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

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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Sialylated human milk oligosaccharides program cognitive development through a non-genomic transmission mode

Molecular Psychiatry ◽

10.1038/s41380-021-01054-9 ◽

2021 ◽

Author(s):

Jonas Hauser ◽

Edoardo Pisa ◽

Alejandro Arias Vásquez ◽

Flavio Tomasi ◽

Alice Traversa ◽

...

Keyword(s):

Cognitive Development ◽

Gut Microbiota ◽

Human Milk ◽

Molecular Mechanisms ◽

Brain Regions ◽

Nervous System Development ◽

Bioactive Molecules ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Eye Opening

AbstractBreastmilk contains bioactive molecules essential for brain and cognitive development. While sialylated human milk oligosaccharides (HMOs) have been implicated in phenotypic programming, their selective role and underlying mechanisms remained elusive. Here, we investigated the long-term consequences of a selective lactational deprivation of a specific sialylated HMO in mice. We capitalized on a knock-out (KO) mouse model (B6.129-St6gal1tm2Jxm/J) lacking the gene responsible for the synthesis of sialyl(alpha2,6)lactose (6′SL), one of the two sources of sialic acid (Neu5Ac) to the lactating offspring. Neu5Ac is involved in the formation of brain structures sustaining cognition. To deprive lactating offspring of 6′SL, we cross-fostered newborn wild-type (WT) pups to KO dams, which provide 6′SL-deficient milk. To test whether lactational 6′SL deprivation affects cognitive capabilities in adulthood, we assessed attention, perseveration, and memory. To detail the associated endophenotypes, we investigated hippocampal electrophysiology, plasma metabolomics, and gut microbiota composition. To investigate the underlying molecular mechanisms, we assessed gene expression (at eye-opening and in adulthood) in two brain regions mediating executive functions and memory (hippocampus and prefrontal cortex, PFC). Compared to control mice, WT offspring deprived of 6′SL during lactation exhibited consistent alterations in all cognitive functions addressed, hippocampal electrophysiology, and in pathways regulating the serotonergic system (identified through gut microbiota and plasma metabolomics). These were associated with a site- (PFC) and time-specific (eye-opening) reduced expression of genes involved in central nervous system development. Our data suggest that 6′SL in maternal milk adjusts cognitive development through a short-term upregulation of genes modulating neuronal patterning in the PFC.

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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 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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Human Milk Oligosaccharides to Prevent Gut Dysfunction and Necrotizing Enterocolitis in Preterm Neonates

Nutrients ◽

10.3390/nu10101461 ◽

2018 ◽

Vol 10 (10) ◽

pp. 1461 ◽

Cited By ~ 26

Author(s):

Stine Bering

Keyword(s):

Preterm Birth ◽

Human Milk ◽

Preterm Infants ◽

Necrotizing Enterocolitis ◽

Bacterial Colonization ◽

Health Benefits ◽

Preterm Neonates ◽

Human Milk Oligosaccharides ◽

High Concentration ◽

Milk Oligosaccharides

This review focuses on the evidence for health benefits of human milk oligosaccharides (HMOs) for preterm infants to stimulate gut adaptation and reduce the incidence of necrotizing enterocolitis (NEC) in early life. The health benefits of breastfeeding are partly explained by the abundant HMOs that serve as prebiotics and immunomodulators. Gut immaturity in preterm infants leads to difficulties in tolerating enteral feeding and bacterial colonization and a high sensitivity to NEC, particularly when breast milk is insufficient. Due to the immaturity of the preterm infants, their response to HMOs could be different from that in term infants. The concentration of HMOs in human milk is highly variable and there is no evidence to support a specifically adapted high concentration in preterm milk. Further, the gut microbiota is not only different but also highly variable after preterm birth. Studies in pigs as models for preterm infants indicate that HMO supplementation to formula does not mature the gut or prevent NEC during the first weeks after preterm birth and the effects may depend on a certain stage of gut maturity. Supplemented HMOs may become more important for gut protection in the preterm infants when the gut has reached a more mature phase.

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

Nutrients ◽

10.3390/nu13093198 ◽

2021 ◽

Vol 13 (9) ◽

pp. 3198

Author(s):

Yingying He ◽

Zhicheng He ◽

Serena Leone ◽

Shubai Liu

Keyword(s):

Immune System ◽

Human Milk ◽

Critical Role ◽

Mucosal Immune System ◽

Intestinal Damage ◽

Intestinal Immunity ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Mature Milk ◽

Natural Manner

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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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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The Protective and Long-Lasting Effects of Human Milk Oligosaccharides on Cognition in Mammals

Nutrients ◽

10.3390/nu12113572 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3572

Author(s):

Sylvia Docq ◽

Marcia Spoelder ◽

Wendan Wang ◽

Judith R. Homberg

Keyword(s):

Human Milk ◽

Molecular Mechanisms ◽

Memory Performance ◽

Long Term Potentiation ◽

Accelerated Learning ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Beneficial Effects ◽

Term Potentiation

Over the last few years, research indicated that Human Milk Oligosaccharides (HMOs) may serve to enhance cognition during development. HMOs hereby provide an exciting avenue in the understanding of the molecular mechanisms that contribute to cognitive development. Therefore, this review aims to summarize the reported observations regarding the effects of HMOs on memory and cognition in rats, mice and piglets. Our main findings illustrate that the administration of fucosylated (single or combined with Lacto-N-neoTetraose (LNnT) and other oligosaccharides) and sialylated HMOs results in marked improvements in spatial memory and an accelerated learning rate in operant tasks. Such beneficial effects of HMOs on cognition already become apparent during infancy, especially when the behavioural tasks are cognitively more demanding. When animals age, its effects become increasingly more apparent in simpler tasks as well. Furthermore, the combination of HMOs with other oligosaccharides yields different effects on memory performance as opposed to single HMO administration. In addition, an enhanced hippocampal long-term potentiation (LTP) response both at a young and at a mature age are reported as well. These results point towards the possibility that HMOs administered either in singular or combination forms have long-lasting, beneficial effects on memory and cognition in mammals.

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Fucosylated human milk oligosaccharide foraging within the species Bifidobacterium pseudocatenulatum is driven by glycosyl hydrolase content and specificity

Applied and Environmental Microbiology ◽

10.1128/aem.01707-21 ◽

2021 ◽

Author(s):

Guy Shani ◽

Jennifer L Hoeflinger ◽

Britta E Heiss ◽

Chad F Masarweh ◽

Jules A Larke ◽

...

Keyword(s):

Human Milk ◽

Gene Cluster ◽

Bacterial Colonization ◽

Glycosyl Hydrolase ◽

Pool Analysis ◽

Consumption Pattern ◽

Human Breast Milk ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Carbohydrate Utilization

Human milk enriches members of the genus Bifidobacterium in the infant gut. One species, Bifidobacterium pseudocatenulatum , is found in the gastrointestinal tracts of adults and breastfed infants. In this study, B. pseudocatenulatum strains were isolated and characterized to identify genetic adaptations to the breastfed infant gut. During growth on pooled human milk oligosaccharides (HMOs) we observed two distinct groups of B. pseudocatenulatum , isolates that readily consumed HMOs and those that did not, a difference driven by variable catabolism of fucosylated HMOs. A conserved gene cluster for fucosylated HMO utilization was identified in several sequenced B. pseudocatenulatum strains. One isolate, B. pseudocatenulatum MP80, which uniquely possessed GH95 and GH29 α-fucosidases consumed the majority of fucosylated HMOs tested. Furthermore, B. pseudocatenulatum SC585, which possesses only a single GH95 α-fucosidase, lacked the ability to consume the complete repertoire of linkages within the fucosylated HMO pool. Analysis of the purified GH29 and GH95 fucosidase activities directly on HMOs revealed complementing enzyme specificities with the GH95 enzyme preferring 1-2 fucosyl linkages and the GH29 enzyme favoring 1-3 and 1-4 linkages. The HMO binding specificity of the Family 1 solute binding protein component linked to the fucosylated HMO gene cluster in both SC585 and MP80 are similar, suggesting differential transport of fucosylated HMO is not a driving factor in each strain’s distinct HMO consumption pattern. Taken together, this data indicates the presence or absence of specific α-fucosidases directs the strain-specific fucosylated HMO utilization pattern among bifidobacteria and likely influences competitive behavior for HMO foraging in situ . IMPORTANCE Often isolated from the human gut, microbes from the bacterial family Bifidobacteriaceae commonly possess genes enabling carbohydrate utilization. Isolates from breast fed infants often grow on and possess genes for the catabolism of human milk oligosaccharides (HMOs), glycans found in human breast milk. However, catabolism of structurally diverse HMOs differs between bifidobacterial strains. This study identifies gene differences between Bifidobacterium pseudocatenulatum isolates that may impact whether a microbe successfully colonizes an infant gut. In this case, the presence of complementary α-fucosidases may provide an advantage to microbes seeking residence in the infant gut. Such knowledge furthers our understanding of how diet drives bacterial colonization of the infant gut.

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