Advances and challenges for obtaining human milk oligosaccharides: Extraction from natural sources and synthesis by intentional design

Human milk oligosaccharides (HMOs) are a group of structurally diverse unconjugated carbohydrates that are bioactive and functional beyond their important function as the reference for prebiotics. As the health benefits of HMOs are becoming more apparent, both academia and industry have shown increasing interest in accessing HMOs. This review describes the structure and endogenous biosynthesis of HMOs and provides an overview of current approaches to obtain HMOs, which are classified based on source materials and production technologies. Strategies of each approach are highlighted. Challenges and future needs for HMO production are discussed. HMOs can be extracted from natural sources, such as human milk as the original source for a wide spectrum of HMOs and domestic animal milk for certain oligosaccharides. Oligosaccharides that are chemically and structurally identical to their naturally occurring counterpart present in human milk can be synthesized through various approaches, including chemical synthesis, enzymatic synthesis, chemoenzymatic synthesis, microbial fermentation, and mammary cell cultivation. Systematically considering the strategies and challenges of these approaches for obtaining HMOs may lead to new solutions and accelerate the advances in this field. The advances in HMO generation and production will accelerate their application in infant formulas, medical foods, and dietary supplements to improve the health of infants, mothers, those with special healthcare needs, and the general population. •Up-to-date description of the existing approaches to obtain HMOs.•Full HMOs can be extracted from human milk and few can be enriched from dairy streams.•Microbial fermentation is currently the mainstream approach for commercial manufacturing of HMOs.•Chemical, enzymatic and chemoenzymatic syntheses generate libraries of diverse HMOs.•Cell cultivation technology is emerging to produce milk components including HMOs.