Projektbeschreibung
Beitrag der Darmflora zur Ausbildung des Immunsystems
Nach der Geburt wird der Darm mit Mikroorganismen besiedelt, die zusammenwirken und so die Darmflora (Mikrobiom) und Basis für die Entwicklung der Immunabwehr bilden. Wie eine neuere Studie an neugeborenen Mäusen zeigt, kann die schnelle Diversifizierung der Darmflora zu einer vorübergehenden Darmentzündung führen, der so genannten „Entwöhnungsreaktion“. Das Mikrobiom und dessen Metaboliten induzieren während dieser Entwöhnung im Darm die Bildung einer Unterart regulatorischer T-Zellen, die prägend ist für die spätere Abwehrfähigkeit des Immunsystems. Das EU-finanzierte Projekt IMPRINT untersucht, wie die Darmflora zur Ausbildung des frühen Immunsystems beiträgt, und ob dies im Erwachsenenalter die Anfälligkeit für Infektions- und Immunkrankheiten (Allergien oder Colitis) begünstigt.
Ziel
Humans acquire a complex community of intestinal microorganisms in early life (gut microbiota), which helps development of the immune system, and which may reduce risk of inflammatory disease. However, these complex microbiota-immune interactions in early life are underexplored and their subsequent influence on susceptibility to infection remains unknown. The Eberl lab recently reported that a temporary intestinal inflammatory state, termed the ‘weaning reaction’, occurs in mice during a specific window in early life (2-4 weeks) in response to the rapid diversification of the gut microbiota. During weaning, the gut microbiota and its metabolites induce a sub-type of T regulatory cells in the intestine (RORγt+ Tregs) which mediate immune tolerance throughout life. Suppression of the microbiota-induced weaning reaction suppresses RORγt+ Tregs and heightens susceptibility to immunopathology such as allergy and colitis in adulthood. However, it is unknown how the weaning reaction influences the later susceptibility and response to infection. IMPRINT will investigate how the gut microbiota influences the immune system in early life to regulate the response to infection in adulthood. Using mice, this project will evaluate the impact of suppressing the weaning reaction on susceptibility to Citrobacter rodentium infection in adulthood. Next, Treg depletion models will be used to examine whether microbiota-induced Tregs during weaning influence susceptibility to C. rodentium infection in adulthood. Finally, metagenomics, metabolomics and add-back experiments will be performed to identify specific bacteria or metabolites that promote induction of Tregs during weaning and modulate subsequent susceptibility to C. rodentium infection. By combining my skills in metagenomics and metabolomics with the host lab’s expertise in intestinal immunology, IMPRINT poses potential to uncover insights into early-life microbiota-immune interactions and the pathogenesis of infectious disease.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
75724 Paris
Frankreich