The key to “next generation” formula? Researchers locate proteins that deliver HMOs to babies’ guts

06 Sep 2019 --- Assembling a formula-fed infant’s microbiota is still an area that warrants more research, but a new study has pinpointed the key proteins that deliver human milk oligosaccharides (HMOs) to nourish important bifidobacterium, contributing to a healthy infant gut microbiota. The researchers from the Technical University of Denmark (DTU) and Kyoto University, Japan, created a framework to identify and describe the function of the proteins that mediate the uptake of nutrients from the mother’s breast milk to an important group of bacteria in the child’s intestines. This could be used to guide milk formula producers in synthesizing new sugar additives to ensure that formula contains similarly beneficial sugars to breast milk.

“Currently, the effect of formulas on infants’ microbiota varies widely depending on the producer. Most producers have only recently started to add HMOs to formulas. There is still work to do to understand what it takes to assemble a formula-fed infant’s gut microbiota in the way that most closely resembles that of a breast-fed infant,” Professor Maher Abou Hachem from DTU Bioengineering, one of the study authors, tells NutritionInsight. 

Bifidobacteria play a major role in the development of children’s healthy gut microbiota. This can help reduce risk factors for immune and metabolic disorders such as allergy, asthma, diabetes, obesity and a variety of other diseases. Hachem notes that it is crucial that the right gut microbiota is established early in the child’s life. Interference of this process is associated with life-long health disorders, with it being very difficult to re-select beneficial bacteria once the wrong organisms are accepted as part of the microbiota. 

“Once HMO-assimilating bifidobacteria disappear from mother's intestines, the infants lose an opportunity to receive the bacteria via direct transmission from mothers. In these cases, the infants might receive probiotic bifidobacteria, but we have to be aware that the probiotics suitable for adults are not the same as those suitable for infants,” explains Takane Katayama of Kyoto University, another study co-author. 

Published in Science Advances, the study is the result of a broad collaboration between researchers with expertise in microbiology, protein and carbohydrate chemistry as well as bioinformatics. One aspect of the study analyzed fecal bacteria and mother’s milk from mother-infant pairs and a control group of human adults was conducted in Japan. Meanwhile, the molecular description of the transport proteins and their HMO preferences was conducted in Denmark.

Bifidobacteria play a major role in the development of children’s healthy gut microbiota.“We need to perform more research of this type to have a more comprehensive understanding of how specific structures in human milk are influencing the infant gut microbiota. Furthermore, we need a dialogue and collaboration with the formula industry to accelerate the process of developing the next generation formula with a mechanistic view to guide the best products,” Hachem continues. The research teams are continuing to collaborate on unraveling the mechanisms and the impact of the additional transport system in this taxonomic group.

One of the major obstacles was the lack of genetic tools to perform genetic manipulations in bifidobacteria, which dominate the infant’s gut, says Hachem. Another obstacle was that the HMO transport proteins were defiant to structural analysis, but this was overcome by another researcher determining a high-resolution structure of an HMO transport protein of a major type of HMOs.

Critical infant nutrition
The gut microbiota is established between birth and the ages of two to three years old. During this period before the immune system occurs, large changes can occur in the gut microbiota. Following weaning, the immune system remains programmed for a specific structure of the gut community that persists throughout adulthood.

The complex sugars that HMOs consist of are a key element of this process and can contain over a hundred different sugar structures that differ in size and complexity when found in breast milk. It is currently unknown what the specific impact of distinct sugars on the composition of the gut microbiota is. HMOs are also the third most abundant component in breast milk and are non-digestible by infants. Instead, they are exclusively synthesized as “nutrient sugars” to attract a healthy gut microbiota, dominated by members of Bifidobacterium.

As many infants are raised on milk formula derived from cow milk, which does not naturally contain HMOs, it is critical that the industry is able to provide the best nutrients possible for babies. The first generation of infant formula contained oligosaccharides from plants, but many companies are now attempting to add synthetic sugars identical to authentic HMOs. These synthesized HMOs are chosen based on ease of production or level of abundance in breast milk, but it is unknown how the different types of HMOs influence the assembly of a healthy infant gut microbiota.

Meanwhile, goat milk has recently been highlighted as a promising base for formulas, with fourteen varieties of oligosaccharides found to naturally occur in goat milk, which could be used to bolster infants’ gut health. However, parents starting to wean their children from all forms of milk risk overfeeding or underfeeding according to a computer modeling study.

By Katherine Durrell