Researchers have found a new way to produce human milk oligosaccharides (HMOs) using genetically modified plants, a process that would likely be cheaper than using microbial platforms.
Human breast milk contains around 200 unique prebiotic sugars, known as HMOs. These nutritional properties are difficult to manufacture, and often missing in infant formulas, which is one reason the World Health Organization (WHO) recommends that children be exclusively breastfed for the first six months of life.
Breast milk is recognised as the best form of nutrition for babies, but it is not always feasible: some people cannot breastfeed while others choose not to. Given that approximately 75% of babies worldwide consume formula in their first six months of life — either as their single source of nutrition or in conjunction with breast milk—, replicating the nutritional profile of human breast milk in commercial infant formula is indeed a challenge, but one that is worthwhile.
In a study published in the Nature Food journal, a team of scientists from the University of California discovered a way to genetically engineer plants to produce HMOs. By reprogramming the sugar-making machinery in plants, the team was able to produce a diverse array of HMOs. In a press release, senior author of the study Patrick Shih, who is an assistant professor of plant and microbial biology and an investigator at UC Berkeley’s Innovative Genomics Institute said: "Plants are these phenomenal organisms that take sunlight and carbon dioxide from our atmosphere and use them to make sugars. And they don't just make one sugar — they make a whole diversity of simple and complex sugars."
The engineered plants produced 11 HMOs, including all three major groups. Shih added: "To my knowledge, no one has ever demonstrated that you could make all three of these groups simultaneously in a single organism."
HMOs are made up of monosaccharides, or simple sugars, which are linked together in specific patterns to form complex sugar structures. The benefits of HMOs come from the way these monosaccharides are connected, called linkages. To achieve the correct linkages, the researchers needed to engineer the plants with genes that produce the enzymes responsible for creating these specific connections.
Nicotiana benthamiana, a close relative of tobacco, was chosen as the host plant. The scientists introduced the specific genes responsible for creating HMOs into the DNA of N.benthamiana, effectively reprogramming the plant’s natural sugar-making processes to produce these particular sugars.
To ensure the plants could consistently produce these HMOs, the team first temporarily tested the genes. Once they confirmed that the genes worked as intended, they created a stable line of N.benthamiana plants, which means that the introduced genes were permanently integrated into the plant’s DNA, allowing the plant to consistently produce HMOs across multiple generations. The genetically modified plants successfully produced 11 different HMOs, including three major types: neutral, fucosylated, and acidic.
One key study finding was the team's ability to optimise the N.benthamiana plants to produce LNFP1, a single HMO. Collin Barnum, lead author of the study said: “LNFP1 is a five-monosaccharide-long HMO that is supposed to be really beneficial, but so far cannot be made at scale using traditional methods of microbial fermentation.” Barnum added that LNFP1 is a large and complex HMO, and if the team were able to produce these, they could solve a problem that the industry has thus far been unable to solve.
Plant-based HMOs likely cheaper and more scalable than microbial fermentation
Since making their debut in the European market back in 2018, HMO-enriched infant formulas have been steadily garnering interest from both manufacturers and consumers. Regulatory bodies including the US Food and Drug Administration (FDA) and European Food Safety Authority (EFSA) have given the green light for specific HMOs to be incorporated into infant formulas, including 2′-fucosyllactose (2′-FL) and Lacto‐N‐neotetraose (LNnT).
The nutritional benefits of infant formula enriched with HMOs may be clear, but the cost does remain a barrier to making these formulas more accessible and affordable. To explore this and understand the costs associated with HMO production, the researchers conducted economic analyses. The analysis compared the costs of plant-based HMO production with traditional microbial fermentation methods such as precision fermentation, a common technique used to produce HMOs.
The results indicated that the plant production would likely be cheaper and more scalable. Shih said: "Imagine being able to make all the HMOs in a single plant. Then you could just grind up that plant, extract all the oligosaccharides simultaneously, and add that directly into infant formula."
In addition to affordability, the team outlined how the plant technology could have uses beyond infant nutrition and be added to non-dairy plant milk to create a more nutritious formulation for adults.
