A delicate balance between bacterial iron and reactive oxygen species supports optimal C. elegans development
Open accessAbstract
Iron is an essential micronutrient for all forms of life; low levels of iron cause human disease, while too much iron is toxic. Low iron levels induce reactive oxygen species (ROS) by disruption of the heme and iron-sulfur cluster-dependent electron transport chain (ETC). To identify bacterial metabolites that affect development, we screened the Keio Escherichia coli collection and uncovered 244 gene deletion mutants that slow Caenorhabditis elegans development. Several of these genes encode members of the ETC cytochrome bo oxidase complex, as well as iron importers. Surprisingly, either iron or anti-oxidant supplementation reversed the developmental delay. This suggests that low bacterial iron results in high bacterial ROS and vice versa, which causes oxidative stress in C. elegans that subsequently impairs mitochondrial function and delays development. Our data indicate that the bacterial diets of C. elegans provide precisely tailored amounts of iron to support proper development.
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Caenorhabditis elegans fed on a mutant strain of Escherichia coli with reduced iron uptake had diminished iron uptake, impaired mitochondrial ETC function, enhanced ROS production, and developmental defects.
“Caenorhabditis elegans fed on a mutant strain of Escherichia coli, which exhibits reduced iron uptake, lead to diminished iron uptake by the worms resulting in significantly impaired mitochondrial ETC function, enhanced ROS production and developmental defects (Zhang et al., 2019).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Zhang et al., 2019
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“For instance, enterobactin, an iron carrier produced mainly by enterobacteria, is absorbed and transported into the host mitochondria, where it interacts with ATP synthases to regulate host development [41, 42].”
Liu, H., Chen, P., Yang, X., Hao, F., Tian, G., Shan, Z., & Qi, B. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.115021 · Cited by 8 · see citing works
Iron mishandling in the brain and periphery in Parkinson’s disease
Bolen, M. L., Menees, K. B., Dupreez, A. C., & Tansey, M. G. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-01089-7 · Cited by 8 · see citing works
“A possible in fl ammatory catalyst for iron loading in the periphery could be from ACD, which impairs complex I and II in the electron transport chain (ETC) within immune cells, induces excess ROS production 88 , increases immune cell activation, and proliferation 89 .”
Metabolic modeling of host-microbe interactions
Srinak, N., Krüger, F., Kaleta, C., & Taubenheim, J. (2025) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2025.10.006 · Cited by 8 · see citing works
“Reversily, metabolic modeling of Escherichia coli was used to understand how mutants for the cytochrome oxidase cause developmental delay in C. elegans [124].”
The marine environmental microbiome mediates physiological outcomes in host nematodes
Xue, Y., Xie, Y., Cao, X., & Zhang, L. (2024) · BMC Biology · doi:10.1186/s12915-024-02021-w · Cited by 7 · see citing works
“The effects of several microbial metabolites on host physiology have been investigated in C. elegans , e.g., vitamins [16–18], sidero-phores [19, 20], and neurotransmitters [21].”
BackgroundZhang, W., Sun, G., Hu, X., Cheng, H., Chen, T., Ni, A., Tang, F., & Ye, J. (2025) · Pesticide Biochemistry and Physiology · doi:10.1016/j.pestbp.2025.106504 · Cited by 6 · see citing works
Zhao, Y., Zhang, C., Yu, L., Tian, F., Zhao, J., Zhang, H., Chen, W., & Zhai, Q. (2022) · Food & Function · doi:10.1039/d2fo02675a · Cited by 6 · see citing works
Host–microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency
Lee, Y., Fox, B. W., Guo, R., Curtis, B. J., Yu, J., Kim, S., Nanda, S., Baumann, V., Yilmaz, L. S., Haynes, C. M., et al. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01098-5 · Cited by 5 · see citing works
Hematological and iron status in aerobic vs. anaerobic female athletes: an observational study
Osman, D. A., Elassal, M. I., Hamada, H. A., Hamza, R. H. S., Zakaria, H. M., Alwhaibi, R. M., & Abdelsamea, G. A. (2024) · Frontiers in Sports and Active Living · doi:10.3389/fspor.2024.1453254 · Cited by 5 · see citing works
Tian, Z., Zha, M., Cai, L., Michaud, J. P., Cheng, J., Shen, Z., Liu, X., & Liu, X. (2022) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2022.113414 · Cited by 5 · see citing works
Frézal, L., Saglio, M., Zhang, G., Noble, L. M., Richaud, A., & Félix, M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.17.540956 · Cited by 5 · see citing works
Guo, R., Li, G., Lu, L., Sun, S., Liu, T., Li, M., Zheng, Y. H., Walhout, A. J. M., Wu, J., & Li, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095003 · Cited by 4 · see citing works
Wang, L., Yang, Z., Pang, Y., Wu, X., Zhang, X., Zhu, T., Ding, X., Liu, W., Zhou, Y., Zhang, P., et al. (2025) · Advanced Science · doi:10.1002/advs.202505469 · Cited by 3 · see citing works
A gut-brain-gut axis orchestrates host responses counteracting microbiome-induced iron insufficiency
Li, G., Wu, Y., Huang, X., Du, M., & Tang, H. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00619-6 · Cited by 4 · see citing works
“Since competition for iron occurs commonly between bacteria and the host (Wilson et al, 2016; Zhang et al, 2019), we fi rst tested whether bacteria might cause a change in iron metabolism to trigger the neuronal expression of bas-1 in the host.”
Wei, W., Cao, B., Xu, D., Liu, Y., Zhang, X., & Wang, Y. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2022.1058062 · Cited by 3 · see citing works
“It is principally implicated in processes like DNA synthesis, ATP generation, and oxygen transportation (Zhang et al., 2019).”
BackgroundInsights into the genetic influences of the microbiota on the life span of a host
Zhang, F., Wang, L., Jin, J., Pang, Y., Shi, H., Fang, Z., Du, Y., Du, Y., Zhang, Y., Ding, X., et al. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1138979 · Cited by 3 · see citing works
“elegans through the balance between bacterial iron and reactive oxygen species (ROS) (Zhang et al., 2019).”
BackgroundPetersen, C., Dierking, K., Johnke, J., & Hinrich Schulenburg, Y. (2022) · Journal of Visualized Experiments · doi:10.3791/64249 · Cited by 3 · see citing works
Hinokitiol disrupts iron homeostasis and reduces virulence in Acinetobacter baumannii
Lo, H., Wu, Y.-E., Lo, C.-C., Yeh, T.-H., Yeh, R.-Y., & Lin, W. (2025) · Microbial Pathogenesis · doi:10.1016/j.micpath.2025.108062 · Cited by 2 · see citing works
Venero, E. C. S., Giambartolomei, L., Sosa, E. J., Porto, D. F. D., López, N. I., & Tribelli, P. M. (2024) · PLoS ONE · doi:10.1371/journal.pone.0301252 · Cited by 2 · see citing works
Bacterial purine metabolism modulates C. elegans development and stress tolerance via DAF ‐16
Feng, M., Gao, B., Garcia, L. R., & Sun, Q. H. (2024) · FEBS Journal · doi:10.1111/febs.17363 · Cited by 2 · see citing works
A lipid-mTORC1 nutrient sensing pathway regulates animal development by peroxisome-derived hormonesPreprint
Li, N., Hua, B., Chen, Q., Ruan, M., Zhu, M., Shen, H., Zhang, L., & Zhu, H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.15.444169 · Cited by 2 · see citing works
The marine natural microbiome mediates physiological outcomes in host nematodesPreprint
Xue, Y., Xie, Y., Cao, X., & Zhang, L. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.10.540299 · Cited by 2 · see citing works
Antibiotics Trigger Host Innate Immune Response via Microbiota–Brain Communication in C. elegans
Wu, Y., Li, G., & Tang, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168866 · Cited by 1 · see citing works
“The overlap in gene lists identified through whole-genome screening and the study by Zhang suggest that iron deficiency caused by mutant bacteria may trigger the activation of the host’s immune response [46].”
BackgroundMallick, S., Pradhan, J., Daimai, C., & Negi, V. D. (2025) · Microbiology Spectrum · doi:10.1128/spectrum.00420-25 · Cited by 1 · see citing works
Gut Microbial Genetic Variation Regulates Host Reproduction
Ding, X., Wu, Y., Zhou, D., Gu, R., Zhu, T., Cai, W., Ren, Y., Li, Y., Wang, C., Tan, A., et al. (2025) · Microbial Biotechnology · doi:10.1111/1751-7915.70248 · Cited by 1 · see citing works
“Gene mutations in Escherichia coli can substantially affect the development and lifespan of its host, Caenorhabditis elegans (nematode) (Han et al. 2018; Zhang et al. 2019).”
Context-dependent serotonin signaling links dietary quality to foraging decisions
Feng, L., Marquina-Solis, J., Yue, L., Harnagel, A., Greenfeld, Y., & Bargmann, C. I. (2025) · Nature Communications · doi:10.1038/s41467-025-65491-8 · Cited by 15 · see citing works
“An hsp-6::GFP reporter for mitochondrial stress was also signi fi cantlyinducedby Δ crp and Δ fepB bacteria 46 (Fig.2b).”
InfluentialDynamic response by commensal E. coli two-component system Cpx contributes to C. elegans development
Xiong, H., Hua, B., & Zhu, H. (2026) · BMC Biology · doi:10.1186/s12915-026-02513-x · Cited by 1 · see citing works
“Significances were displayed as * p 0.05, ** p 0.01, *** p 0.001, **** p 0.0001, ns — not significant exhibited similar phenotypes [9], with Δ cyoA , Δ sdhC , Δ ycbB , and Δ fepG independently validated [10, 28, 34].”
InfluentialXue, Y., Xue, B., & Zhang, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25169111 · Cited by 1 · see citing works
“Zhang et al. identified 244 bacterial mutants that attenuated C. elegans development, with several of the causal bacterial genes encoding the bo oxidase of the electron transport chain and iron transporters [35].”
BackgroundSuppressing APOE4-induced mortality and cellular damage by targeting VHLPreprint
Jiang, W. I., Cao, Y., Xue, Y., Ji, Y., Winer, B. Y., Zhang, M., Singhal, N. S., Pierce-Shimomura, J. T., Chen, S., & Dengke, K. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.28.582664 · Cited by 1 · see citing works
Li, G., Wu, Y., Huang, X., Du, M., & Tang, H. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.17.599455 · Cited by 1 · see citing works
Bacterial diets differentially alter lifespan and healthspan trajectories in C. elegansPreprint
Stuhr, N. L., & Curran, S. P. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.29.068288
Li, N., Hua, B., Chen, Q., Ruan, M., Teng, F., Zhu, M., Zhang, L., Huali, S., & Zhu, H. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3917161
Feng, M., Gao, B., Garcia, L. R., & Sun, Q. H. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.17.558182
“In a previous publication, E. coli gene deletion mutants that hindered C. elegans development were identified, including genes involved in fatty acid metabolism and energy production 7 .”
Bacterial sensing via Neuronal Receptor Initiates Gut Mitochondrial Surveillance for Host AdaptationPreprint
Liu, H., Chen, P., Yang, X., Hao, F., Tian, G., Shan, Z., & Qi, B. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.08.615749
Mechanistic study of the Tβ4/SLC7A11 signaling pathway regulating breast cancer evolution
Jin, Z., Li, H., Li, J., Chang, Y., Piao, Z., Jin, Q., & Jin, T. (2025) · Cellular Signalling · doi:10.1016/j.cellsig.2025.112111
Du, M., Wu, Y., Li, G., & Tang, H. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.30.679430
Host Oxidative Response Capacity Determines Longevity Outcomes of Microbial Interventions
Hao, X., Yuan, R., Guo, Y., Chen, G., Guo, Y., Liu, L., Lu, F., Bai, Y., & Tian, Y. (2026) · Aging Cell · doi:10.1111/acel.70418
“Caenorhabditis elegans provides a powerful platform for investigating host–microbe interactions in aging due to its short lifespan, tractable genetics, and modifiable microbial environment (Watson et al. 2014; Zhang et al. 2019; Qi and Han 2018; O'Donnell et al. 2020; Samuel et al. 2016).”
Llontop, M. E. M., Nauta, K. M., Gates, D. R., Wang, X., Cooper, J. F., & Burton, N. O. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.04.709558
“Finally, Zhang et al found that bacterially derived iron is essential for managing oxidative stress and promoting optimal animal development 56 .”
Du, M., Wu, Y., Li, G., & Tang, H. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117210
Aging regulation by gut microbiota: molecular insights from Caenorhabditis elegans
Liu, Q., & Tang, H. (2026) · Biogerontology · doi:10.1007/s10522-026-10496-z
“Low bacterial iron levels inhibit nematode development by elevating ROS levels, whereas iron supplementation or reduction of ROS levels can reverse this phenotype (Zhang et al. 2019).”
Zhang, Z., Mai, H., Xu, N., Zhu, J., Wang, J., Wang, J., Niu, H., Liang, L., Cao, J., 杨爱军, et al. (2026) · Hygiene and Environmental Health Advances · doi:10.1016/j.heha.2026.100200
- Authors
- Zhang, J., Li, X., Olmedo, M., Holdorf, A. D., Shang, Y., Artal-Sanz, M., Yilmaz, L. S., & Walhout, A. J. M.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Walhout, Albertha J.M.
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 26
- Issue
- 3
- Pages
- 400-411.e3
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC6742550
- OpenAlex
- W2969609872
- Cited by
- 77
- References
- 54
- Citations by year
- 2026: 6 · 2025: 18 · 2024: 14 · 2023: 12 · 2022: 9 · 2021: 9 · 2020: 7 · 2019: 2
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship@UMassChan (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- National Institutes of Health (GM122502, P40 OD010440)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- reactive oxygen species, Caenorhabditis elegans development, electron transport chain, oxidative stress, mitochondrial function, dietary iron, antioxidant supplementation, iron homeostasis
- MeSH terms
- Host Microbial Interactions, Animals, Antioxidants, Diet, Escherichia coli, Iron, Mitochondria, Mutation, Caenorhabditis elegans, Gene Deletion, Reactive Oxygen Species, Electron Transport Chain Complex Proteins
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