Year: 2026
Type: preprint
Abstract: ABSTRACT Aging populations face a growing burden of neurodegenerative disease and behavioral decline. The microbiota is increasingly implicated in host physiology, highlighting an urgent need to understand how gut microbes modulate brain function and late-life health. Here, we develop a high-throughput microbe–host screening platform to systematically dissect how bacterial genes shape organismal behavior. Using the Escherichia coli Keio library of 3,985 distinct non-essential single-gene deletion mutants in combination with Caenorhabditis elegans , we quantitatively profiled 768 behavioral features per bacterial clone and uncovered a coherent module of bacterial genes involved in iron homeostasis that robustly reprogrammed host behavior. Bacterial omics analyses revealed that alterations in iron homeostasis amplify siderophore production in a TCA cycle-dependent manner, and loss of enterobactin biosynthesis abolished the bacteria-induced changes in worm movement. Transcriptional, molecular and functional studies demonstrated that bacterial enterobactin activates host neuromuscular responses to shape both lifespan and healthspan in a manner dependent on the mitochondrial unfolded protein response. Thermal proteome profiling identified mitochondrial glutaryl-CoA dehydrogenase and the electron-transfer flavoproteins A and B as enterobactin-binding targets that control mitochondrial function. Finally, genetic manipulation of neuronal mitochondrial and cytosolic reactive oxygen species via superoxide dismutase and catalase revealed that redox state modulates enterobactin-driven changes in movement and lifespan through the secretin-family GPCR neuropeptide receptor PDFR-1. Together, these findings establish microbial enterobactin as a non-canonical neurotransmitter regulating neuronal mitochondrial function, behavior and aging, defining a gut bacteria–brain axis with broad implications for maintaining late-life health.
Authors: Yifan Wu, Saul Moore, Cassandra Backes, Alan Koh, Aleksandra Zečić, Daniel W. Djamriani, Björn Heinemann, Cecile Angermann, Riju Balachandran, Tanara V. Peres, Jennifer van der Laan, Ali Ahmadi, Julian Strippel, André-Marcel Wesseling, Iliyana Kaneva, Alex Montoya, Susanne Brodesser, Helena M. Cochemé, Stephanie Kath-Schorr, Aleksandra Trifunovic, Tatjana Hildebrandt, André E.X. Brown, Filipe Cabreiro
Institutions: University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Hammersmith Hospital, MRC London Institute of Medical Sciences, Imperial College London, Medical Research Council, Cluster of Excellence on Plant Sciences, Heinrich Heine University Düsseldorf
Language: English
Subfield: Aging
Domain: Life Sciences
Open Access status: green
Awards: G2167935963, EXC 2030: CECAD Exzellent in Alternsforschung, G2623117106, G2642650165, G2958780423, G3469463779, G4353328979, G4591806611, EXC 2048: CEPLAS Exzellenzcluster für Pflanzenwissenschaften, Exploring the Gut Microbial Action of Metformin: Targeting the Gut Microbiota to Treat Metabolic Disease., G8948663249, G9000249672
OpenAlex ID: W7220919983