A Gestational Supplementation With 2′‐Fucosyllactose Is an Effective Strategy to Prevent Food Allergy
Authors: A. Rousseaux, B. Misme‐Aucouturier, M. Le Romancer, R. Villette, M. Larsen, M. De Carvalho, G. Bouchaud, E. Perrin, S. Barbarot, C. Brosseau, M. Bodinier
Journal: Allergy (2024)

Currently, no effective strategy exists to prevent food allergy (FA). FA can occur during the first months of life and is linked to the dysfunction of three biological systems: the immune system, the commensal microbiota, and the epithelial barriers that together lead to a failure in tolerance induction [1, 2]. The maternal diet during pregnancy and breastfeeding can strongly impact the establishment of these three systems, in accordance with the Developmental Origins of Health and Disease (DOHaD) concept, and can thus contribute to the emergency or prevention of allergies [3, 4]. For example, human milk oligosaccharides (HMOs) can modulate the immune function, reinforce the gut barrier, and shape the gut microbiota of infants [5]. Besides human milk, these HMOs are found in the blood, urine, and amniotic fluid of pregnant women. Therefore, we hypothesized that a gestational supplementation with 2′-FL, which is the main HMO, would create a specific microbial and immune imprinting, protecting them from FA. We investigated this hypothesis in a murine model of FA to wheat (Figure 1A and Data S1). Mice were fed either a control diet or a diet supplemented with 2′-FL from mating to delivery. After weaning, wheat-FA was induced in female pups born from mothers exposed to a control diet (CT FA) or 2′-FL diet (2′-FL FA). Non-allergic pups were used as control (CT and 2′-FL). Interestingly, the mother's exposure to 2′-FL during gestation fully abrogated FA symptoms in the offspring (Figure 1B). The 2′-FL FA group had a significantly lower clinical score and no drop in rectal temperature, as opposed to the CT FA group. Biomarkers of allergy, such as mMCP-1 and wheat-specific immunoglobulins were measured in the sera of pups (Figure 1C). Both mMCP-1 concentration and the secretion of specific IgE and IgG1 of the 2′-FL FA group were reduced compared with the CT FA group. Finally, the secretion of IgG2a was significantly higher in the 2′-FL FA group than in the CT FA group. Next, we evaluated the impact of 2′-FL supplementation on the gut microbiota composition of mothers and pups. In the mothers, the α-diversity of the gut microbiota was significantly different during gestation between the CT and 2′-FL groups, but not during lactation when the supplementation was stopped (Figure 2A). The β-diversity was also different between CT and 2′-FL groups during gestation, and remained different during lactation. In the pups, the β-diversity but not the α-diversity was different between CT and 2′-FL groups at 3 weeks of age (Figure 2B). At 6 weeks of age, both the α- and β-diversity were different between the CT and 2′-FL groups and modified by the allergic status of the pups (Figure 2C). These results demonstrate that the protective effect of gestational 2′-FL intake on FA occurrence is associated with a microbial imprint in the pups. This microbial imprint reinforced the gut intestinal epithelial barrier of allergic pups, as demonstrated by a decrease in jejunal permeability and an increase in mucus-containing colonic crypts (Data S2). Taken together, we show, for the first time, that the gestational supplementation with 2′-FL leads to a full protection against FA in the offspring, which is associated with a microbial imprint and a reinforcement of the gut barrier in the pups. These results are in line with a previous report showing a correlation between the presence of 2′-FL in breastmilk and a lower risk of allergy in infants [6]. It is important to recognize that maternal nutrition has a significant influence on the HMO profiles in the breastmilk [7, 8]. Improving maternal dietary quality during pregnancy may not only optimize HMO levels in breastmilk, enhancing infant health, but also positively impact HMO levels in amniotic fluid, thereby supporting the development of vital biological systems in the fetus. It would be of great interest to investigate the effectiveness of a gestational supplementation with 2′FL to prevent allergy in high-risk children, in a similar manner as our ongoing clinical trial PREGRALL (NCT03183440). Study conceptualization: A.R., C.B., and M.B. Methodology: A.R., B.M.A., G.B., R.V., M.L., C.B., and M.B. Formal analysis and investigation: A.R., C.B., B.M.A., L.R.M., M.B., R.V., M.L., and E.P. Resources: M.B. and G.B. Writing – original draft preparation: A.R. and C.B. Writing – review and editing: C.B., A.R., M.B., G.B., and S.B. Supervision, project administration, and funding acquisition: M.B. We thank GLYCOM-DSM for providing us with 2′-FL. We are most grateful to the Genomics Core Facility GenoA, member of Biogenouest and France Genomique and to the Bioinformatics Core Facility BiRD, member of Biogenouest and Institut Français de Bioinformatique (IFB) (ANR-11-INBS-0013) for the use of their resources and their technical support. Figure 1A was made with Biorender.com. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.