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Review
. 2021 Jun 1;9(6):584.
doi: 10.3390/vaccines9060584.

Neonatal Immune System Ontogeny: The Role of Maternal Microbiota and Associated Factors. How Might the Non-Human Primate Model Enlighten the Path?

Natalia Nunez  1 , Louis Réot  1 , Elisabeth Menu  1   2
Affiliations
Review

Neonatal Immune System Ontogeny: The Role of Maternal Microbiota and Associated Factors. How Might the Non-Human Primate Model Enlighten the Path?

Natalia Nunez et al. Vaccines (Basel). .

Abstract

Interactions between the immune system and the microbiome play a crucial role on the human health. These interactions start in the prenatal period and are critical for the maturation of the immune system in newborns and infants. Several factors influence the composition of the infant's microbiota and subsequently the development of the immune system. They include maternal infection, antibiotic treatment, environmental exposure, mode of delivery, breastfeeding, and food introduction. In this review, we focus on the ontogeny of the immune system and its association to microbial colonization from conception to food diversification. In this context, we give an overview of the mother-fetus interactions during pregnancy, the impact of the time of birth and the mode of delivery, the neonate gastrointestinal colonization and the role of breastfeeding, weaning, and food diversification. We further review the impact of the vaccination on the infant's microbiota and the reciprocal case. Finally, we discuss several potential therapeutic interventions that might help to improve the newborn and infant's health and their responses to vaccination. Throughout the review, we underline the main scientific questions that are left to be answered and how the non-human primate model could help enlighten the path.

Keywords: birth; breastfeeding; colonization; immune system maturation; microbiota; non-human primate; pregnancy; probiotics; vaccination; weaning.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Kinetics of the local environment impact, the gut microbiota evolution, and the immune system maturation from fetal development to the neonatal period. (a) Factors affecting the evolution of the microbiota and the immune system. During the prenatal period and even after birth, maternal infection and antibiotic treatment disturbs fetal development. After birth, the gut microbiota and the development of the immune system are both influenced by environmental exposure. The mode of delivery and feeding impacts the colonization of the neonatal intestinal mucosa. Around weaning, the timing of solid food introduction and the composition of the diet determines the gut microbiota dynamics and the immune system maturation. (b) Evolution during the prenatal period and early childhood of the main bacteria families in the gut microbiota. The size of each triangle reflects the relative abundance of each bacteria family or the bacterial richness. Fetal colonization is still a matter of debate. Neonate gut presents a reduced microbial diversity at an individual level (α-diversity) but a high variation of microbial communities when compared between individuals (β-diversity). After weaning, the α-diversity strongly increases and the gut microbiota becomes more resilient. In this figure, bacteria belonging to the same phylum are grouped in the same color. (c) Immune system development kinetics in the prenatal period and early childhood. Innate and adaptive immune cells develop throughout the fetal period and early in life. Before and around birth, the fetal immune system is dominated by a pro-tolerogenic response and a Th2 cell polarization. Maternal IgG are transferred to the fetus before birth and confer a protective immunity to the neonate. The neonate B cells and innate immune cells are phenotypically similar to the adult before weaning. After weaning, the proportion of regulatory T cells (Tregs) increases and the infant presents a balanced lymphocyte Th1/Th2-polarization. Created by BioRender.com, accessed on 20 April 2021.
Figure 2
Figure 2
Comparison between the adult (a) or the infant (b) in human and in the non-human primate model: main characteristics relevant for the microbiota and the immune system study in neonates. Similar characteristics between models are shown in the middle of the figure. Specific characteristics for each model are shown in the lateral sides of the figure. Created by BioRender.com, accessed on 20 April 2021.
Figure 3
Figure 3
Summary of active research topics and questions to address the relationship between the microbiota and the immune system in the NHP model. Pink boxes represent the mother or parental-associated parameters, blue boxes represent microbiota studies, and green boxes represent immune system studies. The numbers represent the main references addressing the issue in the literature. Created by BioRender.com, accessed on 20 April 2021, [22,24,25,28,40,49,109,115,125,126,150,151,152,162,177,180,197,198].
Figure 4
Figure 4
Comparison of the non-human primate and mouse models to the human. Created by BioRender.com, accessed on 20 April 2021.
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