The worldwide prevalence of Gestational Diabetes Mellitus (GDM) has increased steadily over the last decade, affecting up to 10.8 % of the pregnancies in France, mainly due to the rising proportion of women with pre-pregnancy overweight, sedentary lifestyle and advanced maternal age at birth. GDM fuels the type 2 diabetes (T2D) epidemic in the next generation. Whether nutritional interventions during critical time windows in early life, such as breastfeeding could mitigate this risk remains to be explored. Indeed, despite emerging evidence of the infant-health benefit of breastfeeding in GDM, there is still a paucity of data concerning GDM-breast milk (BM) composition in regard with consensual key regulators of energy homeostasis and insulin sensitivity. In original studies, GDM-MILK consortium reported adaptations of BM composition in link with maternal diet or physiological status in human cohorts and in a cross-fostering rodent model of programming. Interestingly, in a pilot study conducted on GDM mothers, using comprehensive human BM (HBM) metabolomics/lipidomics analyses, we evidenced a specific GDM-HBM signature. Based on these preliminary data, GDM-MILK plans to (i) achieve the identification and validation of BM bioactive compounds associated with maternal glycaemia in existing human cohorts and integrate compositional and clinical data, (ii) validate the HBM bioactive components in a pre-clinical rodent model of GDM and explore the mechanisms of adaptations of key maternal organs (pancreas-placenta-mammary gland) impacting GDM-milk composition, and (iii) in vivo using cross-fostering, evaluate the functional impact of a cocktail of milk components previously selected by in vitro studies, on the sensitivity/secretion of insulin in the male and female offspring. This project will provide a major breakthrough in the understanding of lactation period as a sustainable intervention that may curb the T2D pandemic in the next generations and also yield the scientific basis for nutritional recommendations for mothers with GDM and their infants. Therefore, GDM-MILK perfectly fits the research axis Translational Health Research.

Atopic disease affects 30-40% of the world's population, and the overall increase in their prevalence is a public health issue to date. Atopic dermatitis (AD) is the earliest and the most common manifestation of allergic diseases (prevalence 20%). AD is most often associated with food allergies (FA), followed by allergic rhinitis and/or asthma. The "atopic march" (AM) describes the tendency for allergic diseases to develop sequential throughout childhood. The pathophysiology of AD is not fully elucidated and there is currently no effective strategy for prevention of the disease. AD is a multifactorial disease influenced by genetic (including early functional alteration of the skin barrier) and environmental factors. AD is associated with a dysregulated Immune System (IS) and a decrease of gut microbiota diversity. This observation raises the interesting possibility that an early intervention that acts to induce an optimal gut microbiota, such as prebiotic supplementation, may function to prevent AD development, and therefore prevent the initial phase of the AM. The immune and microbial systems (which regulate allergic processes) begin to develop prior to birth, and as such, pregnancy could be the optimal time window for an intervention. Indeed, our previous preclinical study showed a significant reduction in FA after mother exposure to prebiotics galactooligosaccharide (GOS)/inulin during pregnancy and lactation. In the second semester 2017, we will perform the first clinical trial in the world assessing maternal antenatal prebiotic supplementation on AD occurrence in children of high allergic risk (PREGRALL). The PREGRALL study is a parallel multicenter double-blind randomized controlled trial funded by the Ministry of Health. It will recruit 376 pregnant women, at risk of having an atopic infant, from 4 centres. Participants will be randomized to receive prebiotic supplementation or placebo, from 20 weeks of amenorrhea to delivery. Primary endpoint is AD occurrence in infants at one year old. PREGRALL will allow us to set up an ancillary study, CIMMAP, which is the subject of this ANR application. CIMMAP aims to improve the understanding of the pathophysiology of AM and AD, to identify early biomarkers of allergy and potentially characterize the mechanisms of prevention of allergic diseases by prenatal nutrition intervention with prebiotics. CIMMAP will use biological samples from at least 60 mother-child dyads (n=30 per arm) recruited in PREGRALL (blood and stools from mothers and infants, cord blood, colostrum and breast milk) in order to characterize: 1) IS activity and maturation in mother and newborn, respectively, by exploring the innate cell responsiveness/functionality (response to Toll-Like Receptor (TLR) agonists and cell phenotyping) and the adaptive immunity (phenotyping of regulatory and auxiliary T cells); 2) the modulation of the infant IS by maternal gut microbiota and its derived products; 2) the composition and function (production of metabolites such as SCFA) of the maternal and newborn microbiota; 3) the composition of breast milk (immune and growth factors, nutrients and miRNA) and its impact on immune and microbial factors of the newborn; Additionally, a preclinical model of cutaneous sensitization, to mimic the clinical symptoms of AD associated with FA, will be used to study the mechanisms of AM and the effects of prebiotics. These results should allow to identify the immunological, physiological and microbial biomarkers of allergy and the potential effect of prebiotics. CIMMAP should improve our understanding of the occurrence of allergic pathologies and, from an industrial perspective, yield new opportunities to develop foods enriched in prebiotics to prevent allergies.