PHAGOMIC

In mammals, the intestine is home to trillions of bacteria that cooperate with their host to establish mutualistic relationships. In humans, many emerging pathologies such as allergies, autoimmune and inflammatory disorders arise from a loss of symbiotic relationships with our microbial partners. Actually, microbial colonization during infancy shapes our intestinal immune system and recent studies have shown that microbial diversity during the first years of life is critical to the establishment of tolerance to environmental factors. Thus, exposure to antibiotics in childhood has been linked to the development of asthma and allergy and, even later in life, to the development of inflammatory bowel diseases. Microbial colonization also ensures protection against infection either directly by competition or indirectly by promoting mucosal immunity against pathogens. Therefore, understanding the mechanisms of interaction between the microbiota and the mucosal immune system is critical to imagine novel therapeutic approaches for preventing/treating inflammatory diseases or for boosting immunity against pathogens. Studies in mice have shown that the intestinal adaptive immune responses are mainly initiated in the small intestine Peyer’s patches (PPs). Microbial colonization of the intestine appears to be a crucial component of the normal maturation of these gut-associated lymphoid structures. Interestingly, mouse PPs are colonized by a specific microbiota, among which Segmented Filamentous Bacteria (SFB) profoundly influence the postnatal maturation of the mucosal immune system and promote the establishment of a physiological inflammatory environment that provides protection from enteropathogens. Our on-going work unambiguously identifies SFB in the microbiota of young children, suggesting that the biology of host-SFB interactions that we intend to describe in depth in mice will help to address the role of SFB in humans. Recently, another symbiont living close to PPs, Bifidobacterium adolescentis was associated with the stimulation of intestinal immunity. Among PP phagocytes, the monocyte-derived lysozyme-expressing dendritic cells termed LysoDC are ideally located, just below the epithelium, to interact with the commensal flora. We have shown that (i) LysoDC are responsible for the sampling of intestinal bacteria and particulate antigens; (ii) they participate in helper T cell priming and polarization. Thus, they clearly emerge as the ideal candidate to initiate adaptive immune responses against gut resident bacteria. This hypothesis is reinforced by the ability of the microbiota to modulate the differentiation state of LysoDC. The goal of our proposal is to decipher the role of the microbiota and especially of SFB and B. adolescentis in tuning up the immunological functions of PP phagocytes, notably LysoDC, and thereby in driving the maturation of gut adaptive immune responses. The project will involve the combined efforts of two scientific partners with complementary skills at the forefront of PP immunology and microbiota-host interactions. We will address the following points: (i) what is the influence of the commensal flora colonization on the phagocyte maturation state and on the initiation of the adaptive immune response in PPs? (ii) How specific individual symbionts or selected bacteria consortia are involved in this process? (iii) What is the role of LysoDC and other PP phagocytes in microbiota-driven mucosal adaptive immune response? (iv) Which bacterial-derived/induced factors are susceptible to modulate PP phagocyte functions? In summary, this project will provide valuable insights into how the microbiota influences the mucosal immune system through its interaction with PP phagocytes, which may provide new therapeutic opportunities based on targeted colonization, on the promotion of beneficial microbiota and on the strengthening/readjustment of microbiota-immune system crosstalk.