Inflammation-modulated Metabolic Reprogramming is Required for DUOX-dependent Gut Immunity in Drosophila

DUOX, a member of the NADPH oxidase family, acts as the first line of host defense against enteric pathogen by producing microbicidal reactive oxygen species. Despite the extensive research conducted, the elucidation of the DUOX regulatory mechanism remains incomplete. Here, by taking advantages of the Drosophila genetic tools, we showed that enteric infection acts as a ‘pro-catabolic’ signaling capable of initiating metabolic reprogramming of enterocytes toward lipid catabolism through activation of complex signaling cascades involving TNF receptor-associated factor 3, AMP-activated protein kinase, Warts kinase of the Hippo pathway, and ATG1 kinase of autophagy. We further showed that inflammation-modulated metabolic reprogramming is necessary for cellular NADPH homeostasis, which is essential for sustained DUOX activity and host survival during enteric infection. The discovery of signaling cascades governing inflammation-induced metabolic reprogramming will provide a novel perspective on physiology and pathophysiology of immune-metabolic interactions in microbe-laden gut epithelia. Overall design: mRNA expression profiles of Drosophila anterior midgut at 2, 4, and 16 hr after infection with Ecc15 (Erwinia carotovora carotovora strain 15; Ecc) and sucrose treatment (Suc) were examined by Illumina HiSeq2000.