Educating the human immune system: direct and indirect effects of bovine milk components

Research output: Thesisinternal PhD, WU


In this thesis, we aimed to evaluate the immunomodulatory effects of (selected) bovine milk components (and metabolites induced by them) on the immune function of humans. Chapter 1 gives an introduction to the topic and provides an outline of fundamental aspects of the immune system that are referred to in later chapters. In Chapter 2, we summarized and addressed the primary components of bovine milk that have the potential to induce epigenetic changes to exert their immune-supportive effects during childhood. We reviewed the proposed mechanisms, including innate immune training that induces epigenetic modification. Through these mechanisms, the components may exert an effect on the immune system with implications for allergies and asthma. Living in a farm environment and raw bovine milk bioactive components were addressed as contributing factors that may reduce allergies in infancy and beyond. HMOs and bovine milk oligosaccharides (mainly 3'-Sialyllactose) serve as substrates for the SCFA-producing microbiota. SCFAs are potent immune modulators and have significant roles in maintaining homeostasis and steering the response of the immune cells to the environment. In Chapter 3, we showed that butyrate and propionate had inhibitory effects on the activation of myeloid cells and lymphocytes, whereas acetate had a more selective impact on the immune cells. Production of inflammatory cytokines was suppressed in monocytes, mDCs, and pDCs, as well as T lymphocytes. SCFAs could not train the monocytes for enhanced response to secondary TLR stimulation in vitro but instead induced a tolerance-like phenotype. We attempted to explain the observed effects according to the differential expression of relevant SCFA receptors and transporters. Bovine milk IgG (bIgG) binds to human pathogens such as RSV and, via the Fc portion, interacts with the FcγRs on human immune cells. The relevance of bIgG-containing immune complexes (ICs) on activation of CD32 was studied in Chapter 4, where we could establish a method to show the direct binding of bIgG ICs to immune cells. It was demonstrated that ICs containing bIgG are directly bound to human CD14+. Subsequently, we could show the role of bIgG ICs on induction of trained immunity after binding to monocytes while contrary to previous reports, (monomeric) bIgG alone did not have similar effects suggestive of the presence of other contributing factors. Human infection challenge models are used as an alternative to field trials to study the immune-supportive effects of dietary components. In Chapter 5, we found that ingestion of a dairy product (WPC) in a human challenge model did not influence the responsiveness of myeloid cells from healthy volunteers to ex vivo stimulation with TLR ligands. It also did not change the gene expression pattern of the PBMCs isolated from the same donors. Although the model was utilized successfully before, the study product did not exert beneficial effects. We speculated that the study population might be a critical factor for no apparent impact. In Chapter 6, we focused on optimizing an E. coli infection challenge model in humans to study the protective effects of dietary components and the correlates of protection at rechallenge. Primary infection with even low doses (1E6 CFU) of E. coli protected the subjects against reinfection with a high dose (1E10 CFU) of the same pathogen. Following the primary infection, serum anti-CFAII IgG levels were raised, and monocytes and mDCs responded more strongly to ex vivo stimulation. The latter may indicate the occurrence of trained immunity in vivo. Throughout Chapter 7, we reviewed and discussed the most important findings of our research and placed the findings in a broader context by relating them to the most recent published literature. In addition, we identified subjects for future study perspectives to follow the work done in this project. Immunomodulation by nutrition or supplementation of the food with potent immunomodulatory components can provide immune support for the immune system in individuals with an immature or impaired immune system. To substantiate the dietary components' beneficial effects and define the supporting mechanisms involved, we studied bovine IgG and metabolites induced by milk oligosaccharides to substantiate their health-promoting and immune-mediated effects.

Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
  • van Neerven, Joost, Promotor
  • Savelkoul, Huub, Promotor
  • Teodorowicz, Gosia, Co-promotor
Award date27 Jun 2022
Place of PublicationWageningen
Print ISBNs9789464472233
Publication statusPublished - 27 Jun 2022


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