Background

• The neonatal period: A ‘window’of maturational opportinity
• Hygiene hypothesis
• Effects of early diet on gut and brain maturation
• Type of early diet

• References

The neonatal period: A ‘window’ of maturational opportinity

At birth, there is a dramatic shift from a sterile environment with constant placental supply of nutrients, to a microbe-rich environment with intermittent uptake of complex milk nutrients via the gut. A successful birth transition involves rapid mucosal maturation and tolerance to food antigens and the billions of colonizing microbes during the first days and weeks (1).

Newborns depend mainly on inborn (innate) immunity, while adaptive, cell-mediated immunity gradually develops throughout the body. Maturation of immunity interacts with development of many organ systems, and is influenced by factors in milk and by colonizing bacteria just after birth. The neonatal period thus becomes a highly sensitive ‘window’ of maturation that influences health at this time, but also later in life (2-3).

Hygiene hypothesis

This forms the background for our overall working hypothesis in NEOMUNE:

Optimal milk and microbiota in early life improve later immune, gut and brain functions

Immune-related disorders have increased over the last 50 years in industrialized countries and have led to the so-called 'hygiene hypothesis'. This hypothesis suggests that exposure to a balanced microbiota early in life, with a well-controlled activation of Toll-like receptors (TLRs) on epithelial and immune cells, is crucial in facilitating optimal immune maturation (2-6).

The evidence for the hygiene hypothesis remains weak and is based mainly on population studies on allergies and other auto-immune diseases in older children and adults. Few studies have addressed the important question of how we can best support development immediately after birth, and provide optimal resistance against both mucosal and systemic infections.

Effects of early diet on gut and brain maturation

Cross-talk among immune cells in different parts of the body connects the local gut mucosal immunity with systemic immunity (2) and with immunity at more distant sites such as the brain (7). In the neonatal period, the gut and the brain are both very sensitive to inflammatory insults and infections (1-3,7-8). Milk and microbiota interventions may affect gut and brain functions by affecting the inter-organ, neuro-endocrine signaling, and by the circulating gut-derived inflammatory mediators, intact milk immunomodulatory factors and metabolites of dietary or bacterial origin (7-10).

The phenotype, density and cytokines of the brain glial cells may play the key role for brain functions that are affected by diet and microbiota (10-12). Such combined diet and microbiota effects on the gut and brain are likely to be most pronounced in hyper-sensitive newborns, such as preterm or growth-restricted infants (born <37 weeks gestation, <2000 g, 15% of all infants) (8,13-15). 

Due to immaturity, such infants are particularly dependent on milk bioactive factors and a balanced microbiota, but they are also intolerant to large amounts of oral feeds (8,13), leading to ‘minimal enteral nutrition’ (MEN) for the first week(s).

Brain dysfunction is the most serious late complication of preterm birth and is more prevalent after the feeding and bacteria-dependent gut-inflammatory disease, necrotizing enterocolitis (NEC) (8). The links may be direct or indirect, but the recent finding that gut microbial colonization affects brain maturation and motoric control in mouse pups (10) supports direct links among diet, immunity, gut and brain in early life. In both preterm and term infants, breastfeeding relates to fewer infections (16) and improved gut health and cognition (13,14).

Birth by Caesarean section in high-hygiene hospital environments, and widespread use of antibiotics, are factors that reduce gut microbiota density and diversity in the newborn for some time after birth (5,20-22). On the other hand, high-hygiene environments and antibiotics are essential tools to combat infections, especially for the weakest newborn infants.

Type of early diet

The time is now ripe for a concerted effort that verifies early diet and gut colonization effects on maturation of immunity gut and brain.

It remains unknown, how the effects of milk and colostrum, from own mother, other mothers, or even from another species, exert immuno-modulatory effects. There is some evidence from new animal models (17-19) but more studies, from basic mechanisms to clinical application, are required.

Knowledge of diet and microbial factors that influence immune maturation is crucial in designing milk formulas for infants for whom breastfeeding is restricted, or not possible. Addition of probiotics to milk feedings have been speculated to promote colonization of beneficial gut bacteria, suppress pathogens and stimulate immune development (19,23,24), but the current level of evidence inhibits widespread use of probiotics, especially for vulnerable newborn infants. Likewise, intense focus is also on the prebiotic human milk oligosaccharides (HMOs) that may promote epithelial defense and healthy gut colonization (24,25), but effects in newborns are not known.

The benefits of breast-feeding may be explained by absorption of milk bioactives, such as milk fat globule membrane (MFGM) fractions, polyunsaturated fatty acids (PUFA), caseinoglycomacropeptide (CGMP) and phospholipids (PL) and preliminary evidence suggests effects on immunity, gut and brain (13,14,26,27). Beneficial effects may even be induced by feeding amniotic fluid (‘the fetal enteral diet’), as indicated in studies in newborn pig (18) and mice (28).

New advice for diet and microbiota regimens for infants must be based on safety, science and technical and commercial availability of high-quality products.

References

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