Immunomodulation by raw bovine milk and its ingredients: effects in nutritional intervention, oral vaccination and trained immunity

Research output: Thesisinternal PhD, WU


Both infants and elderly people have compromised immune systems. For infants human milk provides support for the immune system. Infants need immunological support, as their immune system needs time to develop. Furthermore, infants are faced with microbial colonisation and changed nutrition from breast milk towards solid food. In addition to commensal bacteria, infants are increasingly exposed to food- and airborne pathogens as well, which can cause infections in the intestine and airways. As especially, RSV and Influenza infections in the airways can be quite severe, it would be beneficial to improve airway immunity by dietary modulation. Next to this, the epithelial barrier of infants is not fully closed, especially just after birth. As a result intact food an microbial components can cross the epithelium into the mucosa. The infant should not develop allergies or anti-inflammatory immune responses towards these macronutrients and is supposed to induce oral tolerance against both food components as well as to commensal bacteria.

Elderly people often suffer from non-communicable inflammation-related inflammatory diseases as a result of immunosenescence and inflammaging. Next to this, elderly respond less to vaccination and are more vulnerable to infections. The ageing population is growing worldwide and therefore the burden of age-related disease on the global health care system is increasing as well. Hence, it would be beneficial when people become older without developing these diseases, which is termed healthy ageing. The main objective of this project was to study the immunomodulatory effect of raw bovine milk and its ingredients in nutritional intervention, oral cholera vaccination and trained immunity and its possible relevance for different stages in life.

Consumption of raw bovine milk is associated in epidemiological studies with a reduced incidence of asthma, allergies, rhinitis and respiratory tract infections, which are all related to immunity in the airways. However, not much is known about the mechanisms by which raw milk can exert this enhanced airway immunity. Therefore, the aim of this thesis was to investigate to which extent raw bovine milk can modulate immune responses to improve immunity in the airways. Chapter 2, 3, 4 and 5 are relevant for modulating the immune responses in children and adults, by raw bovine milk and it’s components.

We started in this thesis by giving a literature overview of potential mechanisms by which milk components modulate immune function in the upper respiratory tract as well as the gastrointestinal tract (chapter 2). Furthermore, in chapter 3 we investigate the potential of raw bovine milk, milk fractions, lactoferrin and bovine IgG to induce trained immunity. We could demonstrate that raw bovine milk as well as isolated bovine IgG can induce trained immunity in human monocytes. This can serve as mechanistic concept for protection against infections.

Next to this, we characterized the immune responses upon oral cholera vaccination in chapter 4, including expression of homing markers that enable homing towards the airways. Oral cholera vaccination induces a clear vaccination response in serum. Furthermore, oral cholera vaccination induces a homing marker expression profile consistent with homing to the large intestine and airways in IgA+ memory B cells. In IgA- memory B cells a homing marker expression profile towards the small intestine was induced. In chapter 5, we investigated the immunomodulatory effect of raw milk, pasteurized milk and ultra-heat treated milk on oral cholera vaccination responses in blood and mucosal tissues, including saliva and nasal wash in two vaccination studies. Oral cholera vaccination induces a clear vaccination response in serum, nasal wash, and saliva. Opposite results in modulatory capacity of milk on the oral cholera vaccination response were obtained for both MOSAIC studies. Hence, it cannot be concluded whether raw bovine milk is able to increase or decrease the production of vaccine-specific antibodies after oral cholera vaccination. We also compared homing potential towards the airways between the control and raw milk vaccine group. In the current experimental set-up, raw milk did not enhance an increase in airway homing potential.

The aim of chapter 6 was to compare innate immune function towards TLR-mediated responses between elderly and young adult women. Elderly women were shown to have lower pDCs frequencies, comparable mDC frequencies, lower basal production of cytokines by pDCs and mDCs in steady state, and increased serum markers involved in inflammation, compared to young adult women. Especially after TLR 7/8 stimulation, reduced numbers of pDCs and mDCs positive for pro-inflammatory cytokines were observed in elderly compared to young adult women. This confirms the concept of both immunosenescence and inflammaging in elderly women. In chapter 7 we performed a double-blind placebo-controlled nutritional intervention study, to investigate the potential of bovine lactoferrin, galactooligosaccharides (GOS) and vitamin D to restore TLR responsiveness of pDCs and mDCs and to reduce inflammatory cytokines in serum in elderly women. Nutritional supplementation with bLF, GOS and vitamin D is safe and enhances responses to TLR stimuli in elderly women in both pDCs and mDCs. No clear effects on pro-inflammatory markers in serum were observed, probably due to the group size in this study that was set up to study pDC responses as primary outcome. Especially TLR7-mediated responses in pDCs were enhanced after bLF supplementation compared to placebo, suggesting that bLF may contribute to protection against viral infections in elderly women.

In chapter 8 I discuss the main outcomes of our research and their relevance by placing the results in a broader perspective. I will focus on four themes: 1). Induction of trained immunity by diet; 2). Modulation of respiratory immunity by raw bovine milk; 3). Immunomodulation in elderly by bovine milk components; 4). The potential role of trained immunity throughout life.

Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
  • van Neerven, Joost, Promotor
  • Savelkoul, Huub, Promotor
  • Brugman, Sylvia, Co-promotor
  • van Hoffen, E., Co-promotor, External person
Award date4 Sep 2018
Place of PublicationWageningen
Print ISBNs9789463433037
Publication statusPublished - 2018

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