In addition to essential nutrients and bioactive antibodies, human milk is unique in providing a rich pool of free- reducing human milk glycans (HMG) that are minimally digested in the upper GI tract and transported intact into the lower intestine, where, they have well-known pre- and probiotic effects and interfere with pathogen attachment by acting as soluble decoy receptors. HMGs also appear in the circulation, suggesting they participate systemically in physiological processes. HMGs may enhance the epithelial barrier function of the gut and regulate neuronal dependent gut motility and perhaps enhancement of cognition via the gut-brain axis. Benefits of breastfeeding stimulated manufacturers of nutritionals to develop supplements to infant formula that provide the beneficial effects of mother's milk. Abbott Nutrition and Nestle Nutrition recently introduced infant formula containing LNnT and/or 2'-FL. These HMG are now commodities manufactured as supplements using fermentation process to supply a global market. Although HMG are beneficial to infants, we know little about the biological mechanisms of any of the hundreds of HMG. A primary function of glycans in living organisms is their specific recognition by glycan binding proteins (GBPs), and protein-glycan interactions have been investigated for many years. Currently the most effective technology for investigating protein-glycan interactions is the printed glycan microarray where glycans are attached to a glass microscope slides and interrogated with GBP to discover and characterize protein-glycan interactions. We have discovered several potentially important interactions of viruses, antibodies, galectins and DC-SIGN using the first HMG glycan microarrays, believe that these discovery platforms can reveal therapeutically relevant protein-glycan interactions. Using our HMG glycan array with the glycan binding domain (VP8*) of rotavirus adhesins, we discovered, for the first time, several glycan determinants that may function as anti-adhesins, and the HMG structures carrying these determinants had never been identified in spite of 60 years of study on the structure of HMG. These studies led us to look at HMG as a subset of the larger human glycome. We developed a method to predict what structures make up HMG glycome, compiled these structures in a database that we can use for a new approach to glycan sequencing that could be a model for the more monumental task of sequencing the larger human glycome. Having constructed 2 version of an HMG glycan microarray, we know the difficulties of constructing and maintaining the required glycan libraries in an academic setting, and here we propose a commercial solution using large-scale processes developed by NatGlycan to build a sustainable HMG library of pure structures and construct a comprehensive array of completely defined glycans that represent the complete HMG glycome, which will be a discovery, screening platform for relevant protein-glycan interactions for use by pharmaceutical companies seeking glycan based drugs.
Public Health Relevance Statement: Manufacturers of infant formulas currently supplement their products with one or two Human Milk Glycans (HMG) to make them more like mother's milk, hoping to provide the well-known benefits of HMG to breastfed infants. Although HMG are very important in normal physiology, much is yet to be learned about the physiological mechanisms of any individual HMG among hundreds in milk. NatGlycan proposes to use its proprietary method for extracting natural glycans to produce the full array of HMGs at a commercial scale to support the academic and pharmaceutical research industry in discovering and characterizing physiologically relevant protein-glycan interactions.
Project Terms: Academic support; Acids; Address; Antibodies; Bacterial Adhesins; base; Binding; Binding Proteins; Biological; Blood Circulation; Breast Feeding; Breastfed infant; CD209 gene; cell motility; Cognition; Common Core; Databases; Development; Epithelial; Fermentation; Fucose; Galactose Binding Lectin; Galectin 1; Genetic; Glass; Glycoside Hydrolases; Goals; gut-brain axis; Hexoses; Human; Human Milk; Immune; Individual; Industry; Infant; Infant formula; Intestines; Investigation; Isomerism; Label; Lactation; Lactose; Libraries; Link; Lipids; Manufacturer Name; Methods; Microscope; Milk; Modeling; Monosaccharides; N-acetyllactosamine; Neurons; novel strategies; Nutrient; nutrition; Nutritional; Oligosaccharides; Online Systems; Organism; pathogen; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Physiological Processes; Physiology; Polysaccharides; Probiotics; Process; Proteins; receptor; Reporting; Research; Rotavirus; screening; Shotguns; Sialic Acids; Slide; Source; Stomach; Structure; Technology; Therapeutic; Time; tool; Upper digestive tract structure; virtual human; Virus; Work
