Characterising glycosaminoglycans in human breastmilk and their potential role in infant health

Abstract

Human breastmilk is composed of many well researched bioactive components crucial for infant nutrition and priming of the neonatal microbiome and immune system. Understanding these components gives us crucial insight to the health and wellbeing of infants. Research surrounding glycosaminoglycans (GAGs) previously focused on those produced endogenously; however, recent efforts have shifted to understanding GAGs in human breastmilk. The structural complexity of GAGs makes detection and analysis complicated therefore, research is time consuming and limited to highly specialised teams experienced in carbohydrate analysis. In breastmilk, GAGs are present in varying quantities in four forms; chondroitin sulphate, heparin/heparan sulphate, dermatan sulphate and hyaluronic acid, and are hypothesised to behave similar to other bioactive components with suspected roles in pathogen defense and proliferation of beneficial gut bacteria. Chondroitin sulphate and heparin, being the most abundant, are expected to have the most impact on infant health. Their decreasing concentration over lactation further indicates their role and potential importance during early life.

Keywords: breastmilk; chondroitin sulphate; glycosaminoglycan; heparan sulphate; heparin; microbiome.

Figure 1. Percentage change of bioactive components in breastmilk from colostrum (1-4 days pp) compared to mature breastmilk (>15 days pp) , , , .

Figure 2. Schematic representation of the structure andsulphation positions of chondroitin sulphate, dermatan sulphate, heparan sulphate, heparin and hyaluronic acid .

Figure 3. Simplified schematic representation of GAG synthesis in human breastmilk. UPD sugars are synthesised in the cytoplasm where they remain until biosynthesis begins. Left: non-sulphated hyaluronic acid; UPD sugars diffuse into the plasma membrane where they are polymerised by hyaluronic acid synthases, forming the HA polysaccharide. HA is then excreted unmodified into the pericellular space . Right: sulphated GAG synthesis of CS, DS, Hep and HS; UPD sugars are transferred to the cis Golgi by transmembrane nucleotide transporters where they act as sugar donors for glycosyltransferases , . Synthesis of the common linkage tetrasaccharide on the proteoglycan core begins in the endoplasmic reticulum (ER) and finishes in the Golgi apparatus, allowing for CS and Hep/HS chain building. CS, Hep and HS undergo sulphation and modifications in the Golgi before secretion at the trans-golgi network . Created with Biorender.com.

Figure 4. The average composition of mature human breast milk of mothers who delivered term infants. Data compiled from published studies , , , .