The Combination of 2′-Fucosyllactose with Short-Chain Galacto-Oligosaccharides and Long-Chain Fructo-Oligosaccharides that Enhance Influenza Vaccine Responses Is Associated with Mucosal Immune Regulation in Mice

Ling Xiao,Phillip A Engen,Thea Leusink-Muis,Ingrid Van Ark,Bernd Stahl,Saskia A Overbeek,Johan Garssen,Ankur Naqib,Stefan J Green,Ali Keshavarzian,Gert Folkerts,Belinda Van'T Land

doi:10.1093/jn/nxz006

Abstract

ABSTRACTBackgroundA critical role for host-microbe interactions and establishment of vaccine responses has been postulated. Human milk oligosaccharides, of which 2′-fucosyllactose (2′FL) is the most prevalent, are known to alter host-associated microbial communities and play a critical role in the immunologic development of breastfed infants.ObjectivesDietary supplementation with a combination of 2′FL and prebiotic short-chain (sc) galacto-oligosaccharides (GOS) and long-chain (lc) fructo-oligosaccharides (FOS) was employed to examine human milk oligosaccharide effects on immune responsiveness, within a murine influenza vaccination model.MethodsFemale mice (6 wk old, C57Bl/6JOlaHsd) were fed either control diet (CON) or scGOS/lcFOS/2′FL-containing diet (GF2F) for 45 d. After starting dietary intervention (day 14), mice received a primary influenza vaccination (day 0) followed by a booster vaccination (day 21), after which ear challenges were conducted to measure vaccine-specific delayed type hypersensitivity (DTH). Serum immunoglobulin (Ig) levels, fecal and cecal microbial community structure, short-chain fatty acids, host intestinal gene expression and cellular responses in the mesenteric lymph nodes (MLNs) were also measured.ResultsRelative to CON, mice fed the GF2F diet had increased influenza vaccine–specific DTH responses (79.3%; P < 0.01), higher levels of both IgG1 (3.2-fold; P < 0.05) and IgG2a (1.2-fold; P < 0.05) in serum, and greater percentages of activated B cells (0.3%; P < 0.05), regulatory T cells (1.64%; P < 0.05), and T-helper 1 cells (2.2%; P < 0.05) in their MLNs. GF2F-fed mice had elevated cecal butyric (P < 0.05) and propionic (P < 0.05) acid levels relative to CON, which correlated to DTH responses (R2 = 0.22; P = 0.05 and R2 = 0.39; P < 0.01, respectively). Specific fecal microbial taxa altered in GF2F diet fed mice relative to CON were significantly correlated with the DTH response and IgG2a level increases.ConclusionsDietary GF2F improved influenza vaccine–specific T-helper 1 responses and B cell activation in MLNs and enhanced systemic IgG1 and IgG2a concentrations in mice. These immunologic changes are correlated with microbial community structure and metabolites.

Highlights

In addition to the provision of clean water and hygiene measures, vaccinations are an important public health intervention providing protection against serious infections [1]
Enhanced cellular and humoral vaccination responses in GF2F mice A significant increase in influenza-specific delayed type hypersensitivity (DTH) response, measured as ear swelling and ear weight gain, was detected in vaccinated mice receiving the GF2F diet compared with those receiving the control diet (CON) diet (Figure 1B: P < 0.01 for DTH; Figure 1C: P < 0.01 for ear weight increase)
A significant increase in the median fluorescence intensity (MFI) of CD86 expression (P < 0.05) was observed between the CD103+ dendritic cells (DCs) of mesenteric lymph nodes (MLNs) from GF2F mice compared with CON mice; no such effect was observed in the MFI of CD40 expression in CD103+ DCs (Figure 2D)

Summary

Introduction

In addition to the provision of clean water and hygiene measures, vaccinations are an important public health intervention providing protection against serious infections [1]. Dietary supplementation with a specific HMOS 2 -fucosyllactose (2 FL) [14] and prebiotic short-chain galacto-oligosaccharides/longchain fructo-oligosaccharides (scGOS/lcFOS) [15, 16] has been shown to improve influenza vaccine responses in mice, respectively. We examined whether dietary intervention with a combination of 2 FL and prebiotic scGOS/lcFOS (GF2F) was capable of influencing vaccine-specific immune responses, and investigated whether there is a causal link between alterations of gut microbiota (structure and metabolism) on immune responses induced by GF2F. Conclusions: Dietary GF2F improved influenza vaccine–specific T-helper 1 responses and B cell activation in MLNs and enhanced systemic IgG1 and IgG2a concentrations in mice. These immunologic changes are correlated with microbial community structure and metabolites.

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