The microbiome in early life: implications for health outcomes

Journal name:
Nature Medicine
Volume:
22,
Pages:
713–722
Year published:
DOI:
doi:10.1038/nm.4142
Received
Accepted
Published online

Abstract

Recent studies have characterized how host genetics, prenatal environment and delivery mode can shape the newborn microbiome at birth. Following this, postnatal factors, such as antibiotic treatment, diet or environmental exposure, further modulate the development of the infant's microbiome and immune system, and exposure to a variety of microbial organisms during early life has long been hypothesized to exert a protective effect in the newborn. Furthermore, epidemiological studies have shown that factors that alter bacterial communities in infants during childhood increase the risk for several diseases, highlighting the importance of understanding early-life microbiome composition. In this review, we describe how prenatal and postnatal factors shape the development of both the microbiome and the immune system. We also discuss the prospects of microbiome-mediated therapeutics and the need for more effective approaches that can reconfigure bacterial communities from pathogenic to homeostatic configurations.

At a glance

Figures

  1. Factors shaping the neonatal microbiome.
    Figure 1: Factors shaping the neonatal microbiome.

    Maternal vaginal infections or periodontitis can result in bacteria invading the uterine environment. Gut and oral microbiota could be transported through the bloodstream from the mother to the fetus. Delivery mode shapes the initial bacterial inoculum of the newborn. Postnatal factors such as antibiotic use, diet (such as breast-feeding versus formula, and introduction of solid food), genetics of the infant and environmental exposure further configure the microbiome during early life. As diet diversifies with age, the microbiome gradually shifts toward an adult-like configuration, which is usually reached by age 3. Bacteria associated with the different processes are indicated.

  2. Long-lasting effects of early-life interactions between the microbiome and the gut immune system.
    Figure 2: Long-lasting effects of early-life interactions between the microbiome and the gut immune system.

    The development of secondary lymphoid structures, including Peyer's patches and the mesenteric lymph nodes, occurs prenatally before bacterial colonization. Microbial colonization of the gut is established postnatally via interactions between the commensal bacteria and the host's immune system. Microfold (M) cells at the apical surface of Peyer's patches sample luminal antigens and bacteria through endocytosis. Dendritic cells (DCs) then present these antigens to induce T cell–dependent B cell maturation to promote the secretion of dimeric IgA, which play a critical role in defense against pathogens, by plasma cells in the lamina propria. Bacteria can also be transcytosed by DCs in the lamina propria and be presented to T cells in the draining mesenteric lymph node to induce T cell differentiation. In a homeostatic environment (bottom left), the MAMPs associated with commensal bacteria stimulate regulatory cytokine production (IL-25, IL-33, thymic stromal lymphopoietin (TSLP) and transforming growth factor (TGF)-b) by intestinal epithelial cells. The transduction of the signals to DCs induces the development of Treg cells and promotes IL-10 secretion. In a dysbiotic state (bottom right), the reduction of commensal bacteria results in enrichment of pathobionts and pathogens. Pathogenic MAMPs that are sensed by the intestinal epithelial cells induce the secretion of pro-inflammatory cytokines (IL-1, IL-6 and IL-18), prompting the development of effector T cells. These effector T cells differentiate into CD4+ TH1 and TH17 cells, which secrete pro-inflammatory cytokines, such as IL-17, tumor necrosis factor (TNF)-a and IFN-g, which induce neutrophil recruitment to protect the host against pathogenic infections. B cell maturation in Peyer's patches results in the production of IgG, which is often associated with autoimmunity and allergy.

  3. Microbial therapeutics throughout the course of disease.
    Figure 3: Microbial therapeutics throughout the course of disease.

    During preclinical stages the disease has not yet manifested, and symptoms are not apparent, yet subtle biological changes might be already occurring. Approaches such as the use of an inoculum of defined bacterial communities might be most effective at the early stages of disease to prevent the development of disease resulting from early dysbiosis. As the disease progresses, disruption of a homeostatic microbiota results in enrichment of pathobionts (as shown in red), production of pro-inflammatory metabolites and activation of inflammatory pathways (Fig. 2). The mucus layer, which protects the epithelium, becomes thinner as damage accumulates owing to an increase in the severity of the disease. Dietary interventions and antibiotics might be used at this stage to manipulate bacterial content more drastically. At late stages, continuous damage leads to further thinning of the mucus layer, allowing for bacteria to break through the epithelial barrier. Aggressive antibiotic therapy combined with fecal microbiota transplantation could restore microbial balance at this point.

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Author information

  1. These authors contributed equally to this work.

    • Sabrina Tamburini &
    • Nan Shen

Affiliations

  1. Icahn Institute for Genomics and Multiscale Biology. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Sabrina Tamburini,
    • Nan Shen &
    • Jose C Clemente
  2. Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Han Chih Wu &
    • Jose C Clemente
  3. Department of Medicine, Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Han Chih Wu &
    • Jose C Clemente

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The authors declare no competing financial interests.

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