Human Milk Glycomics and Gut Microbial Genomics in Infant Feces Show a Correlation between Human Milk Oligosaccharides and Gut Microbiota: A Proof-of-Concept Study

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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Human milk oligosaccharides and infant gut microbiota: Molecular structures, utilization strategies and immune function

Carbohydrate Polymers ◽

10.1016/j.carbpol.2021.118738 ◽

2021 ◽

pp. 118738

Author(s):

Bin Zhang ◽

Long-Qing Li ◽

Feitong Liu ◽

Jian-Yong Wu

Keyword(s):

Gut Microbiota ◽

Human Milk ◽

Immune Function ◽

Molecular Structures ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides

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Mo1320 IMPACT OF HUMAN MILK OLIGOSACCHARIDES ON THE GUT MICROBIOTA COMPOSITION FROM IRRITABLE BOWEL SYNDROME PATIENTS; A PARALLEL DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL

Gastroenterology ◽

10.1016/s0016-5085(20)32798-0 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-848

Author(s):

Louise K. Vigsnæs ◽

Cristina Iribarren ◽

Maria K. Magnusson ◽

Ingvild D. Amundsen ◽

Bruce McConnell ◽

...

Keyword(s):

Irritable Bowel Syndrome ◽

Gut Microbiota ◽

Human Milk ◽

Controlled Trial ◽

Microbiota Composition ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Double Blind ◽

Irritable Bowel ◽

Gut Microbiota Composition

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Human milk oligosaccharides: Shaping the infant gut microbiota and supporting health

Journal of Functional Foods ◽

10.1016/j.jff.2020.104074 ◽

2020 ◽

Vol 72 ◽

pp. 104074 ◽

Cited By ~ 1

Author(s):

Clodagh Walsh ◽

Jonathan A. Lane ◽

Douwe van Sinderen ◽

Rita M. Hickey

Keyword(s):

Gut Microbiota ◽

Human Milk ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides

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Fucosylated Human Milk Oligosaccharides and N-Glycans in the Milk of Chinese Mothers Regulate the Gut Microbiome of Their Breast-Fed Infants during Different Lactation Stages

mSystems ◽

10.1128/msystems.00206-18 ◽

2018 ◽

Vol 3 (6) ◽

Cited By ~ 16

Author(s):

Yaqiang Bai ◽

Jia Tao ◽

Jiaorui Zhou ◽

Qingjie Fan ◽

Man Liu ◽

...

Keyword(s):

Gut Microbiota ◽

Human Milk ◽

Gut Microbiome ◽

Longitudinal Research ◽

Protein Glycosylation ◽

Glycoside Hydrolases ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Chinese Mothers ◽

Breast Fed

ABSTRACT The milk glycobiome has a significant impact on the gut microbiota of infants, which plays a pivotal role in health and development. Fucosylated human milk oligosaccharides (HMOs) and N-glycans on milk proteins are beneficial for the development of healthy gut microbiota, and the fucosylation levels of these glycans can be affected by the maternal fucosyltransferase 2 gene (FUT2). Here, we present results of longitudinal research on paired milk and stool samples from 56 Chinese mothers (CMs) and their breast-fed children. Changes of HMOs and fucosylated N-glycans in milk of CMs at different lactation stages were detected, which allowed characterization of the major differences in milk glycans and consequential effects on the gut microbiome of infants according to maternal FUT2 status. Significant differences in the abundance of total and fucosylated HMOs between secretor and nonsecretor CMs were noted, especially during early lactation. Despite a tendency toward decreasing milk protein concentrations, the fucosylation levels of milk N-glycans increased during late lactation. The changes in the levels of fucosylated HMOs and milk N-glycans were highly correlated with the growth of Bifidobacterium spp. and Lactobacillus spp. in the gut of infants during early and later lactation, respectively. Enriched expression of genes encoding glycoside hydrolases, glycosyl transferases, ATP-binding cassette (ABC) transporters, and permeases in infants fed by secretor CMs contributed to the promotion of these bacteria in infants. Our data highlight the important role of fucosylated milk glycans in shaping the gut microbiome of infants and provide a solid foundation for development of “personalized” nutrition for Chinese infants. IMPORTANCE Human milk glycans provide a broad range of carbon sources for gut microbes in infants. Levels of protein glycosylation in human milk vary during lactation and may also be affected by the stages of gestation and lactation and by the secretor status of the mother. This was the first study to evaluate systematically dynamic changes in human milk oligosaccharides and fucosylated N-glycans in the milk of Chinese mothers with different secretor statuses during 6 months of lactation. Given the unique single nucleotide polymorphism site (rs1047781, A385T) on the fucosyltransferase 2 gene among Chinese populations, our report provides a specific insight into the milk glycobiome of Chinese mothers, which may exert effects on the gut microbiota of infants that differ from findings from other study cohorts.

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Variation in Consumption of Human Milk Oligosaccharides by Infant Gut-Associated Strains of Bifidobacterium breve

Applied and Environmental Microbiology ◽

10.1128/aem.01843-13 ◽

2013 ◽

Vol 79 (19) ◽

pp. 6040-6049 ◽

Cited By ~ 123

Author(s):

Santiago Ruiz-Moyano ◽

Sarah M. Totten ◽

Daniel A. Garrido ◽

Jennifer T. Smilowitz ◽

J. Bruce German ◽

...

Keyword(s):

Human Milk ◽

Intestinal Microbiota ◽

Glycosyl Hydrolase ◽

Bifidobacterium Longum ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Content Type ◽

Bifidobacterium Breve ◽

Infant Feces ◽

Breast Fed

ABSTRACTHuman milk contains a high concentration of complex oligosaccharides that influence the composition of the intestinal microbiota in breast-fed infants. Previous studies have indicated that select species such asBifidobacterium longumsubsp.infantisandBifidobacterium bifidumcan utilize human milk oligosaccharides (HMO)in vitroas the sole carbon source, while the relatively fewB. longumsubsp.longumandBifidobacterium breveisolates tested appear less adapted to these substrates. Considering the high frequency at whichB. breveis isolated from breast-fed infant feces, we postulated that someB. brevestrains can more vigorously consume HMO and thus are enriched in the breast-fed infant gastrointestinal tract. To examine this, a number ofB. breveisolates from breast-fed infant feces were characterized for the presence of different glycosyl hydrolases that participate in HMO utilization, as well as by their ability to grow on HMO or specific HMO species such as lacto-N-tetraose (LNT) and fucosyllactose. AllB. brevestrains showed high levels of growth on LNT and lacto-N-neotetraose (LNnT), and, in general, growth on total HMO was moderate for most of the strains, with several strain differences. Growth and consumption of fucosylated HMO were strain dependent, mostly in isolates possessing a glycosyl hydrolase family 29 α-fucosidase. Glycoprofiling of the spent supernatant after HMO fermentation by select strains revealed that allB. brevestrains can utilize sialylated HMO to a certain extent, especially sialyl-lacto-N-tetraose. Interestingly, this specific oligosaccharide was depleted before neutral LNT by strain SC95. In aggregate, this work indicates that the HMO consumption phenotype inB. breveis variable; however, some strains display specific adaptations to these substrates, enabling more vigorous consumption of fucosylated and sialylated HMO. These results provide a rationale for the predominance of this species in breast-fed infant feces and contribute to a more accurate picture of the ecology of the developing infant intestinal microbiota.

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Principal human milk oligosaccharides utilized by human gut microbiota

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.45.4 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Zhuo‐Teng Yu ◽

Bo Liu ◽

David S

Keyword(s):

Gut Microbiota ◽

Human Milk ◽

Human Milk Oligosaccharides ◽

Human Gut ◽

Milk Oligosaccharides ◽

Human Gut Microbiota

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INFANT GUT MICROBIOTA, HUMAN MILK OLIGOSACCHARIDES AND PREBIOTICS – WHAT'S NEW?

Journal of Pediatric Gastroenterology and Nutrition ◽

10.1097/01.mpg.0000489607.50161.a3 ◽

2016 ◽

Vol 63 (1S) ◽

pp. S44 ◽

Cited By ~ 1

Author(s):

K. Venema

Keyword(s):

Gut Microbiota ◽

Human Milk ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides

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Effects of Human Milk Oligosaccharides on the Adult Gut Microbiota and Barrier Function

Nutrients ◽

10.3390/nu12092808 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2808

Author(s):

Tanja Šuligoj ◽

Louise Kristine Vigsnæs ◽

Pieter Van den Abbeele ◽

Athanasia Apostolou ◽

Katia Karalis ◽

...

Keyword(s):

Gut Microbiota ◽

Human Milk ◽

Barrier Function ◽

Distal Colon ◽

Human Milk Oligosaccharides ◽

Gut Barrier ◽

Milk Oligosaccharides ◽

Caco2 Cell ◽

Gut Barrier Function ◽

The Impact

Human milk oligosaccharides (HMOs) shape the gut microbiota in infants by selectively stimulating the growth of bifidobacteria. Here, we investigated the impact of HMOs on adult gut microbiota and gut barrier function using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME®), Caco2 cell lines, and human intestinal gut organoid-on-chips. We showed that fermentation of 2’-O-fucosyllactose (2’FL), lacto-N-neotetraose (LNnT), and combinations thereof (MIX) led to an increase of bifidobacteria, accompanied by an increase of short chain fatty acid (SCFA), in particular butyrate with 2’FL. A significant reduction in paracellular permeability of FITC-dextran probe was observed using Caco2 cell monolayers with fermented 2’FL and MIX, which was accompanied by an increase in claudin-8 gene expression as shown by qPCR, and a reduction in IL-6 as determined by multiplex ELISA. Using gut-on-chips generated from human organoids derived from proximal, transverse, and distal colon biopsies (Colon Intestine-Chips), we showed that claudin-5 was significantly upregulated across all three gut-on-chips following treatment with fermented 2’FL under microfluidic conditions. Taken together, these data show that, in addition to their bifidogenic activity, HMOs have the capacity to modulate immune function and the gut barrier, supporting the potential of HMOs to provide health benefits in adults.

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