Maternal Microbiota, Early Life Colonization and Breast Milk Drive Immune Development in the Newborn

Abstract

The innate immune system is the oldest protection strategy that is conserved across all organisms. Although having an unspecific action, it is the first and fastest defense mechanism against pathogens. Development of predominantly the adaptive immune system takes place after birth. However, some key components of the innate immune system evolve during the prenatal period of life, which endows the newborn with the ability to mount an immune response against pathogenic invaders directly after birth. Undoubtedly, the crosstalk between maternal immune cells, antibodies, dietary antigens, and microbial metabolites originating from the maternal microbiota are the key players in preparing the neonate's immunity to the outer world. Birth represents the biggest substantial environmental change in life, where the newborn leaves the protective amniotic sac and is exposed for the first time to a countless variety of microbes. Colonization of all body surfaces commences, including skin, lung, and gastrointestinal tract, leading to the establishment of the commensal microbiota and the maturation of the newborn immune system, and hence lifelong health. Pregnancy, birth, and the consumption of breast milk shape the immune development in coordination with maternal and newborn microbiota. Discrepancies in these fine-tuned microbiota interactions during each developmental stage can have long-term effects on disease susceptibility, such as metabolic syndrome, childhood asthma, or autoimmune type 1 diabetes. In this review, we will give an overview of the recent studies by discussing the multifaceted emergence of the newborn innate immune development in line with the importance of maternal and early life microbiota exposure and breast milk intake.

Keywords: birth; breast milk; early life; gestation; innate immune system; microbiota; neonate; pregnancy.

Figure 1

Overview of environmental factors shaping the development of the newborn microbiota and mucosal immune system. Throughout pregnancy, fetal immune development is supported by microbial metabolites originating from the maternal microbiota and by dietary compounds. Innate immune cell populations, such as monocytes, ILCs, and neutrophils belong to the most affected immune cells at this stage. Only at birth, the emerging immune system of the newborn is confronted with live bacteria and thus, is still dependent on maternal protection, which is ensured through breastfeeding. Apart from passive immunization via breast milk, neonatal iNKTs, NK cells, ILCs, and the gastrointestinal epithelial barrier protect against invading pathogens and promote the beneficial interplay with the neonatal microbiota. The adaptive immune system in mice develops primarily postnatally, while a component of adaptive immunity is already present in the human fetus. Birth mode, feeding, and the intake of antibiotics are additional factors that shape the early life microbiota and the neonatal immune system. During the subsequent weaning reaction, when solid food is introduced to the infant’s diet, a tremendous shift occurs in its intestinal bacterial community composition. Consequently, the microbiota is no longer represented by Bifidobacteria and Lactobacilli, but increases in metabolomic diversity evolving to a more adult-like microbiota that is established during this early period of life. This period is often also called the window of opportunity since particularly during this time, external cues have a profound impact on life-long health, the evolving microbiota, and the mucosal immune system. IBD, inflammatory bowel disease; sIgA, secretory immunoglobulin A; ILCs, innate lymphoid cells; iNKTs, invariant natural killer T cells; MAIT, mucosal-associated invariant T cells; moDCs, monocyte-derived dendritic cells; NK, natural killer cells; Th cells, T helper cells; Treg, regulatory T cells; T1D, type 1 diabetes.

Figure 2

Architecture of the mucus layer in the small intestine. The small intestine has a loose mucus layer (illustrated in green), which keeps commensals at distance. In addition, the epithelium is covered by a glycocalyx, a dense layer composed of secreted mucus proteins (MUC2) that is attached to epithelial cells via the transmembrane part. These layers do not only protect from bacterial penetration, but also from self-digestion of host intestinal tissue. Secretion of AMPs by Paneth cells and other epithelial cells as well as sIgA by plasma cells regulate the growth of different commensal bacterial strains. Furthermore, signals from the neonatal microbiota shape the DNA methylome in intestinal stem cells from birth until weaning. Genes associated with cell glycosylation are particularly affected by a DNA methylation gain, which also correlates with an increase in gene expression. Hence, barrier integrity during early life is additionally ensured through epigenetic remodeling triggered by the microbiota.

Figure 3

Crosstalk between the microbiota and intestinal epithelial cells. Different signaling molecules from the microbiota bind to PRRs expressed on the epithelium, which subsequently activate innate immune mechanisms. This activation can elicit a wide range of effects: It may trigger a pro-inflammatory state for the elimination of pathogens or induce tolerance to commensals by increasing the production of mucins and AMPs, promoting epithelial cell turnover, and mediating stem cell survival. AMPs, antimicrobial peptides; MDP, muramyl dipeptide; PGE2, prostaglandin E2; ROS, reactive oxygen species; TSS, type secretion system.

Figure 4

Breastfeeding mediates the transfer of biologically active molecules from the mother to the infant. Breast milk contains a huge diversity of components, ranging from simple sugars, antibodies, and cells to molecules that directly trigger reactions in target cells and/or tissues, such as cytokines, growth factors, and exosomes. Thereby, milk molecules ensure the infant’s well-being by driving innate and adaptive immune maturation, and further contributing to the development of its mucosal and nervous system. HMOs, human milk oligosaccharides; ILCs, innate lymphoid cells; Mφ, macrophages; MDSCs, mononuclear-derived suppressor cells; MO, monocytes; NP, neutrophils; SC, stem cells.