Research progress on biosynthesis of human milk oligosaccharides

WAN Li; YANG Longhao; LUO Guocong; ZHU Yingying; MU Wanmeng

doi:10.12211/2096-8280.2025-047

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Research progress on biosynthesis of human milk oligosaccharides

Invited Review | 更新时间：2026-09-04

- Research progress on biosynthesis of human milk oligosaccharides
- 母乳低聚糖生物合成研究进展
- Synthetic Biology Journal Vol. 7, Issue 4, Pages: 835-851(2026)
- 作者机构：
  
  1.江南大学食品学院，食品科学与资源挖掘全国重点实验室，江苏无锡 214122
  2.江南大学生物工程学院，江苏无锡 214122
- 作者简介：
- 基金信息：
- DOI：10.12211/2096-8280.2025-047
  CLC： Q81
- Received：20 May 2025，
  
  Revised：2025-07-21，
  
  Published：31 August 2026
- 稿件说明：
移动端阅览
万李，杨龙浩，罗国聪，朱莺莺，沐万孟. 母乳低聚糖生物合成研究进展［J］. 合成生物学， 2026， 7（4）： 835-851

WAN Li， YANG Longhao， LUO Guocong， ZHU Yingying， MU Wanmeng. Research progress on biosynthesis of human milk oligosaccharides［J］. Synthetic Biology Journal， 2026， 7（4）： 835-851
万李，杨龙浩，罗国聪，朱莺莺，沐万孟. 母乳低聚糖生物合成研究进展［J］. 合成生物学， 2026， 7（4）： 835-851 DOI： 10.12211/2096-8280.2025-047.

WAN Li， YANG Longhao， LUO Guocong， ZHU Yingying， MU Wanmeng. Research progress on biosynthesis of human milk oligosaccharides［J］. Synthetic Biology Journal， 2026， 7（4）： 835-851 DOI： 10.12211/2096-8280.2025-047.

摘要

母乳低聚糖（human milk oligosaccharide，HMO）是母乳中的核心营养成分，对于婴幼儿的生长发育具有无可替代的生理功效，是新一代婴幼儿配方奶粉的核心原料。目前针对HMO的研究主要集中在生理功能、临床应用以及生物合成技术开发等方面。鉴于HMO广阔的市场需求，高效生物合成HMO逐渐成为研究热点。合成生物技术的突破使微生物发酵法大规模生产HMO成为可能，显著提升了产业化进程的经济可行性。本文系统综述了HMO生物合成的主要策略，包括基于核苷酸供体的酶法合成、体外多酶级联反应体系、代谢工程改造微生物细胞工厂等研究进展，重点讨论了关键糖基转移酶的特异性、前体供给瓶颈及合成途径的调控机制。同时，对当前合成效率、产物谱系多样性及规模化生产面临的挑战进行了梳理，以期为HMO的高效可控合成提供理论参考。未来HMO生物合成将借助人工智能辅助的酶工程开发具有宽泛受体特异性的糖基转移酶工具箱，同时合成生物技术的发展与底盘细胞的深度改造推动结构多样化HMO的精准高效生物合成。

Abstract

Human milk oligosaccharides (HMOs)

recognized as key bioactive constituents of human milk

play indispensable roles in infant growth and development through immunomodulation

gut microbiota regulation

and pathogen defense mechanisms. These multifaceted compounds have emerged as pivotal ingredients in next-generation infant formula formulations. Current investigations primarily concentrate on three domains: elucidation of biological functions

exploration of therapeutic applications

and optimization of biosynthesis platforms. The growing commercial demand for HMOs has driven significant advancements in enzymatic synthesis and metabolic engineering approaches to achieve cost-effective production at industrial scales. The rapid development of synthetic biology has revolutionized the production of HMOs

making large-scale microbial fermentation a viable and economically feasible strategy for industrial applications. This paradigm shift has significantly accelerated the commercialization of HMOs

which are increasingly recognized for their critical roles in infant nutrition

gut microbiota modulation

and immune system development. In this comprehensive review

we systematically evaluate the latest research progress in HMOs

with particular emphasis on their biosynthesis

functional mechanisms

and biotechnological production

focusing on four key dimensions: (1) Physiological functions and mechanistic insights of HMOs: recent studies have elucidated the prebiotic

antimicrobial

and immunomodulatory properties of HMOs

highlighting their structural diversity and structure-function relationships. Advances in glycomics and microbiome research have deepened our understanding of how HMOs influence host-microbe interactions and metabolic pathways. (2) Discovery and engineering of glycosyltransferases for HMOs biosynthesis: glycosyltransferases (GTs) play a pivotal role in determining the structural diversity of HMOs. We review the latest strategies for enzyme mining

characterization

and protein engineering

including directed evolution and computational design

to enhance catalytic efficiency and substrate specificity. (3) Metabolic pathway design and optimization in microbial cell factories: the construction of efficient microbial chassis for HMOs production requires systematic pathway engineering. Key considerations include precursor supply

cofactor balancing

and the elimination of metabolic bottlenecks. We also discuss recent advances in dynamic pathway regulation and modular assembly techniques to improve the yield and purity of HMOs. (4) Synthetic biology strategies for chassis cell development: the optimization of host strains involves genome-scale metabolic modeling

CRISPR-based genome editing

and adaptive laboratory evolution. Additionally

novel approaches such as cell-free biosynthesis and consortia-based fermentation are emerging as promising alternatives for complex HMOs synthesis. Furthermore

we discuss emerging challenges and future directions in this field.

关键词

Keywords

references

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Key Laboratory of Carbohydrate Chemistry and Biotechnology of Ministry of Education， School of Biotechnology， Jiangnan University

Guangxi Luwu Eurasia Sugar Industry Co.， Ltd.

Inner Mongolia Key Laboratory of Microbial Metabolism and Green Fermentation Engineering， Huhehaote

State Key Laboratory of Biopharmaceutical Preparation and Delivery， Institue of Process Engineering， Chinese Academy of Sciences

Postal code：100011
Tel：010-64519339/9292 Email：synbioj@cip.com.cn
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