Human milk extracellular vesicles target nodes in interconnected signalling pathways that enhance oral epithelial barrier function and dampen immune responses

Abstract

Maternal milk is nature’s first functional food. It plays a crucial role in the development of the infant’s gastrointestinal (GI) tract and the immune system. Extracellular vesicles (EVs) are a heterogeneous population of lipid bilayer enclosed vesicles released by cells for intercellular communication and are a component of milk. Recently, we discovered that human milk EVs contain a unique proteome compared to other milk components. Here, we show that physiological concentrations of milk EVs support epithelial barrier function by increasing cell migration via the p38 MAPK pathway. Additionally, milk EVs inhibit agonist-induced activation of endosomal Toll like receptors TLR3 and TLR9. Furthermore, milk EVs directly inhibit activation of CD4+ T cells by temporarily suppressing T cell activation without inducing tolerance. We show that milk EV proteins target key hotspots of signalling networks that can modulate cellular processes in various cell types of the GI tract.

Neonatal enteroids absorb extracellular vesicles from human milk-fed infant digestive fluid

“…Protein complexes can also mimic the appearance and size of EVs in NTA or RPS. To circumvent these pitfalls, it is common to perform HMEV isolations on large starting volumes, which allow for multiple processing steps to enrich for EVs and remove other bioactive factors that may complicate data interpretation (15,17,18,46,80,81). This can be prohibitive if sample volumes are limited (≤ 2mL).…”

“…Human milk is replete with extracellular vesicles (EVs), which are nanoparticlesized structures secreted by most cells within the human body (13). EVs, including human milk EVs (HMEVs), carry biological information between donor and recipient cells, to confer changes in cellular function or biological activity (14)(15)(16)(17)(18)(19)(20)(21)(22). HMEVs have putative beneficial effects, as shown by a combination of in vitro and animal studies demonstrating that HMEVs promote intestinal epithelial cell (IEC) proliferation (16,19,20), reduce experimental necrotizing enterocolitis (NEC), limit inflammatory (15-17, 21, 22) or non-inflammatory damage (15,19,23), promote expression of intestinal barrier proteins (21), or enhance epithelial barrier function (15,18).…”

Editorial: Impact of Early Life Nutrition on Immune System Development and Related Health Outcomes in Later Life

“…Previous studies suggest antipathogenic effects of HM components and that the addition of these bioactive molecules (i.e., HMOs, lactoferrin, immunoglobulins, and milk fat globule membrane FGM, extracellular vesicles) to infant formulas may benefit child health ( 20 , 26 – 36 ), although the studies usually lack methodological rigor and outcomes were based on a small sample size. The studies on recombinant immunoglobulins and bioactivity in the digestive tract are limited.…”

Anti-Inflammatory Potential of Cow, Donkey and Goat Milk Extracellular Vesicles as Revealed by Metabolomic Profile

“…In recent years, studies on the molecular mechanisms underlying this mother to child information transfer have increased. Among them, immune modulatory, anti-infective and anti-inflammatory properties of milk emerged and seemed to be mediated by signaling molecules enclosed in micro and nano-sized membrane-bound structures called Extracellular Vesicles (EVs) and capable of carrying several types of information [ 2 , 3 ].…”