Plant-powered HMOs: Researchers unlock sustainable source with genetic engineering

20 Jun 2024 --- Researchers state they have successfully produced human milk oligosaccharides (HMOs) from genetically engineered plants. They reprogrammed the plants’ processes to create sugar to create a range of HMOs, which “provides a path to the large-scale production of specific HMOs at lower prices than microbial production platforms.”

Although HMOs are increasingly added to infant formula to offer nutritional benefits similar to breastfeeding, these nutrition products do not yet replicate the complete nutritional profile of breast milk. The study’s authors from the University of California (UC) in Davis and Berkeley explain that most of the prebiotic sugar molecules in breast milk are challenging to manufacture.

“We hope that this provides a new and possibly more sustainable way to produce HMOs,” Patrick Shih, assistant professor of plant and microbial biology and an investigator at UC Berkeley’s Innovative Genomics Institute, US, and the study’s senior author, tells Nutrition Insight.

He adds that the discovery provides an entirely “new biological platform for the biosynthesis and production of HMOs.”

“We hope to be introducing HMO biosynthesis into crop plants that could be scaled up for larger scale production,” he continues. “We’re interested in figuring out the logistics in scaling up this process.”

HMO production
Like other complex sugars, HMOs are made from simple sugars — monosaccharides. These can be linked together to form various arrays of chains and branched chains. Shih explains that plants create a range of simple and complex sugars. “Since plants already have this underlying sugar metabolism, why don’t we try rerouting it to make HMOs?”

For the study published in Nature Food, the researchers engineered the genes responsible for the enzymes that make the specific linkages for HMOs. Next, they introduced the genes into the Nicotiana benthamiana plant, closely related to tobacco.

The genetically modified plants produced eleven known HMOs, “all three major groups of HMOs” and several other complex sugars with similar linkage patterns.

The researchers note the finding provides a path to the large-scale production of specific HMOs at lower prices.Currently, commercial HMO production relies on microbial fermentation. Shih underscores: “There are limitations to bacterial fermentation and plants may offer unique advantages from both a metabolic and an economic perspective.”

For example, fermentation can only commercially produce two to five simple HMOs of the 200 found in human milk at a scale suitable for supplementing food products. Although these five HMOs cover a large portion of the compound found in breast milk, the researchers stress that diverse HMOs are essential for the growth of beneficial gut microbes.

Moreover, isolating beneficial molecules from toxic byproducts when manufacturing HMOs through engineered E. coli bacteria, used for a limited number of baby formulas, is costly.

Plant power
The study’s first author, Collin Barnum from UC Davis, created a stable line of N. benthamiana plants optimized to produce the HMO LNFP1.

“LNFP1 is a five-monosaccharide-long HMO that is supposed to be beneficial, but so far cannot be made at scale using traditional microbial fermentation methods,” he explains. “We thought that if we could start making these larger, more complex HMOs, we could solve a problem that that industry currently can’t solve.”

The researchers highlight that the HMOs produced in these transgenic plants provided strong bifidogenic properties — enhancing the growth of bifidobacteria in the gut. This indicates their ability to serve as a prebiotic supplement with potential applications in adult and infant health.

HMOs are increasingly added to infant formula to offer nutritional benefits similar to breastmilk.Moreover, developing a diverse range of plant-produced HMOs will enable researchers to study previously inaccessible HMOs.

“Since the structure of an HMO determines its bioactivity, this could lead to the discovery of HMOs that treat various gastrointestinal illnesses,” suggests the study.

Product applications
The researchers also suggest that producing HMOs in plants could “permit direct consumption as food” by ingesting the plant or products made from the plant. For example, this may lead to a consumable source of prebiotic HMOs for humans or an addition to forage crops for animal consumption.

“Imagine being able to make all the HMOs in a single plant. Then you could grind up that plant, extract all the oligosaccharides simultaneously and add that directly into infant formula,” adds Shih. “There would be a lot of challenges in implementation and commercialization, but this is the big goal that we’re trying to move toward.”

The researchers further assert that producing HMOs from plants at an industrial scale would likely be cheaper than using microbial platforms. They predict that plants may “emerge as a cost-competitive and sustainable platform for the production of diverse HMOs” as demand for HMOs continues to grow for applications in infant nutrition and beyond.

By Jolanda van Hal

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