Role of Human Milk Bioactives on Infants' Gut and Immune Health

Abstract

Exclusive human milk feeding of the newborn is recommended during the first 6 months of life to promote optimal health outcomes during early life and beyond. Human milk contains a variety of bioactive factors such as hormones, cytokines, leukocytes, immunoglobulins, lactoferrin, lysozyme, stem cells, human milk oligosaccharides (HMOs), microbiota, and microRNAs. Recent findings highlighted the potential importance of adding HMOs into infant formula for their roles in enhancing host defense mechanisms in neonates. Therefore, understanding the roles of human milk bioactive factors on immune function is critical to build the scientific evidence base around breastfeeding recommendations, and to enhance positive health outcomes in formula fed infants through modifications to formulas. However, there are still knowledge gaps concerning the roles of different milk components, the interactions between the different components, and the mechanisms behind health outcomes are poorly understood. This review aims to show the current knowledge about HMOs, milk microbiota, immunoglobulins, lactoferrin, and milk microRNAs (miRNAs) and how these could have similar mechanisms of regulating gut and microbiota function. It will also highlight the knowledge gaps for future research.

Keywords: breastmilk; development; gut; human milk; immune system; immunity; infants; neonates.

Figure 1

Schematic overview of specific bioactive components of human milk (HM) and their role in immunomodulation. (A) An iron-binding antimicrobial protein lactoferrin (LF) inhibits a number of pathogenic bacteria (i.e., Escherichia coli) from adhering to epithelial cell. LF can promote the growth of intestinal villi. After pathogenic bacteria invasion into the lamina propria of the epithelial gut cells, LF can inhibit the signal between lipopolysaccharide (LPS) released by gram-negative bacteria and the CD14—TLR complex (macrophage signaling). LF can enhance the maturation of B and T cells to improve the immune response. Immunoglobulins IgA, IgM, and IgG present in HM provide passive immunity to the newborn. IgA and IgG can bind to pathogenic bacteria and prevent them from adhering to the epithelial cells in the gut mucosa. Also, IgA can serve as a substrate to obligate anaerobes (i.e., Bacteroides) promoting a healthy microbiota colonization. IgM inhibits enteric bacterial and viral infections by opsonizing the antigen for complement fixation and destruction. (B) In the lumen, human milk oligosaccharides (HMO) inhibit bacterial binding to cell receptors by directly binding to the pathogens. HMOs can stimulate the growth of commensal bacteria by serving as substrates. On epithelial cells, HMOs can prevent pathogen binding by acting as binding decoy receptors. Metabolites of HMOs including short-chain fatty acids can influence epithelial cell maturation and intestinal barrier (i.e., tight junctions) function. HMOs can interact with dendritic cells present in the lamina propria leading to T-cell proliferation, subsequently, T/B cell interaction resulting in increased production of antibodies in order to keep the immune system homeostasis. In the absence of HMOs (no HMO) pathogenic bacteria binding to the epithelial cells increase cytokine production in the lamina propria as a pro-inflammatory response. (C) Bifidobacterium and Lactobacillus, commensal bacteria found in HM, can adhere to intestinal cells, resulting in greater beneficial microbiota colonization. Furthermore, Bacteroides fragilis can interact with dendritic cells, resulting in suppression of inflammation by inducing T regulatory cell (Treg) production. (D) The extracellular vesicles (EVs) contain cargos such as microRNAs (miRNAs). EV-miRNAs likely have immunological and microbial impact on the gastrointestinal tract of neonates. Human milk miRNAs such as miR-21 can regulate gene expression by binding to toll-like receptors 7 and 8 (TLR7/TLR8). Other milk miRNAs (i.e., miR-148 and miR-30) may play a role in gut immune response by decreasing cytokine production via T-cell inhibition and preventing antigen presentation by dendritic cells and macrophages, respectively.