Millington, J. W.; Lopez, J. A.; Sajjadian, A. M.; Scheffler, R. J.; DeFelice, B. C.; Ludington, W. B.; Good, B. H.; O'Brien, L. E.; Huang, K. C.

Gut microbes convert dietary compounds into an array of metabolites that can directly provide energy to their host and indirectly impact host metabolism as systemic endocrine signals. Here, we show that gut microbe-derived metabolites can extend Drosophila melanogaster survival during starvation, despite minimal alteration of dietary energy intake. Combining survival assays with mathematical modeling and untargeted metabolomics, we identify a single, dominant mediator of starvation resilience: lactic acid produced by the commensal bacterium Lactiplantibacillus plantarum. We discover that the basis of starvation resilience is not catabolism of lactic acid using lactate dehydrogenase, but rather increased dietary energy yield through lactic acid-driven promotion of oxidative phosphorylation. Our findings emphasize the role of the microbiome as a source of endocrine cues coordinating host metabolism and underscore the potential of microbiome-derived metabolites as therapeutic molecules for manipulating metabolic health and preventing disease.