Breast milk microRNAs: Potential players in oral tolerance development

Abstract

Breast milk is an essential source of nutrition and hydration for the infant. In addition, this highly complex biological fluid contains numerous immunologically active factors such as microorganisms, immunoglobulins, cytokines and microRNAs (miRNAs). Here, we set out to predict the function of the top 10 expressed miRNAs in human breast milk, focusing on their relevance in oral tolerance development and allergy prevention in the infant. The top expressed miRNAs in human breast milk were identified on basis of previous peer-reviewed studies gathered from a recent systematic review and an updated literature search. The miRNAs with the highest expression levels in each study were used to identify the 10 most common miRNAs or miRNA families across studies and these were selected for subsequent target prediction. The predictions were performed using TargetScan in combination with the Database for Annotation, Visualization and Integrated Discovery. The ten top expressed miRNAs were: let-7-5p family, miR-148a-3p, miR-30-5p family, miR-200a-3p + miR-141-3p, miR-22-3p, miR-181-5p family, miR-146b-5p, miR-378a-3p, miR-29-3p family, miR-200b/c-3p and miR-429-3p. The target prediction identified 3,588 potential target genes and 127 Kyoto Encyclopedia of Genes and Genomes pathways; several connected to the immune system, including TGF-b and T cell receptor signaling and T-helper cell differentiation. This review highlights the role of breast milk miRNAs and their potential contribution to infant immune maturation. Indeed, breast milk miRNAs seem to be involved in several pathways that influence oral tolerance development.

Immune‐related microRNAs in breast milk and their relation to regulatory T cells in breastfed children

“…As the 24 miRNAs we study here were specifically selected on basis of their immune relevance (i.e., their involvement in immunomodulatory pathways and specifically in T helper cell subset regulation, mitochondrial function, and epigenetic modifications, see supporting information “qPCR TaqMan advanced miRNA human A and B cards”), we did not make any further attempt to summarize their predicted functions. If further interested, please refer to a recent review 28 …”

“…miR‐148a‐3p is the most abundant miRNA in human breast milk, 28 regardless of milk fraction 10 . Milk miR‐148a‐3p has been suggested to function as an epigenetic regulator targeting DNA methyltransferase 1 (DNMT1) 29,30 .…”

“…If further interested, please refer to a recent review. 28 Human milk exosomes have been shown to increase the number of Tregs and downregulate IL-2 production in vitro. 12 In the current study, we show that seven breast milk miRNAs are associated with aTreg and rTreg frequencies in the child, at 6 and 24 months.…”

The Protective Role of Exosome-Derived MicroRNAs and Proteins from Human Breast Milk against Infectious Agents

“…Our results demonstrated a strong association between the HBM-derived exosomal miRNAs and two vital signaling pathways: the Fc-epsilon receptor signaling pathway, associated with allergenic reactions, and the toll-like receptor-signaling pathway; these results support previous findings ( Figure 3 B,C). Furthermore, a previous study determined that miRNAs in infants may have an allergy-preventative effect; the ten most commonly expressed HBM-derived exosomal miRNAs targeted specific genes and modulated infant oral tolerance development [ 33 ]. In addition, the miRNA–TLR interaction initiates an immune response by regulating immune and inflammatory gene expressions [ 34 ].…”

Salivary extracellular vesicles isolation methods impact the robustness of downstream biomarkers detection

“…MiRNAs, small non-coding RNAs crucial in regulatory roles [35], impact about 60% of protein-encoding genes, orchestrate cellular signaling, and can translocate to the nucleus [36][37][38], making them increasingly recognized as potential biomarkers in various biofluids [39][40][41] including saliva [42] for many diseases [41][42][43].…”