Effect of the Microbiome on Intestinal Innate Immune Development in Early Life and the Potential Strategy of Early Intervention

Abstract

Early life is a vital period for mammals to be colonized with the microbiome, which profoundly influences the development of the intestinal immune function. For neonates to resist pathogen infection and avoid gastrointestinal illness, the intestinal innate immune system is critical. Thus, this review summarizes the development of the intestinal microbiome and the intestinal innate immune barrier, including the intestinal epithelium and immune cells from the fetal to the weaning period. Moreover, the impact of the intestinal microbiome on innate immune development and the two main way of early-life intervention including probiotics and fecal microbiota transplantation (FMT) also are discussed in this review. We hope to highlight the crosstalk between early microbial colonization and intestinal innate immunity development and offer some information for early intervention.

Keywords: FMT; early life; innate immunity; intestine; microbiome colonization; probiotics.

Figure 1

The variation of intestinal core microbiota after birth. The neonatal intestinal microbiota is mainly composed of Bifidobacterium, Enterococcus, Lactobacillus, Escherichia, Bacteroides, and Clostridium. After birth, facultative anaerobe bacteria Escherichia and Enterococcus increase rapidly and decrease gradually. The abundance of Bifidobacterium, Lactobacillus, and Bacteroides rises at the peak before weaning and then declines by degrees. Clostridium expands rapidly after weaning.

Figure 2

The crosstalk between microbiota and innate immune system in the neonatal intestine. Lactobacillus enhances DC differentiation and upregulates surface markers, which activates NK cells. Furthermore, STAT1 and NF-kB p65 nuclear translocation are influenced by Lactobacillus in both intestinal epithelial cells and underlying macrophages. Lactobacillus produced lactate and P40 can promote ISC-mediated epithelial development and tight junction formation. Bifidobacterium transfers amino acids into ALC, which activates monocytes and promotes the expression of beta-defensin2 of IECs. Additionally, ILA has anti-inflammatory effects on immature enterocytes through STAT1 pathways. Bifidobacterium releases SCFAs by metabolizing HMOs, which exert anti-inflammatory effects through GPR109A and increase tight junction and mucus gene expression. Furthermore, Bifidobacterium Tad pili stimulate the growth of the newborn mucosa. Escherichia increases the number of GCs and promotes mucus. The antigens of E. coli can be taken up by DCs and then present to CD4⁺ T cells to induce Th17. Bacteroides-produced Polysaccharide A mediates the migration of pDCs from the colon to the thymus to maintain PLZF⁺ lymphocyte homeostasis. Enterococcus attenuates proinflammatory cytokine secretions, especially IL-8 through JNK and p38 signaling pathways. Furthermore, Enterococcus promotes PPAR phosphorylation activity to activate the transcription of IL-10. Propionibacterium combines with SIGNR1 on the DCs to regulate macrophages. Gammaproteobacteria express cell-surface LPS, which is recognized by the host intestinal cells via TLR4 and then ILC3 produces the cytokine IL-17A. By Figdraw (www.figdraw.com).