A Neuronally Active Bacterial Siderophore Manipulates Host Behavior and Longevity
- 1University of Cologne
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.
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BibTeX
@misc{wu2026neuronally,
title = {{A Neuronally Active Bacterial Siderophore Manipulates Host Behavior and Longevity}},
author = {Y. Wu and S. Moore and C. Backes and A. Koh and A. Zecic and D. W. Djamriani and B. Heinemann and C. Angermann and R. Balachandran and T. V. Peres and A. Ahmadi and J. Strippel and A.-M. Wesseling and I. Kaneva and A. Montoya and S. Brodesser and S. Kath-Schorr and A. Trifunovic and T. M. Hildebrandt and A. E. X. Brown and F. Cabreiro},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755717},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755717v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A Neuronally Active Bacterial Siderophore Manipulates Host Behavior and Longevity
AU - Y. Wu
AU - S. Moore
AU - C. Backes
AU - A. Koh
AU - A. Zecic
AU - D. W. Djamriani
AU - B. Heinemann
AU - C. Angermann
AU - R. Balachandran
AU - T. V. Peres
AU - A. Ahmadi
AU - J. Strippel
AU - A.-M. Wesseling
AU - I. Kaneva
AU - A. Montoya
AU - S. Brodesser
AU - S. Kath-Schorr
AU - A. Trifunovic
AU - T. M. Hildebrandt
AU - A. E. X. Brown
AU - F. Cabreiro
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755717
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755717v1
AB - 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.
ER -