Abstract
Animals integrate internal states to guide survival-critical decisions, but whether and how intestinal bacteria influence this process by interacting with host metabolic cues remains unclear. Here we show that the intestinal pathogen P. aeruginosa overrides host decision-making in fasted C. elegans by modulating central serotonin (5-HT) signaling. Fasting promotes risk-taking by activating an intestinal energy-sensing pathway that induces the chemoreceptor SRI-36 in ADF 5-HT neurons, sensitizing ADF to food odors and triggering moderate 5-HT release that drives food attraction despite risk. In contrast, intestinal P. aeruginosa reverses this strategy by activating a distinct immune-brain axis that further amplifies SRI-36 expression and ADF sensitivity, leading to excessive 5-HT release that suppresses food attraction and prioritizes safety. These findings reveal a gut-to-brain mechanism by which metabolic and immune signals converge on central 5-HT to reshape behavioral strategies.
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All data generated or analyzed during this study are included in this published article and its supplementary information files. Source data are provided with this paper.
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Acknowledgements
We would like to thank Jianke Gong, Bin Qi, Anbing Shi, and Taihong Wu for providing bacterial strains; Jianke Gong, Long Lin, Anbing Shi, Haijun Tu, Wenxing Yang, and Donglei Zhang for plasmids; and Cornelia I. Bargmann, Jianke Gong, Long Lin, and Yun Zhang for C. elegans strains. We also acknowledge the Caenorhabditis Genetics Center (USA), which is funded by NIH Office of Research Infrastructure Programs (P40OD010440), for providing E. coli OP50 and C. elegans strains. This work was supported by grants from the National Natural Science Foundation of China (32571188 and 32171003 to P.L.) and the Interdisciplinary Research Program of HUST (5003170102 to P.L.).
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Y.L., C.C., and P.L. conceived and initiated the study. Y.L. and P.L. designed the experiments. Y.L., X.Z., M.X., Y.W., H.L., and J.Z. performed the experiments and analyzed the data. Y.L. and P.L. interpreted the results. P.L. wrote the manuscript.
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Lei, Y., Chen, C., Zhan, X. et al. Intestinal pathogens override hunger-driven decision-making via immune regulation of central serotonin signaling in C. elegans. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69924-w
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DOI: https://doi.org/10.1038/s41467-026-69924-w
