Relationship between human milk oligosaccharides and fecal microbiome of breastfed infants

Human milk oligosaccharides (HMOs), which are natural bifidogenic prebiotics, were recently commercialized to fortify formula milk. However, HMO-assimilation phenotypes of bifidobacteria vary by species and strain, which has not been fully linked to strain genotype. We have recently shown that specialized uptake systems, particularly for the internalization of major HMOs (fucosyllactose (FL)), are associated with the formation of a bifidobacteria-rich gut microbial community. Phylogenetic analysis has revealed that FL transporters have diversified into two clades harboring four clusters within the Bifidobacterium genus, but the underpinning functional diversity associated with this divergence remains underexplored. In this study, we examined the HMO-consumption phenotypes of two bifidobacterial species, Bifidobacterium catenulatum subspecies kashiwanohense and Bifidobacterium pseudocatenulatum , which both possess FL binding proteins that belong to phylogenetic clusters with unknown specificities. Growth assays, heterologous gene expression experiments, and HMO-consumption analysis showed that the FL transporter type from B. catenulatum subspecies kashiwanohense JCM 15439 T conferred a novel HMO-uptake pattern that includes the complex fucosylated HMOs (lacto- N- fucopentaose II and lacto- N- difucohexaose I/II). Further genomic landscape analyses of FL transporter-positive bifidobacterial strains revealed that H-antigen or Lewis antigen-specific fucosidase gene(s) and FL transporter specificities were largely aligned. These results suggest that bifidobacteria have acquired FL transporters along with the corresponding gene sets necessary to utilize the imported HMOs. Our results provide insight into the species- and strain-dependent adaptation strategies of bifidobacteria to HMO-rich environments. Importance The gut of breastfed infants is generally dominated by health-promoting bifidobacteria. Human milk oligosaccharides (HMOs) from breastmilk selectively promote the growth of specific taxa such as bifidobacteria, thus forming an HMO-mediated, host-microbe symbiosis. While the co-evolution of humans and bifidobacteria has been proposed, the underpinning adaptive strategies employed by bifidobacteria require further research. Here, we analyzed the divergence of the critical fucosyllactose (FL) HMO transporter within Bifidobacterium . We have shown that the diversification of the solute-binding proteins of the FL-transporter led to uptake specificities of fucosylated sugars ranging from simple trisaccharides to complex hexasaccharides. This transporter and the congruent acquisition of the necessary intracellular enzymes allows for bifidobacteria to import different types of HMOs in a predictable and strain-dependent manner. These findings explain the adaptation and proliferation of bifidobacteria in the competitive and HMO-rich infant gut environment and enable accurate specificity annotation of transporters from metagenomic data.

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Maternal Fucosyltransferase 2 Status Associates with the Profiles of Human Milk Oligosaccharides and the Fecal Microbiota Composition of Breastfed Infants

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.0c04575 ◽

2021 ◽

Vol 69 (10) ◽

pp. 3032-3043

Author(s):

Fan Liu ◽

Jingyu Yan ◽

Xifan Wang ◽

Chenyuan Wang ◽

Lingli Chen ◽

...

Keyword(s):

Human Milk ◽

Fecal Microbiota ◽

Microbiota Composition ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Breastfed Infants

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Varied Pathways of Infant Gut-Associated Bifidobacterium to Assimilate Human Milk Oligosaccharides: Prevalence of the Gene Set and Its Correlation with Bifidobacteria-Rich Microbiota Formation

Nutrients ◽

10.3390/nu12010071 ◽

2019 ◽

Vol 12 (1) ◽

pp. 71 ◽

Cited By ~ 8

Author(s):

Mikiyasu Sakanaka ◽

Aina Gotoh ◽

Keisuke Yoshida ◽

Toshitaka Odamaki ◽

Hiroka Koguchi ◽

...

Keyword(s):

Human Milk ◽

Future Perspectives ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Probiotic Supplementation ◽

Formula Milk ◽

Fecal Microbiome ◽

The Third ◽

Bifidobacterium Species ◽

Gene Sets

The infant’s gut microbiome is generally rich in the Bifidobacterium genus. The mother’s milk contains natural prebiotics, called human milk oligosaccharides (HMOs), as the third most abundant solid component after lactose and lipids, and of the different gut microbes, infant gut-associated bifidobacteria are the most efficient in assimilating HMOs. Indeed, the fecal concentration of HMOs was found to be negatively correlated with the fecal abundance of Bifidobacterium in infants. Given these results, two HMO molecules, 2′-fucosyllactose and lacto-N-neotetraose, have recently been industrialized to fortify formula milk. As of now, however, our knowledge about the HMO consumption pathways in infant gut-associated bifidobacteria is still incomplete. The recent studies indicate that HMO assimilation abilities significantly vary among different Bifidobacterium species and strains. Therefore, to truly maximize the effects of prebiotic and probiotic supplementation in commercialized formula, we need to understand HMO consumption behaviors of bifidobacteria in more detail. In this review, we summarized how different Bifidobacterium species/strains are equipped with varied gene sets required for HMO assimilation. We then examined the correlation between the abundance of the HMO-related genes and bifidobacteria-rich microbiota formation in the infant gut through data mining analysis of a deposited fecal microbiome shotgun sequencing dataset. Finally, we shortly described future perspectives on HMO-related studies.

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TERM INFANT FORMULA SUPPLEMENTED WITH HUMAN MILK OLIGOSACCHARIDES (2’FUCOSYLLACTOSE AND LACTO-NEOTETRAOSE) SHIFTS STOOM MICROBIOTA AND METABOLIC SIGNATURES CLOSER TO THAT OF BREASTFED INFANTS.

Journal of Pediatric Gastroenterology and Nutrition ◽

10.1097/01.mpg.0000489632.17881.57 ◽

2016 ◽

Vol 63 (1S) ◽

pp. S55 ◽

Cited By ~ 6

Author(s):

Philippe Alliet ◽

Giuseppe Puccio ◽

Elke Janssens ◽

Cinzia Cajozzo ◽

Giovanni Corsello ◽

...

Keyword(s):

Human Milk ◽

Infant Formula ◽

Term Infant ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Breastfed Infants ◽

Metabolic Signatures

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Human Milk Oligosaccharides Influence Neonatal Mucosal and Systemic Immunity

Annals of Nutrition and Metabolism ◽

10.1159/000452818 ◽

2016 ◽

Vol 69 (Suppl. 2) ◽

pp. 41-51 ◽

Cited By ~ 72

Author(s):

Sharon M. Donovan ◽

Sarah S. Comstock

Keyword(s):

Human Milk ◽

Infant Formula ◽

Bovine Milk ◽

Complex Mixture ◽

Structural Diversity ◽

Host Cells ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Immune Development ◽

Breastfed Infants

The immune system of the infant is functionally immature and naïve. Human milk contains bioactive proteins, lipids, and carbohydrates that protect the newborn and stimulate innate and adaptive immune development. This review will focus on the role human milk oligosaccharides (HMO) play in neonatal gastrointestinal and systemic immune development and function. For the past decade, intense research has been directed at defining the complexity of oligosaccharides in the milk of many species and is beginning to delineate their diverse functions. These studies have shown that human milk contains a higher concentration as well as a greater structural diversity and degree of fucosylation than the milk oligosaccharides in other species, particularly bovine milk from which many infant formulae are produced. The commercial availability of large quantities of certain HMO has furthered our understanding of the functions of specific HMO, which include protecting the infant from pathogenic infections, facilitating the establishment of the gut microbiota, promoting intestinal development, and stimulating immune maturation. Many of these actions are exerted through carbohydrate-carbohydrate interactions with pathogens or host cells. Two HMOs, 2′-fucosyllactose (2′FL) and lacto-N-neotetraose (LNnT), have recently been added to infant formula. Although this is a first step in narrowing the compositional gap between human milk and infant formula, it is unclear whether 1 or 2 HMO will recapitulate the complexity of actions exerted by the complex mixture of HMO ingested by breastfed infants. Thus, as more HMO become commercially available, either isolated from bovine milk or chemically or microbially synthesized, it is anticipated that more oligosaccharides will be added to infant formula either alone or in combination with other prebiotics.

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Human Milk Oligosaccharides (HMOs) and Infant Microbiota: A Scoping Review

Foods ◽

10.3390/foods10061429 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1429

Author(s):

Cristina Sánchez ◽

Cristina Fente ◽

Patricia Regal ◽

Alexandre Lamas ◽

María Paz Lorenzo

Keyword(s):

Breast Milk ◽

Human Milk ◽

Mode Of Delivery ◽

Geographic Location ◽

Microbial Colonization ◽

Human Milk Oligosaccharides ◽

Maternal Factors ◽

Milk Oligosaccharides ◽

Breastfed Infants ◽

The Impact

Human milk oligosaccharides (HMOs) are the third most abundant solid component of breast milk. However, the newborn cannot assimilate them as nutrients. They are recognized prebiotic agents (the first in the newborn diet) that stimulate the growth of beneficial microorganisms, mainly the genus Bifidobacterium, dominant in the gut of breastfed infants. The structures of the oligosaccharides vary mainly according to maternal genetics, but also other maternal factors such as parity and mode of delivery, age, diet, and nutritional status or even geographic location and seasonality cause different breast milk oligosaccharides profiles. Differences in the profiles of HMO have been linked to breast milk microbiota and gut microbial colonization of babies. Here, we provide a review of the scope of reports on associations between HMOs and the infant gut microbiota to assess the impact of HMO composition.

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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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