BackgroundHuman milk is uniquely suited to provide optimal nutrition and immune protection to infants. Human milk oligosaccharides are structural complex and diverse consisting of short chain and long chain oligosaccharides typically present in a 9:1 ratio. 2′-Fucosyllactose (2′FL) is one of the most prominent short chain oligosaccharides and is associated with anti-infective capacity of human milk.AimTo determine the effect of 2′FL on vaccination responsiveness (both innate and adaptive) in a murine influenza vaccination model and elucidate mechanisms involved.MethodsA dose range of 0.25–5% (w/w) dietary 2′FL was provided to 6-week-old female C57Bl/6JOlaHsd mice 2 weeks prior primary and booster vaccination until the end of the experiment. Intradermal (i.d.) challenge was performed to measure the vaccine-specific delayed-type hypersensitivity (DTH). Antigen-specific antibody levels in serum as well as immune cell populations within several organs were evaluated using ELISA and flow cytometry, respectively. In an ex vivo restimulation assay, spleen cells were cocultured with influenza-loaded bone marrow-derived dendritic cells (BMDCs) to study the effects of 2′FL on vaccine-specific CD4+ and CD8+ T-cell proliferation and cytokine secretions. Furthermore, the direct immune regulatory effects of 2′FL were confirmed using in vitro BMDCs T-cell cocultures.ResultsDietary 2′FL significantly (p < 0.05) enhanced vaccine specific DTH responses accompanied by increased serum levels of vaccine-specific immunoglobulin (Ig) G1 and IgG2a in a dose-dependent manner. Consistently, increased activation marker (CD27) expression on splenic B-cells was detected in mice receiving 2′FL as compared to control mice. Moreover, proliferation of vaccine-specific CD4+ and CD8+ T-cells, as well as interferon-γ production after ex vivo restimulation were significantly increased in spleen cells of mice receiving 2′FL as compared to control mice, which were in line with changes detected within dendritic cell populations. Finally, we confirmed a direct effect of 2′FL on the maturation status and antigen presenting capacity of BMDCs.ConclusionDietary intervention with 2′FL improves both humoral and cellular immune responses to vaccination in mice, which might be attributed in part to the direct effects of 2′FL on immune cell differentiation.

Human milk oligosaccharides (HMOS) are a complex mixture of bioactive components supporting the immune development of breastfed‐infants. Dendritic cells (DCs) play a central role in the regulation of immune responses, being specialized in antigen presentation and driving T‐cell priming as well as differentiation. However, little is known about the direct effects of HMOS on human DC phenotypes and functions. Here, we report that HMOS mixture isolated from pooled human milk, induced semi‐maturation of human monocytes‐derived DCs (moDCs), and elevated levels of IL‐10, IL‐27 and IL‐6 but not IL‐12p70 and TNF‐α. Consistently, HMOS‐conditioned human moDCs promoted Treg generation from naïve CD4+ T cells. Interestingly, HMOS limited LPS‐induced maturation of human moDCs, while maintained IL‐10 and IL‐27 secretion and reduced LPS‐induced production of IL‐12p70, IL‐6 and TNF‐α. Furthermore, HMOS+LPS‐stimulated DCs induced a higher frequency of Tregs and increased IL‐10 production, while a reduction in Tbet+Th1 frequency and IFN‐γ production was detected as compared to LPS‐DCs. The regulatory effects of HMOS seemed to be mediated by interactions of HMOS with receptors, including but not limited to TLR4 and DC‐SIGN on human moDCs. In conclusion, HMOS contain tolerogenic factors influencing human moDCs and thereby modulating the development of the neonatal immune system.

Development of Type 1 diabetes (T1D) is influenced by non-genetic factors, such as optimal microbiome development during early life that “programs” the immune system. Exclusive and prolonged breastfeeding is an independent protective factor against the development of T1D, likely via bioactive components. Human Milk Oligosaccharides (HMOS) are microbiota modulators, known to regulate immune responses directly. Here we show that early life provision (only for a period of six weeks) of 1% authentic HMOS (consisting of both long-chain, as well as short-chain structures), delayed and suppressed T1D development in non-obese diabetic mice and reduced development of severe pancreatic insulitis in later life. These protective effects were associated with i) beneficial alterations in fecal microbiota composition, ii) anti-inflammatory microbiota-generating metabolite (i.e. short chain fatty acids (SCFAs)) changes in fecal, as well as cecum content, and iii) induction of anti-diabetogenic cytokine profiles. Moreover, in vitro HMOS combined with SCFAs induced development of tolerogenic dendritic cells (tDCs), priming of functional regulatory T cells, which support the protective effects detected in vivo. In conclusion, HMOS present in human milk are therefore thought to be vital in the protection of children at risk for T1D, supporting immune and gut microbiota development in early life.

Type 1 diabetes (T1D) is an immune-mediated disease with a strong genetic basis but might be influenced by non-genetic factors such as microbiome development that “programs” the immune system during early life as well. Factors influencing pathogenesis, including a leaky intestinal mucosal barrier, an aberrant gut microbiota composition, and altered immune responsiveness, offer potential targets for prevention and/or treatment of T1D through nutritional or pharmacologic means. In this review, nutritional approaches during early life in order to protect against T1D development have been discussed. The critical role of tolerogenic dendritic cells in central and peripheral tolerance has been emphasized. In addition, since the gut microbiota affects the development of T1D through short-chain fatty acid (SCFA)-dependent mechanisms, we hypothesize that nutritional intervention boosting SCFA production may be used as a novel prevention strategy. Current retrospective evidence has suggested that exclusive and prolonged breastfeeding might play a protective role against the development of T1D. The beneficial properties of human milk are possibly attributed to its bioactive components such as unique immune-modulatory components human milk oligosaccharides and metabolites derived thereof, including SCFAs. These components might play a key role in healthy immune development and creating a fit and resilient immune system in early and later life.

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