Recent Advances on Lacto-N-neotetraose, a Commercially Added Human Milk Oligosaccharide in Infant Formula

Abstract

Human milk oligosaccharides (HMOs) act as the important prebiotics and display many unique health effects for infants. Lacto-N-neotetraose (LNnT), an abundant HMO, attracts increasing attention because of its unique beneficial effects to infants and great commercial importance. It occurs in all groups of human milk, but the concentration generally decreases gradually with the lactation period. It has superior prebiotic property for infants, and its other health effects have also been verified, including being immunomodulatory, anti-inflammatory, preventing necrotizing enterocolitis, antiadhesive antimicrobials, antiviral activity, and promoting maturation of intestinal epithelial cells. Safety evaluation and clinical trial studies suggest that LNnT is safe and welltolerant for infants. It has been commercially added as a functional ingredient in infant formula. LNnT can be synthesized via chemical, enzymatic, or cell factory approachs, among which the metabolic engineering-based cell factory synthesis is considered to be the most practical and effective. In this article, the occurrence and physiological effects of LNnT were reviewed in detail, the safety evaluation and regulation status of LNnT were described, various approaches to LNnT synthesis were comprehensively summarized and compared, and the future perspectives of LNnT-related studies were provided.

Strategies for Enhancing Microbial Production of 2′-Fucosyllactose, the Most Abundant Human Milk Oligosaccharide

“…Metabolic engineering provides a promising solution for enhancement of GDP- l -fucose supply and highly efficient production of 2′-FL. Actually, metabolic engineering-based microbial synthesis has also been recognized as the most important approach to the manufacture of all other commercialized HMOs, including 3-fucosyllactose, lacto- N -tetraose, lacto- N -neotetraose, difucosyllactose, 3′-sialyllactose, and 6′-sialyllactose …”

“…Metabolic engineering provides a promising solution for enhancement of GDP-L-fucose supply and highly efficient production of 2′-FL. Actually, metabolic engineeringbased microbial synthesis has also been recognized as the most important approach to the manufacture of all other commercialized HMOs, 6 including 3-fucosyllactose, 7 tetraose, 8 lacto-N-neotetraose, 9 difucosyllactose, 10 3′-sialyllactose, and 6′-sialyllactose. 11 In this review, we first summarize GDP-L-fucose synthesis and bacterial α1,2-fucosyltransferases in detail, then comprehensively review various metabolic engineering strategies for enhancing 2′-FL production, and finally discuss the future research hotspots in biotechnological manufacturing and application of 2′-FL.…”

Designing a Highly Efficient Biosynthetic Route for Lacto-N-Neotetraose Production in Escherichia coli

“…It accounts for approximately 6% (expressed as molar ratio) in total HMOs, with the calculated central value of concentration of 250–700 mg/L in breast milk . Its promising physiological effects and safety evaluation have been extensively studied. , Clinical trials of LNnT have been studied in infants, indicating that the LNnT-supplemented formula is safe, giving the same growth pattern as breast-fed infants . It has been approved as Generally Recognized as Safe (GRAS) by American Food and Drug Administration (FDA).…”

“…Its safety evaluation has also been recognized by the European Food Safety Authority (EFSA) and the Food Standards Australia New Zealand (FSANZ). It is the second HMO allowed to be commercially added to infant formula after 2′-fucosyllactose and thus shows the great commercial importance . For example, Wyeth’s Illuma formula contains LNnT at 0.5, 0.13, 0.11, and 0.11 g/L for stages 1, 2, 3, and 4, respectively.…”

“…It is the second HMO allowed to be commercially added to infant formula after 2′-fucosyllactose and thus shows the great commercial importance. 10 For example, Wyeth's Illuma formula contains LNnT at 0.5, 0.13, 0.11, and 0.11 g/L for stages 1, 2, 3, and 4, respectively.…”