Exploring the relationship between HMOs and infant gut health

Summary

• Human milk oligosaccharides (HMOs) are important bioactive components of human breast milk that support the stable colonization of the genus Bifidobacterium in the infant intestine.^1,2
• Studies have demonstrated that bifidobacteria are beneficial to infant health, contributing to the maturation of the immune system and providing protection against infections.³ Understanding the mechanistic link between HMOs and bifidobacteria is imperative to fully ascertain the potential benefits of HMOs on infant health.
• In the first of a series of interviews investigating how dsm-firmenich’s HMO Donation Program has supported research in the field of HMOs, we explore the work of Professor Takane Katayama, Kyoto University, which focuses on the relationship between HMOs and Bifidobacterium.^4–9 dsm-firmenich has supported Professor Katayama’s research by providing the HMOs for his studies.

Which bacterial communities are prominent in the infant gut and what is the link to breast milk?

The gut microbiota is intimately associated with human health and disease. Several studies demonstrate its establishment during early life and long-lasting effects on energy metabolism and immune development.^10,11 Bifidobacterium is the first dominant, stable bacterial genus to colonize the human gut.⁹ Studies indicate that breastfeeding induces an infant gut microbiota rich in Bifidobacterium, which is the predominant bacterial population in the gut of breastfed infants.⁶ Bifidobacteria remain the predominant bacteria in the infant gut until weaning, suggesting that breastmilk contains a compound that selectively stimulates bifodobacterial growth.

In the 1950s, it was first proposed that breastmilk included non-digestible components called human milk oligosaccharides (HMOs) which consist of fucose, galactose, sialic acid, N-acetylglucosamine and glucose.¹² However, it was not until 2011 when we reported that certain species of Bifidobacterium were able to utilize HMOs.⁶ Since this pivotal discovery, ongoing research has focused on investigating the full capacity of HMOs in maintaining a healthy gut microbiota in infants.

How do HMOs influence the infant microbiome?

HMOs are the third most abundant solid component in human milk after lactose and lipids.¹³ They are non-digestible, as they are resistant to pancreatic digestion, allowing them to reach the colon intact where they can be utilized by Bifidobacterium species.¹³

The formation of the infant gut microbiome is affected by the level of HMO consumption by Bifidobacterium species. Indeed, the fecal concentration of HMOs was found to be negatively correlated with the fecal abundance of Bifidobacterium in infants.¹⁴ To investigate how HMOs positively influence the gut microbiome, we identified and characterized two fucosyllactose (FL) transporters from the Bifidobacterium longum infantis species.⁹ Our research revealed that the FL transporters were enriched in fecal samples from breastfed infants and positively correlated with bifidobacteria-rich microbiota formation in breastfed infants.⁹ Whereas the feces of formula fed infants was not enriched with FL transporter genes, suggesting that the genes are exclusive to the breastfed infant gut microbial ecosystem.

These studies, together with the important finding that Bifidobacterium species utilize HMOs, has accelerated research exploring the inclusion of HMOs in infant nutrition solutions. This has led to the commercialization of 2’-fucosyllactose (2’FL) – the most abundant HMO in human milk.⁷

What are the mechanisms of HMO metabolism by bifidobacterial strains?

There are two major pathways by which bifidobacterial strains can utilize HMOs.⁹ Firstly, certain Bifidobacterium species possess enzymes that degrade HMOs to monosaccharides and disaccharides, which are then imported for assimilation.⁵ Whereas other Bifidobacterium species use ATP-binding cassette (ABC) transporters to digest intact HMOs intracellularly.⁴

Does the priority arrival of certain Bifidobacterium species play a role in further development of infant gut microbiota?

The establishment of new Bifidobacterium species in a microbial community can depend on the order and/or timing of their arrival – a phenomenon known as a priority effect. Bifidobacteria are heterogenous bacteria with different species and strains harboring divergent capacities to utilize HMOs and this is partly responsible for affecting the formation of the bifidobacterial community.

For example, the Bifidobacterium breve (B. breve) species has limited HMO-assimilation capabilities as only 10% of B. breve strains possess FL transporter genes and they are only able to assimilate lacto-N-tetraose and lacto-N-neotetrose.⁸ Nonetheless, B. breve sometimes becomes the dominant species in infant gut Bifidobacterium communities because it can benefit from priority effects during the HMO-mediated community formation. For instance, if B. breve arrives in HMO-rich environments earlier than or at the same time as other species, it can utilize fucose and other degradant sugars that are released from HMOs by other Bifidobacterium species, thereby dominating the community. Data show that the abundance of B. breve species in 4-month-old infants was statistically higher when B. breve was detected at birth.⁸ These results indicate that, in addition to the HMO assimilation capacity of each species, the timing of colonization can also influence the maturation trajectory of infant gut microbiota.

Why have humans evolved to synthesize higher amounts of non-digestible oligosaccharides than other primates?

All primate milk contains oligosaccharides, but only human milk includes them as the third most abundant solid component.¹⁵ Interestingly, the occurrence of bifidobacteria-rich microbiota has been reported only in human infants, not other primates. The prevalence of HMO assimilation genes is dependent on Bifidobacterium species and strains. Hence, HMO species richness may correspond to varied occurrence of HMO assimilation genes in the genus Bifidobacterium, so that diversity of this species is maintained among different individuals.

How do you see HMO research and applications evolving in the future?

Shaping a healthy gut microbiota in infants by supplementing formula with HMOs remains a high priority in application studies. An important goal in HMO research is preventing disease, like the occurrence of necrotizing enterocolitis (NEC), one of the most serious diseases affecting premature infants.¹⁶ In the US, novel findings indicate that a single HMO, disialyllacto-N-tetraose (DSLNT), can potentially prevent NEC pathology.¹³ This discovery highlights the promising potential of utilizing HMOs for potentially reducing the risk of a life-threatening disease in infants.

In addition, HMOs could prevent the binding of viruses and toxins to surface glycans on epithelial cells as HMOs share similar structure to these glycans, allowing them to deflect pathogenic adhesions and prevent infection.^17–19

About dsm-firmenich's HMO Donation Program

The HMO Donation Program utilizes dsm-firmenich’s HMO library which consists of nearly 20 different HMO structures and mixtures. The program allows leading scientists in the HMO field to collaborate with dsm-firmenich through HMO accessibility and cutting-edge science. To date, dsm-firmenich has supported over 100 research projects across the globe.

Professor Takane Katayama

Katayama received his PhD in 1999 from Kyoto University. Following this Katayama genetically isolated two enzymes from Bifidobacterium, 1,2-α-l-fucosidase and endo-α-N-acetylgalactosamindase, both of which act on (or decompose) host glycans. Next, Katayama investigated the functionality of genes and enzymes responsible for HMO degradation. His work has significantly contributed to our understanding of the relationship between HMOs in breast milk and Bifidobacterium species in the infant gut.