Human milk oligosaccharides: Mama's sweet immunological secrets

Abstract

Background: Human milk is the very first nutrition and absolutely the best for infants providing them with optimal. Unique for human milk is the fascinating complexity of human milk oligosaccharides (HMOS) consisting of hundreds of different short-chain as well as long chain sugar molecules in a ratio of approximately 9:1. HMOS may benefit the infants’ health through developing an optimal microbiota composition but more importantly aid in building a healthy balanced immune system in early life that is fit to adapt to danger signals for the inside and outside. This thesis aims to investigate the immunomodulatory effects of authentic HMOS and specific oligosaccharide mixtures. For that purpose, an autoimmune diabetes mouse model and a murine vaccination research model have been used. In addition, in vitro mouse bone marrow derived- and human monocyte derived- dendritic cell models have been used to unravel immune mechanism involved. Aims: The following specific aims were explored: 1.What is the effect of HMOS isolated from human milk on the non-obese diabetic mouse model and mouse bone marrow derived dendritic cells (chapter 4)? 2. Are the effects of authentic HMOS translatable/comparable with data obtained using human in vitro cell models (chapter 5)? 3. What is the effect of 2’FL alone and/or combination with scGOS/lcFOS on an influenza vaccination mouse model (chapter 6 and 7)? Results: Chapter 2 provides a general introduction of the important immunological aspects of HMOS. A summary of available evidence regarding the beneficial effects of HMOS in different immune contexts, including autoimmune diabetes and vaccination responsiveness. Chapter 3 provides an in-depth review of dietary intervention in the prevention and treatment of type 1 diabetes, and proposes the potential of HMOS in protecting against type 1 diabetes via regulating the immune system and modulating the gut microbiota composition and metabolism. Moreover, the possible cellular and molecular mechanisms involved in the immunomodulatory effects of HMOS on dendritic cells were postulated. Chapter 4 demonstrates that dietary intervention with authentic HMOS in early life protected NOD-mice from developing T1D in later life through a.o. modulating gut microbiota composition and metabolites, as well as regulating immune responses via dendritic cells. Chapter 5 indicates that HMOS induced direct immunomodulation and suppressed LPS-induced over activation of human DCs. Moreover, this chapter provides deep insights into multiple molecular pathways involved in the immune modulatory effects of HMOS mixture. Chapter 6 presents enhanced humoral and cellular immune responses in an influenza vaccination mouse model by dietary intervention with 2’FL, which might be attributed in part to the direct effects of 2’FL on immune cell differentiation. Chapter 7 demonstrates an even more pronounced vaccine-specific immune responsiveness by mixing of 2’FL and scGOS/lcFOS. Underlying mechanisms indicate that both direct immune effects (systemic and intestinal immune responses) as well as microbiome modulation are involved. Finally, chapter 8 summarizes the most relevant findings of all studies and provides suggestions for future research activities. Conclusions: Oligosaccharides in human milk support the development of the immune system and gut microbiota of the breastfed infants.