Milk Exosomes Transfer Oligosaccharides into Macrophages to Modulate Immunity and Attenuate Adherent-Invasive E. coli (AIEC) Infection

Exosomes are abundance in human body fluids like urine, milk and blood. They act a critical role in extracellular and intracellular communication, intracellular trafficking and physiological regulation. Multiple immune-modulatory components, such as proteins, RNAs and carbohydrates (glycoproteins), have been found in human milk exosomes, which play immune-regulatory functions. However, little is known about oligosaccharides in milk exosomes, the “free sugars”, which act critical roles in the development of infant’s immature mucosal immune system. In this study, the profile of milk exosomes encapsulated human milk oligosaccharides (HMOs) was calibrated with characteristic oligosaccharides in colostrum and mature milk, respectively. The exosomes containing human milk oligosaccharides were uptaken by macrophages, which were responsible for the establishment of intestinal immunity. Furthermore, mice pretreated with exosome encapsulated HMOs were protected from AIEC infection and had significantly less LPS-induced inflammation and intestinal damage. Exosome encapsulated milk oligosaccharides are regarded to provide a natural manner for milk oligosaccharides to accomplish their critical functions in modifying newborn innate immunity. The understanding of the interaction between a mother’s breastfeeding and the development of an infant’s mucosal immune system would be advantageous. The transport of milk oligosaccharides to its target via exosome-like particles appears to be promising.

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Human Milk Oligosaccharides in Colostrum and Mature Milk of Chinese Mothers: Lewis Positive Secretor Subgroups

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.8b02021 ◽

2018 ◽

Vol 66 (27) ◽

pp. 7036-7043 ◽

Cited By ~ 20

Author(s):

M. Elwakiel ◽

J. A. Hageman ◽

W. Wang ◽

I. M. Szeto ◽

J. B. van Goudoever ◽

...

Keyword(s):

Human Milk ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Mature Milk ◽

Chinese Mothers

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Challenges and Pitfalls in Human Milk Oligosaccharide Analysis

Nutrients ◽

10.3390/nu11112684 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2684 ◽

Cited By ~ 7

Author(s):

Sander S. van Leeuwen

Keyword(s):

Human Milk ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Mature Milk ◽

Healthy Development ◽

Milk Oligosaccharide ◽

Functional Studies ◽

Advanced Roles ◽

Human Milk Oligosaccharide ◽

Critical Overview

Human milk oligosaccharides have been recognized as an important, functional biomolecule in mothers’ milk. Moreover, these oligosaccharides have been recognized as the third most abundant component of human milk, ranging from 10–15 g/L in mature milk and up to and over 20 g/L reported in colostrum. Initially, health benefits of human milk oligosaccharides were assigned via observational studies on the differences between breastfed and bottle fed infants. Later, pools of milk oligosaccharides were isolated and used in functional studies and in recent years more specific studies into structure–function relationships have identified some advanced roles for milk oligosaccharides in the healthy development of infants. In other research, the levels, diversity, and complexity of human milk oligosaccharides have been studied, showing a wide variation in results. This review gives a critical overview of challenges in the analysis of human milk oligosaccharides. In view of the myriad functions that can be assigned, often to specific structures or classes of structures, it is very relevant to assess the levels of these structures in the human milk correctly, as well as in other biological sample materials. Ultimately, the review makes a case for a comparative, inter-laboratory study on quantitative human milk oligosaccharide analysis in all relevant biological samples.

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Screening natural libraries of human milk oligosaccharides against lectins using CaR-ESI-MS

The Analyst ◽

10.1039/c7an01397c ◽

2018 ◽

Vol 143 (2) ◽

pp. 536-548 ◽

Cited By ~ 8

Author(s):

Amr El-Hawiet ◽

Yajie Chen ◽

Km Shams-Ud-Doha ◽

Elena N. Kitova ◽

Pavel I. Kitov ◽

...

Keyword(s):

Immune System ◽

Human Milk ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Esi Ms ◽

Protein Receptors ◽

Non Covalent Interactions ◽

Protection Against Infection ◽

Covalent Interactions ◽

Breast Fed

Human milk oligosaccharides (HMOs) afford many health benefits to breast-fed infants, such as protection against infection and regulation of the immune system, through the formation of non-covalent interactions with protein receptors.

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Human Milk Oligosaccharides Protect against Necrotizing Enterocolitis by Inhibiting Intestinal Damage via Increasing the Proliferation of Crypt Cells

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201900262 ◽

2019 ◽

Vol 63 (18) ◽

pp. 1900262 ◽

Cited By ~ 10

Author(s):

Chenyuan Wang ◽

Ming Zhang ◽

Huiyuan Guo ◽

Jingyu Yan ◽

Fan Liu ◽

...

Keyword(s):

Human Milk ◽

Necrotizing Enterocolitis ◽

Intestinal Damage ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Crypt Cells

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Human Milk Oligosaccharides: Their Effects on the Host and Their Potential as Therapeutic Agents

Frontiers in Immunology ◽

10.3389/fimmu.2021.680911 ◽

2021 ◽

Vol 12 ◽

Author(s):

Anaïs Rousseaux ◽

Carole Brosseau ◽

Sophie Le Gall ◽

Hugues Piloquet ◽

Sébastien Barbarot ◽

...

Keyword(s):

Immune System ◽

Human Milk ◽

Molecular Mechanisms ◽

Bacterial Colonization ◽

Therapeutic Agents ◽

Allergy Prevention ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Inflammatory Reactions ◽

Epithelial Barriers

Breastmilk is known to be very important for infants because it provides nutrients and immunological compounds. Among these compounds, human milk oligosaccharides (HMOs) represent the third most important component of breastmilk after lipids and lactose. Several experiments demonstrated the beneficial effects of these components on the microbiota, the immune system and epithelial barriers, which are three major biological systems. Indeed, HMOs induce bacterial colonization in the intestinal tract, which is beneficial for health. The gut bacteria can act directly and indirectly on the immune system by stimulating innate immunity and controlling inflammatory reactions and by inducing an adaptive immune response and a tolerogenic environment. In parallel, HMOs directly strengthen the intestinal epithelial barrier, protecting the host against pathogens. Here, we review the molecular mechanisms of HMOs in these different compartments and highlight their potential use as new therapeutic agents, especially in allergy prevention.

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Human Milk Oligosaccharides and Immune System Development

Nutrients ◽

10.3390/nu10081038 ◽

2018 ◽

Vol 10 (8) ◽

pp. 1038 ◽

Cited By ~ 42

Author(s):

Julio Plaza-Díaz ◽

Luis Fontana ◽

Angel Gil

Keyword(s):

Immune System ◽

Human Milk ◽

Intestinal Mucosa ◽

System Development ◽

Controlled Trials ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Maternal Milk ◽

Breastfed Infants ◽

Immune System Development

Maternal milk contains compounds that may affect newborn immunity. Among these are a group of oligosaccharides that are synthesized in the mammary gland from lactose; these oligosaccharides have been termed human milk oligosaccharides (HMOs). The amount of HMOs present in human milk is greater than the amount of protein. In fact, HMOs are the third-most abundant solid component in maternal milk after lactose and lipids, and are thus considered to be key components. The importance of HMOs may be explained by their inhibitory effects on the adhesion of microorganisms to the intestinal mucosa, the growth of pathogens through the production of bacteriocins and organic acids, and the expression of genes that are involved in inflammation. This review begins with short descriptions of the basic structures of HMOs and the gut immune system, continues with the beneficial effects of HMOs shown in cell and animal studies, and it ends with the observational and randomized controlled trials carried out in humans to date, with particular emphasis on their effect on immune system development. HMOs seem to protect breastfed infants against microbial infections. The protective effect has been found to be exerted through cell signaling and cell-to-cell recognition events, enrichment of the protective gut microbiota, the modulation of microbial adhesion, and the invasion of the infant intestinal mucosa. In addition, infants fed formula supplemented with selected HMOs exhibit a pattern of inflammatory cytokines closer to that of exclusively breastfed infants. Unfortunately, the positive effects found in preclinical studies have not been substantiated in the few randomized, double-blinded, multicenter, controlled trials that are available, perhaps partly because these studies focus on aspects other than the immune response (e.g., growth, tolerance, and stool microbiota).

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Do Human Milk Oligosaccharides Protect Against Infant Atopic Disorders and Food Allergy?

Nutrients ◽

10.3390/nu12103212 ◽

2020 ◽

Vol 12 (10) ◽

pp. 3212

Author(s):

Soo Min Han ◽

Aristea Binia ◽

Keith M. Godfrey ◽

Sarah El-Heis ◽

Wayne S. Cutfield

Keyword(s):

Food Allergy ◽

Immune System ◽

Human Milk ◽

Large Scale ◽

Current Data ◽

Lactation Period ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Microbiome Composition ◽

The Impact

Atopic disorders (AD), often coexistent with food allergy (FA), start developing in early life and have lifelong health consequences. Breastfeeding is thought to be protective against AD and FA, but the data are controversial, and mechanisms are not well understood. Human milk oligosaccharides (HMOs) are complex carbohydrates that are abundant in human milk. These are thought to contribute to the development of the infant immune system by (i) promoting healthy microbiome, (ii) inhibiting pathogen binding to gut mucosa and (iii) modulating the immune system. Differences in microbiome composition between allergic and healthy infants have been observed, regardless of breastfeeding history. To date, limited studies have examined the preventive effects of HMOs on AD and FA in infants and current data relies on observation studies as trials of varying HMO intake through randomising individuals to breastfeeding are unethical. There is evidence for beneficial effects of breastfeeding on lowering the risks of FA, eczema and asthma but there are inconsistencies amongst studies in the duration of breastfeeding, diagnostic criteria for AD and the age at which the outcome was assessed. Furthermore, current analytical methods primarily used today only allow detection of 16–20 major HMOs while more than 100 types have been identified. More large-scale longitudinal studies are required to investigate the role of HMO composition and the impact of changes over the lactation period in preventing AD and FA later in life.

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