Journal Article Preprint Epublish 1 citation
PubMed: 40502158 DOI: 10.1101/2025.05.27.656452
Gut microbe-derived lactic acid optimizes host energy metabolism during starvation.
bioRxiv
Authors: Jason William Millington, Jamie Alcira Lopez, Amin M Sajjadian, Robert J Scheffler, Brian C DeFelice, William Basil Ludington, Benjamin H Good, Lucy Erin O'Brien, Kerwyn Casey Huang
Affiliations
- Department of Molecular and Cellular Physiology and Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305. Department of Bioengineering, Stanford University, Stanford, CA 94305.
- Department of Bioengineering, Stanford University, Stanford, CA 94305. Department of Applied Physics, Stanford University, Stanford, CA 94305.
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD 21218. Department of Biology, Johns Hopkins University, Baltimore, MD 21218.
- Chan Zuckerberg Biohub, San Francisco, CA 94158.
- Department of Applied Physics, Stanford University, Stanford, CA 94305. Chan Zuckerberg Biohub, San Francisco, CA 94158.
- Department of Molecular and Cellular Physiology and Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305. Chan Zuckerberg Biohub, San Francisco, CA 94158.
- Department of Bioengineering, Stanford University, Stanford, CA 94305. Chan Zuckerberg Biohub, San Francisco, CA 94158. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
Abstract
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.
MeSH
Starvation, Lactic Acid