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Cited by 10Evolution and Genetic DynamicsBacterial Genetics and BiotechnologyGut microbiota and health

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Fluctuating selection on bacterial iron regulation in the mammalian gut

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Barreto, Hugo C., Abreu, Beatriz, Gordo, Isabel·2022·Current Biology
DOI 10.1016/j.cub.2022.06.017

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Abstract

Iron is critical in host-microbe interactions, and its availability is tightly regulated in the mammalian gut. Antibiotics and inflammation can perturb iron availability in the gut, which could alter host-microbe interactions. Here, we show that an adaptive allele of iscR, a major regulator of iron homeostasis of Escherichia coli, is under fluctuating selection in the mouse gut. In vivo competitions in immune-competent, immune-compromised, and germ-free mice reveal that the selective pressure on an iscR mutant E. coli is modulated by the presence of antibiotics, the microbiota, and the immune system. In vitro assays show that iron availability is an important mediator of the iscR allele fitness benefits or costs. We identify Lipocalin-2, a host's immune protein that prevents bacterial iron acquisition, as a major host mechanism underlying fluctuating selection of iscR. Our results provide a remarkable example of strong fluctuating selection acting on bacterial iron regulation in the mammalian gut.

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Research works printed but not linked: 74

  1. Schaible, 2004, Iron and microbial infection, Nat. Rev. Microbiol., 2, 946, 10.1038/nrmicro1046 · DOI · Paper page
  2. Nairz, 2010, The struggle for iron – a metal at the host-pathogen interface, Cell Microbiol., 12, 1691, 10.1111/j.1462-5822.2010.01529.x · DOI · Paper page
  3. Yilmaz, 2018, Gut microbiota and iron: the crucial actors in health and disease, Pharmaceuticals (Basel), 11, 98, 10.3390/ph11040098 · DOI · Paper page
  4. Seyoum, 2021, Iron homeostasis in host and gut bacteria – a complex interrelationship, Gut Microbes, 13, 1, 10.1080/19490976.2021.1874855 · DOI
  5. Whitman, 1998, Prokaryotes: the unseen majority, Proc. Natl. Acad. Sci. USA, 95, 6578, 10.1073/pnas.95.12.6578 · DOI · Paper page
  6. Zimmermann, 2007, Nutritional iron deficiency, Lancet, 370, 511, 10.1016/S0140-6736(07)61235-5 · DOI · Paper page
  7. Reddy, 1972, Effect of intestinal microflora on iron and zinc metabolism, and on activities of metalloenzymes in rats, J. Nutr., 102, 101, 10.1093/jn/102.1.101 · DOI
  8. Das, 2020, Microbial metabolite signaling is required for systemic iron homeostasis, Cell Metab., 31, 115, 10.1016/j.cmet.2019.10.005 · DOI · Paper page
  9. Nielsen, 1996, Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases, Gut, 38, 414, 10.1136/gut.38.3.414 · DOI
  10. Chassaing, 2012, Fecal lipocalin 2, a sensitive and broadly dynamic non-invasive biomarker for intestinal inflammation, PLoS One, 7, e44328, 10.1371/journal.pone.0044328 · DOI
  11. Srinivasan, 2012, Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis, J. Immunol., 189, 1911, 10.4049/jimmunol.1200892 · DOI
  12. Flo, 2004, Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron, Nature, 432, 917, 10.1038/nature03104 · DOI · Paper page
  13. Balamurugan, 2010, Low levels of faecal lactobacilli in women with iron-deficiency anaemia in south India, Br. J. Nutr., 104, 931, 10.1017/S0007114510001637 · DOI
  14. Tompkins, 2001, The effects of dietary ferric iron and iron deprivation on the bacterial composition of the mouse intestine, Curr. Microbiol., 43, 38, 10.1007/s002840010257 · DOI
  15. Dostal, 2012, Iron depletion and repletion with ferrous sulfate or electrolytic iron modifies the composition and metabolic activity of the gut microbiota in rats, J. Nutr., 142, 271, 10.3945/jn.111.148643 · DOI
  16. Zimmermann, 2010, The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d’Ivoire, Am. J. Clin. Nutr., 92, 1406, 10.3945/ajcn.110.004564 · DOI · Paper page
  17. Jaeggi, 2015, Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants, Gut, 64, 731, 10.1136/gutjnl-2014-307720 · DOI · Paper page
  18. Constante, 2017, Iron supplements modulate colon microbiota composition and potentiate the protective effects of probiotics in dextran sodium sulfate-induced colitis, Inflamm. Bowel Dis., 23, 753, 10.1097/MIB.0000000000001089 · DOI
  19. Buhnik-Rosenblau, 2012, Genetic modification of iron metabolism in mice affects the gut microbiota, Biometals, 25, 883, 10.1007/s10534-012-9555-5 · DOI · Paper page
  20. Stern, 1954, [The problem of iron resorption], Experientia, 10, 227, 10.1007/BF02159287 · DOI
  21. Forrester, 1962, Measurement of total body iron in animals using whole-body liquid scintillation detectors, Proc. Soc. Exp. Biol. Med., 111, 115, 10.3181/00379727-111-27718 · DOI
  22. Ng, 2019, Recovery of the gut microbiota after antibiotics depends on host diet, community context, and environmental reservoirs, Cell Host Microbe, 26, 650, 10.1016/j.chom.2019.10.011 · DOI
  23. Lupp, 2007, Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae, Cell Host Microbe, 2, 119, 10.1016/j.chom.2007.06.010 · DOI
  24. Wessling-Resnick, 2010, Iron homeostasis and the inflammatory response, Annu. Rev. Nutr., 30, 105, 10.1146/annurev.nutr.012809.104804 · DOI · Paper page
  25. Tagkopoulos, 2008, Predictive behavior within microbial genetic networks, Science, 320, 1313, 10.1126/science.1154456 · DOI · Paper page
  26. Beaumont, 2009, Experimental evolution of bet hedging, Nature, 462, 90, 10.1038/nature08504 · DOI
  27. Sandberg, 2017, Laboratory evolution to alternating substrate environments yields distinct phenotypic and genetic adaptive strategies, Appl. Environ. Microbiol., 83, e00410, 10.1128/AEM.00410-17 · DOI
  28. Turner, 2020, Negative frequency-dependent selection maintains coexisting genotypes during fluctuating selection, Mol. Ecol., 29, 138, 10.1111/mec.15307 · DOI
  29. Nguyen, 2021, A distinct growth physiology enhances bacterial growth under rapid nutrient fluctuations, Nat. Commun., 12, 3662, 10.1038/s41467-021-23439-8 · DOI
  30. Nguyen, 2021, Environmental fluctuations and their effects on microbial communities, populations, and individuals, FEMS Microbiol. Rev., 45, 10.1093/femsre/fuaa068 · DOI
  31. Melbinger, 2015, The impact of environmental fluctuations on evolutionary fitness functions, Sci. Rep., 5, 15211, 10.1038/srep15211 · DOI
  32. Sæther, 2015, The concept of fitness in fluctuating environments, Trends Ecol. Evol., 30, 273, 10.1016/j.tree.2015.03.007 · DOI
  33. Novak, 2017, When does frequency-independent selection maintain genetic variation?, Genetics, 207, 653, 10.1534/genetics.117.300129 · DOI
  34. Erickson, 2017, A global resource allocation strategy governs growth transition kinetics of Escherichia coli, Nature, 551, 119, 10.1038/nature24299 · DOI
  35. Barroso-Batista, 2015, Adaptive immunity increases the pace and predictability of evolutionary change in commensal gut bacteria, Nat. Commun., 6, 8945, 10.1038/ncomms9945 · DOI
  36. Brooks, 2021, The microbiota coordinates diurnal rhythms in innate immunity with the circadian clock, Cell, 184, 4154, 10.1016/j.cell.2021.07.001 · DOI
  37. Schwartz, 2001, IscR, an Fe-S cluster-containing transcription factor, represses expression of Escherichia coli genes encoding Fe-S cluster assembly proteins, Proc. Natl. Acad. Sci. USA, 98, 14895, 10.1073/pnas.251550898 · DOI
  38. Giel, 2013, Regulation of iron-sulphur cluster homeostasis through transcriptional control of the Isc pathway by [2Fe-2S]-IscR in Escherichia coli, Mol. Microbiol., 87, 478, 10.1111/mmi.12052 · DOI
  39. Santos, 2015, What a difference a cluster makes: the multifaceted roles of IscR in gene regulation and DNA recognition, Biochim. Biophys. Acta, 1854, 1101, 10.1016/j.bbapap.2015.01.010 · DOI
  40. Esquilin-Lebron, 2021, Bacterial approaches for assembling iron-sulfur proteins, mBio, 12, e0242521, 10.1128/mBio.02425-21 · DOI
  41. Kim, 2009, IscR modulates catalase A (KatA) activity, peroxide resistance and full virulence of Pseudomonas aeruginosa PA14, J. Microbiol. Biotechnol., 19, 1520, 10.4014/jmb.0906.06028 · DOI
  42. Lim, 2014, IscR is a global regulator essential for pathogenesis of Vibrio vulnificus and induced by host cells, Infect. Immun., 82, 569, 10.1128/IAI.01141-13 · DOI
  43. Miller, 2014, IscR is essential for Yersinia pseudotuberculosis type III secretion and virulence, PLoS Pathog, 10, e1004194, 10.1371/journal.ppat.1004194 · DOI
  44. Fuangthong, 2015, IscR plays a role in oxidative stress resistance and pathogenicity of a plant pathogen, Xanthomonas campestris, Microbiol. Res., 170, 139, 10.1016/j.micres.2014.08.004 · DOI
  45. Yeo, 2006, IscR acts as an activator in response to oxidative stress for the suf operon encoding Fe-S assembly proteins, Mol. Microbiol., 61, 206, 10.1111/j.1365-2958.2006.05220.x · DOI
  46. Barreto, 2020, The landscape of adaptive evolution of a gut commensal bacteria in aging mice, Curr. Biol., 30, 1102, 10.1016/j.cub.2020.01.037 · DOI
  47. Jones, 2020, Consensus Finder web tool to predict stabilizing substitutions in proteins, Methods Enzymol, 643, 129, 10.1016/bs.mie.2020.07.010 · DOI
  48. Nesbit, 2009, Sequence-specific binding to a subset of IscR-regulated promoters does not require IscR Fe-S cluster ligation, J. Mol. Biol., 387, 28, 10.1016/j.jmb.2009.01.055 · DOI
  49. Santos, 2014, The unique regulation of iron-sulfur cluster biogenesis in a Gram-positive bacterium, Proc. Natl. Acad. Sci. USA, 111, E2251, 10.1073/pnas.1322728111 · DOI
  50. Smith, 2017, Regulation of life span by the gut microbiota in the short-lived African turquoise killifish, eLife, 6, e27014, 10.7554/eLife.27014 · DOI · Paper page
  51. Thevaranjan, 2017, Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction, Cell Host Microbe, 21, 455, 10.1016/j.chom.2017.03.002 · DOI · Paper page
  52. Hapfelmeier, 2010, Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses, Science, 328, 1705, 10.1126/science.1188454 · DOI · Paper page
  53. Vaiserman, 2017, Gut microbiota: a player in aging and a target for anti-aging intervention, Ageing Res. Rev., 35, 36, 10.1016/j.arr.2017.01.001 · DOI · Paper page
  54. Shinkai, 1992, RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement, Cell, 68, 855, 10.1016/0092-8674(92)90029-C · DOI
  55. Bakdash, 2017, Repeated measures correlation, Front. Psychol., 8, 456, 10.3389/fpsyg.2017.00456 · DOI
  56. Gopinath, 2018, Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner, Nat. Microbiol., 3, 611, 10.1038/s41564-018-0138-2 · DOI
  57. Leónidas Cardoso, 2020, Dysbiosis individualizes the fitness effect of antibiotic resistance in the mammalian gut, Nat. Ecol. Evol., 4, 1268, 10.1038/s41559-020-1235-1 · DOI
  58. Özkaya, 2018, Cheating on cheaters stabilizes cooperation in Pseudomonas aeruginosa, Curr. Biol., 28, 2070, 10.1016/j.cub.2018.04.093 · DOI
  59. Carey, 2018, Regulated stochasticity in a bacterial signaling network permits tolerance to a rapid environmental change, Cell, 173, 196, 10.1016/j.cell.2018.02.005 · DOI
  60. Mu, 2021, The role of iron homeostasis in remodeling immune function and regulating inflammatory disease, Sci. Bull., 66, 1806, 10.1016/j.scib.2021.02.010 · DOI
  61. Barreto, 2020, Mutation accumulation and horizontal gene transfer in Escherichia coli colonizing the gut of old mice, Commun. Integr. Biol., 13, 89, 10.1080/19420889.2020.1783059 · DOI
  62. Ling, 2012, Protein aggregation caused by aminoglycoside action is prevented by a hydrogen peroxide scavenger, Mol. Cell, 48, 713, 10.1016/j.molcel.2012.10.001 · DOI
  63. Ezraty, 2013, Fe-S cluster biosynthesis controls uptake of aminoglycosides in a ROS-less death pathway, Science, 340, 1583, 10.1126/science.1238328 · DOI
  64. Ezraty, 2016, The “liaisons dangereuses” between iron and antibiotics, FEMS Microbiol. Rev., 40, 418, 10.1093/femsre/fuw004 · DOI
  65. Cohen, 2015, Applying the restaurant hypothesis to intestinal microbiota: anaerobes in mixed biofilms degrade polysaccharides, sharing locally prepared sugars with facultative anaerobes that also colonize the intestine, Microbe Mag, 10, 324
  66. Deatherage, 2014, Identification of mutations in laboratory-evolved microbes from next-generation sequencing data using breseq, Methods Mol. Biol., 1151, 165, 10.1007/978-1-4939-0554-6_12 · DOI
  67. Bolyen, 2019, Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2, Nat. Biotechnol., 37, 852, 10.1038/s41587-019-0209-9 · DOI · Paper page
  68. McMurdie, 2013, phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data, PLoS One, 8, e61217, 10.1371/journal.pone.0061217 · DOI
  69. Hall, 2014, Growth rates made easy, Mol. Biol. Evol., 31, 232, 10.1093/molbev/mst187 · DOI · Paper page
  70. Brunson, 2020, ggalluvial: layered grammar for alluvial plots, J. Open Source Software, 5, 2017, 10.21105/joss.02017 · DOI
  71. Gu, 2016, Complex heatmaps reveal patterns and correlations in multidimensional genomic data, Bioinformatics, 32, 2847, 10.1093/bioinformatics/btw313 · DOI
  72. Chen, 2018, fastp: an ultra-fast all-in-one FASTQ preprocessor, Bioinformatics, 34, i884, 10.1093/bioinformatics/bty560 · DOI · Paper page
  73. Callahan, 2016, DADA2: high-resolution sample inference from Illumina amplicon data, Nat. Methods, 13, 581, 10.1038/nmeth.3869 · DOI · Paper page
  74. Yarza, 2014, Uniting the classification of cultured and uncultured bacteria and archaea using 16S rRNA gene sequences, Nat. Rev. Microbiol., 12, 635, 10.1038/nrmicro3330 · DOI

Metadata

Authors
Barreto, H. C., Abreu, B., & Gordo, I.
Affiliations
Instituto Gulbenkian de Ciência (PT)
Corresponding author
  • Barreto, Hugo C.
  • Gordo, Isabel
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2022-08
Volume
32
Issue
15
Pages
3261-3275.e4
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2022.06.017
OpenAlex
W4284691909
Cited by
10
References
10
Citations by year
2026: 2 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 1
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Fundação para a Ciência e a Tecnologia (PD/BD/128429/2017, PTDC/BIA - EVL/7546/2020, LISBOA-01-0145-FEDER-016417, LISBOA-01-0145-FEDER-022170)
  • European Regional Development Fund (LISBOA-01-0145-FEDER-022170)
  • Yakult Bio-Science Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
fluctuating selection, iron homeostasis, IscR, Escherichia coli, gut microbiota, host-microbe interactions, neutrophil gelatinase-associated lipocalin, antibiotic effects on gut microbiota, immune system, germ-free mice, adaptive alleles, fitness costs and benefits
MeSH terms
Lipocalin-2, Animals, Anti-Bacterial Agents, Escherichia coli, Iron, Mammals, Transcription Factors, Gene Expression Regulation, Bacterial, Escherichia coli Proteins, Mice

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