Advances in biosynthetic preparation and application of human milk oligosaccharides

Human milk oligosaccharides (HMOs) are a group of sugars found abundantly in breast milk. While these suagrs are not digested by infants, they serve as specialized food for beneficial gut bacteria, playing a crucial role in developing a healthy immune system, protecting against pathogens, and promoting brain development. For decades, replicating these benefits in infant formula was a major scientific challenge due to the structural complexity of HMOs.

In a review published in the KeAi journal Glycoscience & Therapy, a team of researchers from China described the latest progress in creating these valuable molecules through bioengineering. The researchers note that the field has evolved from inefficient chemical methods to precision microbial fermentation. Scientists now genetically engineer friendly bacteria like E. coli to function as "cell factories" reprogramming their metabolic pathways to convert simple sugars like glucose or glycerol into specific HMOs. This approach has enabled the industrial-scale production of 2'-FL, which is now added to many premium infant formulas globally.

Novelty: Research is moving beyond the "simpler" HMOs. The review details innovative strategies to tackle the synthesis of more structurally complex and previously difficult-to-produce HMOs. For 3-FL, a bottleneck was the inefficient enzyme (α1,3-fucosyltransferase); researchers have used protein engineering to create improved versions, boosting yields. For larger HMOs like Lacto-N-tetraose (LNT) and Lacto-N-neotetraose (LNnT), a key challenge is balancing the internal supply of two expensive sugar building blocks (UDP-galactose and UDP-GlcNAc). Recent work employs "modular engineering" and chromosomal integration of genes to optimize this delicate balance within the microbial host, achieving record-high titers. Furthermore, for sialylated HMOs like 3'-SL and 6'-SL, scientists are engineering the supply of the activated sialic acid donor (CMP-Neu5Ac), a critical and limiting precursor.

Significance: The ability to biosynthesize a wider variety of HMOs at scale has profound implications. It allows infant formula to more closely mimic the compositional complexity of human milk, potentially offering formula-fed infants benefits in gut microbiota development and immune protection that were once exclusive to breastfeeding.

Beyond infant nutrition, HMOs are emerging as powerful prebiotics and immune modulators for all ages. They are being explored as functional ingredients in foods and supplements aimed at improving gut health, and early research suggests therapeutic potential for conditions like irritable bowel syndrome (IBS), necrotizing enterocolitis (NEC) in preterm infants, and even specific muscle disorders. The review underscores that while production challenges remain—particularly in purifying these complex sugars—the convergence of metabolic engineering, synthetic biology, and enzyme design is rapidly turning the vision of tailored HMO-based nutrition and therapeutics into a tangible reality.

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Contact the author: Hongtao Zhang, Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, Jiangnan University, Wuxi, 214122, China. htzhang@jiangnan.edu.cn

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