The two main results concern the role of the exposure route and the microbial environment and colonization by the intestinal microbiota.

Route of exposure: oral tolerance versus cutaneous or respiratory sensitization

Animal models of oral sensitization with whole foods or purified food allergens generally require the use of a Th2 mucosal adjuvant. Indeed, the same administrations of food allergens without adjuvant were demonstrated to induce an efficient oral tolerance, preventing further sensitization. The study of the underlying mechanisms revealed the induction of regulatory T-cells in the gut associated lymphoid tissue. The allergen structure was then demonstrated to have an impact on the oral tolerance efficiency. Conversely, we demonstrated that cutaneous or respiratory exposures to purified food allergens or whole food could induce allergic sensitization and then enhance further oral sensitization without the need of mucosal adjuvant. These results are in line with epidemiological studies suggesting that sensitization to peanut via cutaneous exposures could precede an active sensitization through the digestive route, in particular in children suffering from atopic dermatitis and who never consumed peanut. This further demonstrated the role of environmental exposures in the increasing prevalence of food allergies.

Microbial environment and gut colonization by microbiota: effect on allergic sensitization

At birth, the neonatal immune response is characterized by a polarized Th2 cytokine profile. Gut bacterial colonization of neonates is then a major stimulus for the development and the homeostasis of the gut immune system. We are currently studying the impact of the gut microbiota on allergic sensitization by using a model of gnotoxenic mice. By comparing experimental sensitization of germ free and conventional mice, with or without adjuvant, we showed that the absence of gut microbiota leads to excessive Th2 but also Th1 immune responses, suggesting defective immune-regulatory mechanisms in germ-free mice. Delayed colonization of six-week-old germ-free mice did not restore completely the immune system reactivity observed in conventional mice, i.e. colonized at birth. Earlier gut colonization of germ-free mice, immediately after weaning, failed also to correctly restore the immune system reactivity and led to excessive anti-inflammatory responses (data not published). These results should be considered in line with studies underlying that gut colonization of human newborn is highly altered because of the excessive cleanliness and diminished exposure to microbes in Western countries. In this regard, delayed bacterial colonization of the gut has been reported in Western infants and a reduced diversity in the composition of early gut microbiota has also been observed in allergic children in comparison with healthy children. Early and sequential gut colonization by commensal bacteria is then essential to the correct maturation of the gut immune system and for the establishment of immune homeostasis in the gut.