Big bang and septate junctions modulates gut immune tolerance in Drosophila. François Bonnay¹, Eva Cohen-Berros¹, Gabrielle L. Boulianne², Jules A. Hoffmann¹, Nicolas Matt¹, Jean-Marc Reichhart¹. 1) UPR9022, CNRS, Université de Strasbourg, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France; 2) Programme in Developmental Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.

   Chronic inflammation of the intestine is detrimental to mammals. Similarly, constant activation of the immune response in the gut by the endogenous flora is suspected to be harmful to Drosophila. Therefore, the innate immune response in the gut of Drosophila melanogaster is tightly balanced in order to simultaneously prevent infections by pathogenic microorganisms and tolerate the endogenous flora. To understand the molecular mechanism underlying this selective immune response in the gut, we undertook a pilot screen that identified the big bang (bbg) gene.
   We show that in the adult Drosophila midgut, BBG is present at the level of the septate junctions, on the apical side of the enterocytes. In the absence of BBG, these junctions become loose enabling the intestinal flora to trigger a constitutive activation of the anterior midgut immune response. This chronic epithelial inflammation leads to a reduced lifespan of bbg mutant flies. Clearing the commensal flora by antibiotics prevents the abnormal activation of the gut immune response and restores a normal lifespan. We provide genetic evidence that Drosophila septate junctions are part of the gut immune barrier, a function that is evolutionary conserved in mammals.
   Collectively, our data suggest that septate junctions are required to maintain the subtle balance between immune tolerance and immune response in the Drosophila gut, which represents a new powerful model to study inflammatory bowel diseases.