state
Immunol. Res.
(2013)- et al.
Immune markers in breast milk and fetal and maternal body fluids: a systematic review of perinatal concentrations
J. Hum. Lact.
(2011) - et al.
Maternal cytokine production patterns in women with pre-eclampsia
Am. J. Reprod. Immunol.
(2005) - et al.
Temporal trends in the inflammatory cytokine profile of human breastmilk
Breastfeeding Med.
(2014) - et al.
Intake of own mother's milk during the first days of life is associated with decreased morbidity and mortality in very low birth weight infants during the first 60 days of life
Neonatology
(2012)
Preterm infants have deficient monocyte and lymphocyte cytokine responses to group B streptococcus
Infect. Immun.
Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection
Nature
Role of Th17Cells in the pathogenesis of human IBD
ISRN Inflamm.
Characterisation of the host inflammatory response to Staphylococcus epidermidis in neonatal whole blood. Archives of disease in childhood
Fetal Neonatal Ed.
Cytokine production by leukocytes from human milk
Adv. Exp. Med. Biol.
Modulation of neonatal microbial recognition: TLR-mediated innate immune responses are specifically and differentially modulated by human milk
J. Immunol.
Innate immunity of the newborn: basic mechanisms and clinical correlates. Nature reviews
Immunology
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These authors have contributed equally to the work.