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Peer-reviewedCC BYProceedings of the National Academy of Sciences

Sex differences in Drosophila intestinal metabolism contribute to sexually dimorphic infection outcome and alter gut pathogen virulence

  • Marko Rubinić1,2,3,4
  • Yi Yu2,5,4
  • Aranzazu Arias-Rojas2,4,6
  • Kaisy A. Martinez2,4,7
  • Wioletta Klimek2,8
  • Dagmar Frahm2,9
  • Volker Brinkmann10,11,12
  • Nicole Paczia13,4
  • Kathirvel Alagesan14
  • David Duneau15,16
  • Igor Iatsenko2
16 affiliations
  1. 1Faculty of Life Sciences, Humboldt-Universität zu Berlin
  2. 2Research group Genetics of host-microbe interactions, Max Planck Institute for Infection Biology
  3. 3Humboldt-Universität zu Berlin, Faculty of Life Sciences, 10099 Berlin, Germany
  4. 4Research group Genetics of host-microbe interactions, Max Planck Institute for Infection Biology, Charitéplatz , 07 Berlin, Germany
  5. 5Broad Institute of MIT and Harvard, Cambridge, MA, USA
  6. 6University of Texas at Arlington, 701 S Nedderman Dr, Arlington, TX 76019
  7. 7Technische Universität Berlin, Straße des 17. Juni 135, 10623 Berlin
  8. 8Core Facility for Metabolomics and Small Molecule Mass Spectrometry, Max Planck Institute for Terrestrial Microbiology, Marburg, Germany
  9. 9Max Planck Unit for the Science of Pathogens, Charitéplatz 1, 10117 Berlin, Germany
  10. 10Microscopy Core Facility, Max Planck Institute for Infection Biology
  11. 11Center for Ecology, Evolution and Environmental Changes (cE3c) & Global Change and Sustainability Institute (CHANGE), Faculty of Sciences, University of Lisbon (FCUL), Lisbon, Portugal
  12. 12Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
  13. 13Core Facility for Metabolomics and Small Molecule Mass Spectrometry, Max Planck Institute for Terrestrial Microbiology
  14. 14Max Planck Unit for the Science of Pathogens
  15. 15Center for Ecology, Evolution and Environmental Changes and Global Change and Sustainability Institute, Faculty of Sciences, University of Lisbon
  16. 16Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh
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Abstract

SUMMARY Sexual dimorphism in infection outcomes is a pervasive phenomenon, the underlying mechanisms of which remain incompletely understood. Here, utilizing Pseudomonas entomophila intestinal infection in Drosophila, we demonstrated that sex differences in intestinal redox processes contribute to female bias in susceptibility to gut infection. Female inability to overcome excessive pathogen-induced oxidative stress results in defecation blockage, pathogen persistence, and host death. Male flies exhibit increased carbohydrate metabolism and pentose phosphate pathway activity – a key antioxidant defense system. This allows males to withstand oxidative stress-induced defecation blockage and clear the pathogen from the intestine, resulting in survival. Additionally, P. entomophila showed increased expression of several virulence factors, including RNA-binding protein Hfq, in the female gut, contributing to female-biased virulence of P. entomophila . Thus, the effect of the gut metabolic environment on host defenses and pathogen virulence determines the sex differences in intestinal infection outcomes. Highlights Intestinal transit of gut pathogen contributes to sexually dimorphic susceptibility to Drosophila gut infection. Male bias in PPP favors pathogen clearance and recovery post-infection. P. entomophila reacts differently to female gut environment, where higher levels of Hfq might contribute to virulence/lethality.

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Cite

BibTeXRIS
BibTeX
@article{rubinic2026differences,
  title = {{Sex differences in Drosophila intestinal metabolism contribute to sexually dimorphic infection outcome and alter gut pathogen virulence}},
  author = {Marko Rubinić and Yi Yu and Aranzazu Arias-Rojas and Kaisy A. Martinez and Wioletta Klimek and Dagmar Frahm and Volker Brinkmann and Nicole Paczia and Kathirvel Alagesan and David Duneau and Igor Iatsenko},
  journal = {Proceedings of the National Academy of Sciences},
  year = {2026},
  month = jun,
  doi = {10.1073/pnas.2514992123},
  url = {https://doi.org/10.1073/pnas.2514992123},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Sex differences in Drosophila intestinal metabolism contribute to sexually dimorphic infection outcome and alter gut pathogen virulence
AU  - Marko Rubinić
AU  - Yi Yu
AU  - Aranzazu Arias-Rojas
AU  - Kaisy A. Martinez
AU  - Wioletta Klimek
AU  - Dagmar Frahm
AU  - Volker Brinkmann
AU  - Nicole Paczia
AU  - Kathirvel Alagesan
AU  - David Duneau
AU  - Igor Iatsenko
PY  - 2026
DA  - 2026/06/24
JO  - Proceedings of the National Academy of Sciences
DO  - 10.1073/pnas.2514992123
UR  - https://doi.org/10.1073/pnas.2514992123
AB  - SUMMARY Sexual dimorphism in infection outcomes is a pervasive phenomenon, the underlying mechanisms of which remain incompletely understood. Here, utilizing Pseudomonas entomophila intestinal infection in Drosophila, we demonstrated that sex differences in intestinal redox processes contribute to female bias in susceptibility to gut infection. Female inability to overcome excessive pathogen-induced oxidative stress results in defecation blockage, pathogen persistence, and host death. Male flies exhibit increased carbohydrate metabolism and pentose phosphate pathway activity – a key antioxidant defense system. This allows males to withstand oxidative stress-induced defecation blockage and clear the pathogen from the intestine, resulting in survival. Additionally, P. entomophila showed increased expression of several virulence factors, including RNA-binding protein Hfq, in the female gut, contributing to female-biased virulence of P. entomophila . Thus, the effect of the gut metabolic environment on host defenses and pathogen virulence determines the sex differences in intestinal infection outcomes. Highlights Intestinal transit of gut pathogen contributes to sexually dimorphic susceptibility to Drosophila gut infection. Male bias in PPP favors pathogen clearance and recovery post-infection. P. entomophila reacts differently to female gut environment, where higher levels of Hfq might contribute to virulence/lethality.
SN  - 0027-8424
SN  - 1091-6490
ER  -