[초청강연] Regulation of innate immunity for host-bacteria symbiosis.

One of the fundamental questions relevant to all metazoans is how commensal microbiota can be maintained despite the robust anti-microbial properties of the digestive tract. At present, host factors required to maintain commensal-gut homeostasis are largely unknown. Here, we show that the intestinal homeobox gene Caudal (Cad) is indispensable for immune homeostasis in preserving the indigenous commensal community and host health. In a commensal-rich gut environment where the NF-kB activation is constitutive albeit at a low level, Cad maintains the minimum antimicrobial potential by repressing NF-kB-dependent antimicrobial peptide (AMP) genes. Cad-RNAi flies with severely reduced Cad expression showed a constitutive gut-specific AMP overexpression, which in turn acts as a novel selection pressure altering the commensal community. In these flies, the dominance of a novel gut pathogenic commensal microbe, Gluconobacter sp. strain EW707, eventually leads to high gut apoptosis, resulting in host mortality. Importantly, the restoration of the basal AMP level, healthy microbiota community structure and normal host survival in the Cad-RNAi flies can be achieved by genetic reintroduction of Cad. Thus, Cad is an essential determinant that regulates a delicate immune homeostasis for healthy commensal-gut interaction. This study presents a potential model wherein the linkage between host genetic deficiency and gut commensal community structure can be utilized to dissect molecular mechanisms of chronic inflammatory diseases frequently found in the commensal-contacting epithelia.