Lipids are pivotal to animal metabolism, immunity and longevity. While the intestine plays an essential role in digestion, processing and assimilation of dietary lipids, less is known about how commensal microbiota and pathogens may integrate or interfere with host lipid metabolism. Using Drosophila as a model, our studies test the effects of the commensal microbiota and the intestinal pathogen Vibrio cholerae on host intestinal and systemic lipid metabolism. Confocal microscopy discovered remarkable changes in lipid distribution among tissues, including gut steatosis, when flies were made germ-free or orally infected with V. cholerae. Interestingly, this phenomenon is correlated with distinct but striking organ-specific changes in glycerolipid and phospholipid compositions, revealed by lipidomics. Further investigation by target gene expression analysis and the use of transgenic flies suggest commensal and pathogenic bacteria affect host lipid metabolism through different molecular mechanisms that involve enteroendrocine cell signaling and inter-organ communication, pathways that are highly conserved in mammals.