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Cited by 58Iron Metabolism and DisordersGut microbiota and healthBacterial Genetics and Biotechnology

The battle for iron in enteric infections

Open access
Sousa Gerós, Ana, Simmons, Alison, Drakesmith, Hal, Aulicino, Anna, Frost, Joe N.·2020·Immunology
DOI 10.1111/imm.13236PMC PMC7576875
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Abstract

Summary: Iron is an essential element for almost all living organisms, but can be extremely toxic in high concentrations. All organisms must therefore employ homeostatic mechanisms to finely regulate iron uptake, usage and storage in the face of dynamic environmental conditions. The critical step in mammalian systemic iron homeostasis is the fine regulation of dietary iron absorption. However, as the gastrointestinal system is also home to >10 14 bacteria, all of which engage in their own programmes of iron homeostasis, the gut represents an anatomical location where the inter‐kingdom fight for iron is never‐ending. Here, we explore the molecular mechanisms of, and interactions between, host and bacterial iron homeostasis in the gastrointestinal tract. We first detail how mammalian systemic and cellular iron homeostasis influences gastrointestinal iron availability. We then focus on two important human pathogens, Salmonella and Clostridia; despite their differences, they exemplify how a bacterial pathogen must navigate and exploit this web of iron homeostasis interactions to avoid host nutritional immunity and replicate successfully. We then reciprocally explore how iron availability interacts with the gastrointestinal microbiota, and the consequences of this on mammalian physiology and pathogen iron acquisition. Finally, we address how understanding the battle for iron in the gastrointestinal tract might inform clinical practice and inspire new treatments for important diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

This review describes how mammalian systemic and cellular iron homeostasis shapes iron availability in the gastrointestinal tract, and how enteric pathogens such as Salmonella and Clostridia sense, acquire, and compete for iron while navigating host nutritional immunity and the gut microbiota. It argues that understanding this inter-kingdom battle for iron may inform new therapies for gastrointestinal infections and inflammatory disorders.

Key findings

  • Humans ingest 20–25 mg iron/day, mostly inorganic iron (85%–90%) with haem-bound iron (10%–15%), but absorb only ~1 mg/day; haem accounts for over 40% of daily absorbed iron despite its smaller dietary share.
  • Host iron homeostasis is centrally regulated by hepcidin (HAMP), which binds, occludes, and induces degradation of ferroportin (FPN), trapping iron in enterocytes and macrophages; inflammation-induced HAMP drives hypoferremia, which can protect against some extracellular pathogens but may promote intracellular Salmonella growth in macrophages.
  • Salmonella iron sensing depends heavily on Fur and RyhB sRNA; approximately 7% of the S. Typhimurium genome is directly or indirectly regulated by iron, and Fur integrates iron handling with virulence, acid tolerance, and oxidative stress responses.
  • C. difficile responds to iron deficiency with Fur-regulated changes in iron transporters, metabolic shifts away from iron-containing proteins, cell-wall remodeling, and up-regulation of virulence-associated genes; C. difficile infection can have mortality up to 6%.
  • Iron supplementation can remodel the gut microbiota, often skewing away from low-iron-requiring commensals such as lactobacilli or Bifidobacterium toward Enterobacteriaceae, and has been linked to increased diarrhoeal disease in infants in low- to middle-income countries.

Methods

  • Narrative review synthesizing molecular mechanisms of host and bacterial iron homeostasis in the gastrointestinal tract, with focused discussion of Salmonella enterica serovar Typhimurium, Salmonella Typhi/Paratyphi, and Clostridium difficile.
  • No primary experimental data, systematic search strategy, or meta-analysis are reported; the paper integrates prior literature on mammalian iron absorption, hepcidin/ferroportin regulation, bacterial Fur/DtxR systems, siderophores, haem acquisition, microbiota interactions, and therapeutic approaches.
  • Main analysis is conceptual and mechanistic synthesis, including proposed models of host–pathogen–microbiota iron competition and future therapeutic opportunities.

Limitations

  • The paper does not include a dedicated limitations section. It states that interactions of iron with complex and diverse commensal and pathogenic gut microbial communities in the context of human disease remain relatively uncharacterized, and that understanding iron homeostasis in multi-species gut interactions remains in its infancy.
  • The review notes several unresolved points, including the unclear importance of haem as a nutrient source for Salmonella, the unclear role of ferrichrome piracy during infection, and uncertainty about how much C. difficile toxin-driven tissue destruction and haemolysis facilitate iron uptake.
  • Evident from the text: as a narrative review, it provides no systematic evidence appraisal, no primary data, and no quantitative synthesis; therapeutic suggestions are largely based on preclinical or indirect evidence.

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Integrity signals

Registry

Crossref · 10.1111/imm.13236

Cites

189 of 189 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 221 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Immediately after crossing the basolateral membrane, Fe2+ is oxidized to Fe3+ by hephaestin, a multicopper oxidase co-localized with FPN.

    “Immediately after crossing the basolateral membrane, Fe2+ is oxidized to Fe3+ by hephaestin, a multicopper oxidase co‐localized with FPN. 25 , 26”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Fuqua BK, Lu Y, Darshan D, Frazer DM, Wilkins SJ, Wolkow N et al The multicopper ferroxidase hephaestin enhances intestinal iron absorption in mice. PLoS One 2014; 9: e98792. 24896847 PMC4045767 source

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    • cites [26] Vulpe CD, Kuo YM, Murphy TL, Cowley L, Askwith C, Libina N et al Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 1999; 21: 195– 9. 9988272 source

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  • Premisecitation

    DCYTB enzymes present within the apical membrane of enterocytes are able to reduce soluble Fe3+ to Fe2+ before DMT1-mediated Fe2+ import.

    “To overcome the low availability of Fe2+, duodenal cytochrome b (DCYTB) enzymes that are present within the apical membrane of enterocytes are able to reduce any soluble Fe3+ to Fe2+ before DMT1‐mediated Fe2+ import. 14 , 15”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] McKie AT, Barrow D, Latunde‐Dada GO, Rolfs A, Sager G, Mudaly E et al An iron‐regulated ferric reductase associated with the absorption of dietary iron. Science 2001; 291: 1755– 9. 11230685 source

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    • cites [15] Gunshin H, Starr CN, Direnzo C, Fleming MD, Jin J, Greer EL et al Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood 2005; 106: 2879– 83. 15961514 PMC1895297 source

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  • Premisecitation

    FPN is found within the membranes of intracellular vesicles, including pathogen-containing phagosomes, particularly in macrophages.

    “FPN is also found within the membranes of intracellular vesicles – including pathogen‐containing phagosomes, 27 particularly in macrophages.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Lim D, Kim KS, Jeong J‐H, Marques O, Kim H‐J, Song M et al The hepcidin‐ferroportin axis controls the iron content of Salmonella‐containing vacuoles in macrophages. Nat Commun 2018; 9: 1– 12. 29844422 PMC5974375 source

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  • Premisecitation

    Approximately 7% of the S. Typhimurium genome is directly or indirectly regulated by iron.

    “Approximately 7% of the S. Typhimurium genome is directly or indirectly regulated by iron, 69 which highlights the importance of iron to Salmonella.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Bjarnason J, Southward CM, Surette MG. Genomic profiling of iron‐responsive genes in Salmonella enterica Serovar Typhimurium by high‐throughput screening of a random promoter library. J Bacteriol 2003; 185: 4973– 82. 12897017 PMC166456 source

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  • Interpretationreasoning

    Any mechanisms that reduce intestinal iron uptake will in turn relatively increase availability of iron in the gastrointestinal tract.

    “It is important to note that any mechanisms that reduce intestinal iron uptake will in turn relatively increase availability of iron in the gastrointestinal tract.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 22
  • May combine two claims. 57

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The activity of the Na+/H+ exchanger NHE3 facilitates the symport of Fe2+ and H+ by DMT1.

    “Finally, the activity of the Na+/H+ exchanger NHE3, which exports H+ from the enterocyte and generates an electrochemical gradient of H+ into the cell, facilitates the symport of Fe2+ and H+ by DMT1. 18”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Shawki A, Engevik MA, Kim RS, Knight PB, Baik RA, Anthony SR et al Intestinal brush‐border Na+/H+ exchanger‐3 drives H+‐coupled iron absorption in the mouse. Am J Physiol Gastrointest Liver Physiol 2016; 311: G423– 30. 27390324 PMC5076011 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Labile iron can be placed into cytosolic iron-containing proteins, transported to mitochondria and incorporated into haem and Fe-S clusters, sequestered inside ferritin, or exported to the extracellular space by FPN.

    “Labile iron can then be: (i) placed into cytosolic iron‐containing proteins; (ii) transported to the mitochondria and incorporated into haem and Fe–S clusters; 2 , 33 (iii) sequestered inside ferritin (Ft); or (iv) exported to the extracellular space by FPN. 30”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Poulos TL. Heme enzyme structure and function. Chem Rev 2014; 114: 3919– 62. 24400737 PMC3981943 source

      Not checked in the free run.

    • cites [30] Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for iron metabolism. Cell 2017; 168: 344– 61. 28129536 PMC5706455 source

      Not checked in the free run.

    • cites [33] Brzóska K, Meczyńska S, Kruszewski M. Iron‐sulfur cluster proteins: electron transfer and beyond. Acta Biochim Pol 2006; 53: 685– 91. 17143336 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cellular iron export, and therefore gastrointestinal absorption of iron, is uniquely mediated by ferroportin.

    “Cellular iron export – and, therefore, gastrointestinal absorption of iron – is uniquely mediated by the iron transporter ferroportin (FPN or SLC40A1). 21 , 22 , 23 , 24”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [21] Abboud S, Haile DJ. A novel mammalian iron‐regulated protein involved in intracellular iron metabolism. J Biol Chem 2000; 275: 19906– 12. 10747949 source

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    • cites [22] Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J et al Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 2000; 403: 776– 81. 10693807 source

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    • cites [23] Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S et al The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005; 1: 191– 200. 16054062 source

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    • cites [24] McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D et al A novel duodenal iron‐regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000; 5: 299– 309. 10882071 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    On average, humans ingest 20-25 mg of iron per day, the majority of which is inorganic iron (85%-90%), followed by haem-bound iron (10%-15%).

    “On average, humans ingest 20–25 mg of iron/day, the majority of which is inorganic iron (85%–90%), followed by haem‐bound iron (10%–15%).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Drakesmith H, Nemeth E, Ganz T. Ironing out ferroportin. Cell Metab 2015; 22: 777– 87. 26437604 PMC4635047 source

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    • cites [11] Hurrell R, Egli I. Iron bioavailability and dietary reference values. Am J Clin Nutr 1461S; 91: 1461S– 7. 20200263 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TfR1 remains bound to iron-free transferrin (apo-transferrin) and the complex returns to the cell surface, where apo-transferrin is released back into the circulation.

    “TfR1 remains bound to the iron‐free Tf – apo‐transferrin (aTf) – and the complex returns to the cell surface. There, aTf is released back into the circulation, where it may capture iron again. 30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for iron metabolism. Cell 2017; 168: 344– 61. 28129536 PMC5706455 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Haem accounts for over 40% of the daily absorbed iron, mainly as a result of its significantly higher bioavailability when compared with inorganic iron.

    “Despite haem’s small contribution to the total amount of iron ingested, it still accounts for over 40% of the daily absorbed iron, mainly as a result of its significantly higher bioavailability when compared with inorganic iron. 11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Hurrell R, Egli I. Iron bioavailability and dietary reference values. Am J Clin Nutr 1461S; 91: 1461S– 7. 20200263 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Iron was highly bioavailable during the early stages of the evolution of life, potentially rendering biochemistry irreversibly addicted to iron as a metallic cofactor.

    “Furthermore, iron was highly bioavailable during the early stages of the evolution of life, potentially rendering biochemistry irreversibly ‘addicted’ to iron as a metallic cofactor. 4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Muchowska KB, Varma SJ, Moran J. Synthesis and breakdown of universal metabolic precursors promoted by iron. Nature 2019; 569: 104. 31043728 PMC6517266 source

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  • May combine two claims.

    Premisecitation

    Fe3+ is the most stable form of inorganic iron in physiological pH and oxygen conditions, and is the most commonly found in dietary products.

    “Of the two oxidation states that inorganic iron may take, Fe3+ is the most stable in physiological pH and oxygen conditions, and also the most commonly found in dietary products. 3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Sharp P, Srai SK. Molecular mechanisms involved in intestinal iron absorption. World J Gastroenterol 2007; 13: 4716– 24. 17729393 PMC4611193 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Only about 1 mg of iron is absorbed per day, because of both poor iron bioavailability and tightly regulated iron homeostasis.

    “However, only ~ 1 mg iron is absorbed per day, because of both poor iron bioavailability and tightly regulated iron homeostasis. 9 , 11”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Drakesmith H, Nemeth E, Ganz T. Ironing out ferroportin. Cell Metab 2015; 22: 777– 87. 26437604 PMC4635047 source

      Not checked in the free run.

    • cites [11] Hurrell R, Egli I. Iron bioavailability and dietary reference values. Am J Clin Nutr 1461S; 91: 1461S– 7. 20200263 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Organic molecules such as dietary vitamin C and microbe-produced short-chain fatty acids can reduce iron and increase its bioavailability.

    “Organic molecules such as dietary vitamin C and microbe‐produced short‐chain fatty acids can also reduce iron and increase its bioavailability. 11 , 16 , 17”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [11] Hurrell R, Egli I. Iron bioavailability and dietary reference values. Am J Clin Nutr 1461S; 91: 1461S– 7. 20200263 source

      Not checked in the free run.

    • cites [16] Jacobs A, Miles PM. Intraluminal transport of iron from stomach to small‐intestinal mucosa. Br Med J 1969; 4: 778– 81. 4243302 PMC1630276 source

      Not checked in the free run.

    • cites [17] Glover J, Jacobs A. Observations on iron in the jejunal lumen after a standard meal. Gut 1971; 12: 369– 71. 4255818 PMC1411612 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ferrireductases, such as six-transmembrane epithelial of the prostate 3, convert Fe3+ into Fe2+ within endosomes.

    “Within these vesicles, ferrireductases, such as six‐transmembrane epithelial of the prostate 3, convert Fe3+ into Fe2+ once again. 29”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Ohgami RS, Campagna DR, McDonald A, Fleming MD. The Steap proteins are metalloreductases. Blood 2006; 108: 1388– 94. 16609065 PMC1785011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inorganic iron uptake from the gastrointestinal lumen by enterocytes depends upon DMT1, which is not able to import Fe3+.

    “However, inorganic iron uptake from the gastrointestinal lumen by enterocytes depends upon the divalent metal transporter protein 1 (DMT1 or NRAMP2), which is not able to import Fe3+. 12 , 13 , 14”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] Fleming MD, Trenor CC, Su MA, Foernzler D, Beier DR, Dietrich WF et al Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 1997; 16: 383– 6. 9241278 source

      Not checked in the free run.

    • cites [13] Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews NC. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 2005; 115: 1258– 66. 15849611 PMC1077176 source

      Not checked in the free run.

    • cites [14] McKie AT, Barrow D, Latunde‐Dada GO, Rolfs A, Sager G, Mudaly E et al An iron‐regulated ferric reductase associated with the absorption of dietary iron. Science 2001; 291: 1755– 9. 11230685 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Every day 200 billion erythrocytes are degraded by reticuloendothelial macrophages in the liver and spleen; replacing these red blood cells requires 2 × 10^15 iron atoms or 20 mg of iron.

    “Every day 200 billion erythrocytes are degraded by reticuloendothelial macrophages in the liver and spleen; replacing these red blood cells has been estimated to require 2 × 1015 iron atoms or 20 mg of iron. 30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for iron metabolism. Cell 2017; 168: 344– 61. 28129536 PMC5706455 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    During iron deficiency, iron can be liberated from the ferritin cage by ferritinophagy mediated by the adaptor protein NCOA4.

    “During iron deficiency, iron can be liberated from the Ft cage by a specific form of autophagy – ferritinophagy – mediated by the adaptor protein NCOA4. 35 , 36”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Mancias JD, Pontano Vaites L, Nissim S, Biancur DE, Kim AJ, Wang X et al Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2‐mediated proteolysis. eLife 2015; 4: e10308 10.7554/eLife.10308 PMC4592949 26436293 source

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    • cites [36] Quiles del Rey M, Mancias JD. NCOA4‐mediated ferritinophagy: a potential link to neurodegeneration. Front Neurosci 2019; 13: 238 10.3389/fnins.2019.00238 30930742 PMC6427834 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In mammals, excretion of iron is not extensively regulated; instead, iron homeostasis is achieved mainly by regulating intestinal absorption in the duodenum, and possibly in the colon to some extent.

    “In mammals, excretion of iron is not extensively regulated; instead, iron homeostasis is achieved mainly by regulating intestinal absorption in the duodenum, 9 and possibly in the colon to some extent. 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Drakesmith H, Nemeth E, Ganz T. Ironing out ferroportin. Cell Metab 2015; 22: 777– 87. 26437604 PMC4635047 source

      Not checked in the free run.

    • cites [10] Takeuchi K, Bjarnason I, Laftah AH, Latunde‐Dada GO, Simpson RJ, McKie AT. Expression of iron absorption genes in mouse large intestine. Scand J Gastroenterol 2005; 40: 169– 77. 15764147 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Nanocages of ferritin, formed from 24 light and heavy subunits, provide a long-term storage site for iron, shielding the cell from potential redox activity of free iron.

    “Nanocages of Ft, formed from 24 light (FtL) and heavy (FtH) subunits, provide a long‐term storage site for iron, shielding the cell from potential redox activity of free iron. 34”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Arosio P, Carmona F, Gozzelino R, Maccarinelli F, Poli M. The importance of eukaryotic ferritins in iron handling and cytoprotection. Biochem J 2015; 472: 1– 15. 26518749 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Uptake of iron-bound transferrin (holo-transferrin) complexes by transferrin receptor 1 is the dominant mechanism of cellular iron acquisition by many cells and tissues.

    “Uptake of iron‐bound Tf – holo‐transferrin (hTf) – complexes by transferrin receptor 1 (TfR1 or CD71) is also the dominant mechanism of cellular iron acquisition by many cells and tissues. 28”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet 1999; 21: 396– 9. 10192390 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Iron plays a central role in the biochemistry of nearly all life forms, where it is found within haem and inorganic compounds.

    “Iron plays a central role in the biochemistry of nearly all life forms, where it is found within haem and inorganic compounds. 1 , 2”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Drakesmith H, Prentice A. Viral infection and iron metabolism. Nat Rev Microbiol 2008; 6: 541– 52. 18552864 source

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    • cites [2] Poulos TL. Heme enzyme structure and function. Chem Rev 2014; 114: 3919– 62. 24400737 PMC3981943 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Inorganic iron may occur as ferrous (Fe2+) and ferric (Fe3+) iron, the reduced and oxidized states of the element.

    “Inorganic iron may occur as ferrous (Fe2+) and ferric (Fe3+) iron, the reduced and oxidized states of the element, respectively. 3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Sharp P, Srai SK. Molecular mechanisms involved in intestinal iron absorption. World J Gastroenterol 2007; 13: 4716– 24. 17729393 PMC4611193 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HAMP is a 25-amino-acid hormone protein mainly produced by liver hepatocytes, and its production is induced by iron loading.

    “HAMP is a 25‐amino‐acid hormone protein mainly produced by liver hepatocytes, and its production is induced by iron loading. 38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P et al A new mouse liver‐specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001; 276: 7811– 9. 11113132 source

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  • May combine two claims.

    Premisecitation

    Fur-independent iron-driven changes in gene expression have been observed; extracellular iron concentration is one of the stimuli of the two-component sensing pathway PhoQ-PhoP.

    “Fur‐independent iron‐driven changes in gene expression have also been observed; 69 for example, extracellular iron concentration is one of the stimuli of the two‐component sensing pathway PhoQ‐PhoP. 75”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [69] Bjarnason J, Southward CM, Surette MG. Genomic profiling of iron‐responsive genes in Salmonella enterica Serovar Typhimurium by high‐throughput screening of a random promoter library. J Bacteriol 2003; 185: 4973– 82. 12897017 PMC166456 source

      Not checked in the free run.

    • cites [75] Groisman EA. The Pleiotropic two‐component regulatory system PhoP‐PhoQ. J Bacteriol 2001; 183: 1835– 42. 11222580 PMC95077 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HAMP-deficient mice and humans present with a severe iron loading phenotype, and injection of synthetic HAMP decreases serum iron concentrations.

    “HAMP‐deficient mice and humans present with a severe iron loading phenotype, and injection of synthetic HAMP decreases serum iron concentrations. 39 , 40 , 41”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A et al Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 2001; 98: 8780– 5. 11447267 PMC37512 source

      Not checked in the free run.

    • cites [40] Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J et al Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 2003; 33: 21– 2. 12469120 source

      Not checked in the free run.

    • cites [41] Rivera S, Nemeth E, Gabayan V, Lopez MA, Farshidi D, Ganz T. Synthetic hepcidin causes rapid dose‐dependent hypoferremia and is concentrated in ferroportin‐containing organs. Blood 2005; 106: 2196– 9. 15933050 PMC1895137 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Clostridium difficile is a Gram-positive extracellular pathogen, which remains localized to the gastrointestinal tract but can cause severe toxin-mediated gastrointestinal pathology, with a mortality rate of up to 6%.

    “Clostridium difficile is a Gram‐positive extracellular pathogen, which remains localized to the gastrointestinal tract but can cause severe toxin‐mediated gastrointestinal pathology, with a mortality rate of up to 6%. 67 , 68”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Karen CC, John GB. Biology of Clostridium difficile: implications for epidemiology and diagnosis. Annu Rev Microbiol 2011; 65: 501– 21. 21682645 source

      Not checked in the free run.

    • cites [68] McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE et al Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018; 66: e1– 48. 29462280 PMC6018983 source

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  • May combine two claims.

    Premisecitation

    Fur and DtxR both bear a DNA-binding domain as well as a metal co-repressor binding site.

    “Fur and DtxR both bear a DNA‐binding domain as well as a metal co‐repressor binding site. 59 , 60”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [59] White A, Ding X, vanderSpek JC, Murphy JR, Ringe D. Structure of the metal‐ion‐activated diphtheria toxin repressor/ tox operator complex. Nature 1998; 394: 502– 6. 9697776 source

      Not checked in the free run.

    • cites [60] Baichoo N, Helmann JD. Recognition of DNA by fur: a reinterpretation of the Fur box consensus sequence. J Bacteriol 2002; 184: 5826– 32. 12374814 PMC135393 source

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  • May combine two claims.

    Premisecitation

    Iron is an essential element for the growth of most bacteria, which rely almost exclusively on Fe2+ uptake mechanisms.

    “Iron is an essential element for the growth of most bacteria, 53 , 54 which rely almost exclusively on Fe2+ uptake mechanisms.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Weinberg ED. The Lactobacillus anomaly: total iron abstinence. Perspect Biol Med 1997; 40: 578– 83. 9269745 source

      Not checked in the free run.

    • cites [54] Posey JE, Gherardini FC. Lack of a role for iron in the Lyme disease pathogen. Science 2000; 288: 1651– 3. 10834845 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fur regulation extends to other fundamental pathways, such as nitrate/nitrite respiration, acid tolerance response, and virulence, including the Type 3 secretion system encoded by Salmonella pathogenicity island-1.

    “Besides controlling the expression of genes directly involved in iron homeostasis, Fur regulation extends to other fundamental pathways, such as nitrate/nitrite respiration, 76 acid tolerance response, 77 and virulence – including the Type 3 secretion system encoded by Salmonella pathogenicity island‐1. 78 , 79 , 80”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [76] Teixidó L, Cortés P, Bigas A, Alvarez G, Barbé J, Campoy S. Control by Fur of the nitrate respiration regulators NarP and NarL in Salmonella enterica. Int Microbiol 2010; 13: 33– 9. 20890837

      Not checked in the free run.

    • cites [77] Hall HK, Foster JW. The role of fur in the acid tolerance response of Salmonella typhimurium is physiologically and genetically separable from its role in iron acquisition. J Bacteriol 1996; 178: 5683– 91. 8824613 PMC178407 source

      Not checked in the free run.

    • cites [78] Teixidó L, Carrasco B, Alonso JC, Barbé J, Campoy S. Fur activates the expression of Salmonella enterica pathogenicity island 1 by directly interacting with the hilD operator in vivo and in vitro. PLoS One 2011; 6: e19711. 21573071 PMC3089636 source

      Not checked in the free run.

    • cites [79] Ellermeier JR, Slauch JM. Fur regulates expression of the Salmonella pathogenicity Island 1 Type III secretion system through HilD. J Bacteriol 2008; 190: 476– 86. 17993530 PMC2223717 source

      Not checked in the free run.

    • cites [80] Troxell B, Sikes ML, Fink RC, Vazquez‐Torres A, Jones‐Carson J, Hassan HM. Fur negatively regulates hns and is required for the expression of HilA and virulence in Salmonella enterica Serovar Typhimurium. J Bacteriol 2011; 193: 497– 505. 21075923 PMC3019815 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Intracellular iron homeostasis in mammals is controlled by two iron regulatory proteins (IRP1 and IRP2), which sense iron and post-transcriptionally regulate the expression of a number of iron homeostatic genes.

    “Intracellular iron homeostasis in mammals is also controlled by two iron regulatory proteins (IRP1 and IRP2), which sense iron and post‐transcriptionally regulate the expression of a number of iron homeostatic genes. 50”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Wilkinson N, Pantopoulos K. The IRP/IRE system in vivo: insights from mouse models. Front Pharmacol 2014; 5: 176. 25120486 PMC4112806 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recycling of erythrocyte-derived iron via reticuloendothelial macrophages is essential for organism survival.

    “Hence, recycling of erythrocyte‐derived iron via reticuloendothelial macrophages is essential for organism survival. 30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for iron metabolism. Cell 2017; 168: 344– 61. 28129536 PMC5706455 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In haemochromatosis, intestinal iron absorption is disconnected from systemic iron availability, resulting in potentially lethal iron loading and susceptibility to fatal siderophilic bacterial infections.

    “In haemochromatosis, intestinal iron absorption is disconnected from systemic iron availability, resulting in potentially lethal iron loading and susceptibility to fatal siderophilic bacterial infections, which exemplify the importance of regulating intestinal iron absorption. 42 , 43”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117: 4425– 33. 21346250 PMC3099567 source

      Not checked in the free run.

    • cites [43] Ganz T, Nemeth E. Iron homeostasis in host defence and inflammation. Nat Rev Immunol 2015; 15: 500– 10. 26160612 PMC4801113 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Salmonella enterica serovar Typhimurium is a Gram-negative facultative intracellular pathogen, which commonly causes localized gastrointestinal disease.

    “Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram‐negative facultative intracellular pathogen, which commonly causes localized gastrointestinal disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Iron deficiency results in stabilization of duodenal HIF2α, which in turn transcriptionally up-regulates expression of DMT1, DCYTB and FPN in enterocytes.

    “Iron deficiency results in stabilization of duodenal Hypoxia‐Inducible Factor 2α (HIF2α), which in turn transcriptionally up‐regulates expression of DMT1, DCYTB and FPN in enterocytes. 46 , 47 , 48”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Mastrogiannaki M, Matak P, Delga S, Deschemin J‐C, Vaulont S, Peyssonnaux C. Deletion of HIF‐2α in the enterocytes decreases the severity of tissue iron loading in hepcidin knockout mice. Blood 2012; 119: 587– 90. 22128145 source

      Not checked in the free run.

    • cites [47] Shah YM, Matsubara T, Ito S, Yim S‐H, Gonzalez FJ. Intestinal hypoxia‐inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab 2009; 9: 152– 64. 19147412 PMC2659630 source

      Not checked in the free run.

    • cites [48] Taylor M, Qu A, Anderson ER, Matsubara T, Martin A, Gonzalez FJ et al Hypoxia‐inducible factor‐2α mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology 2011; 140: 2044– 55. 21419768 PMC3109109 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both Fur and DtxR metalloproteins function similarly, allowing or repressing transcription of target genes and modulating the expression of virulence factors such as toxin secretion, production of adhesins, formation of biofilms and regulation of quorum sensing.

    “Moreover, both metalloproteins function similarly, allowing/repressing transcription of target genes and modulating the expression of virulence factors such as toxin secretion, production of adhesins, formation of biofilms and regulation of quorum sensing. 57 , 58”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [57] Carpenter BM, Whitmire JM, Merrell DS. This is not your mother’s repressor: the complex role of fur in pathogenesis. Infect Immun 2009; 77: 2590– 601. 19364842 PMC2708581 source

      Not checked in the free run.

    • cites [58] Fillat MF. The FUR (ferric uptake regulator) superfamily: diversity and versatility of key transcriptional regulators. Arch Biochem Biophys 2014; 546: 41– 52. 24513162 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In iron deficiency, Fe2+ dissociates from Fur/DtxR, which unbind from DNA, allowing the transcription of essential iron harvesting genes.

    “Conversely, in iron deficiency, Fe2+ dissociates from Fur/DtxR, which unbind from DNA, allowing the transcription of essential iron harvesting genes. 62”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Troxell B, Hassan HM. Transcriptional regulation by Ferric Uptake Regulator (Fur) in pathogenic bacteria. Front Cell Infect Microbiol 2013; 3: 59. 24106689 PMC3788343 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In conditions of iron accumulation, HAMP production is stimulated, and iron is subsequently trapped within enterocytes and macrophages, respectively inhibiting iron export to circulation or preventing recycling of iron derived from red blood cells.

    “In conditions of iron accumulation, the production of HAMP is stimulated, and, as a result, iron is subsequently trapped within enterocytes and macrophages, respectively inhibiting iron export to circulation or preventing recycling of iron derived from red blood cells. 9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Drakesmith H, Nemeth E, Ganz T. Ironing out ferroportin. Cell Metab 2015; 22: 777– 87. 26437604 PMC4635047 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In S. Typhimurium, the haem biosynthetic pathway is essential both for oxidative respiration and for protection against toxic oxygen intermediates such as hydrogen peroxide.

    “In S. Typhimurium, the haem biosynthetic pathway is essential both for oxidative respiration and for protection against toxic oxygen intermediates (such as hydrogen peroxide). 87 , 88”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] Elgrably‐Weiss M, Park S, Schlosser‐Silverman E, Rosenshine I, Imlay J, Altuvia S. A Salmonella enterica Serovar Typhimurium hemA mutant is highly susceptible to oxidative DNA damage. J Bacteriol 2002; 184: 3774– 84. 12081946 PMC135181 source

      Not checked in the free run.

    • cites [88] Wang LY, Brown L, Elliott M, Elliott T. Regulation of heme biosynthesis in Salmonella typhimurium: activity of glutamyl‐tRNA reductase (HemA) is greatly elevated during heme limitation by a mechanism which increases abundance of the protein. J Bacteriol 1997; 179: 2907– 14. 9139907 PMC179053 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced inflow of cytosolic iron decreases intra-vacuolar iron, so reducing iron-catalysed ROS production and originating a more amenable intra-phagosomal environment, which facilitates Salmonella survival and replication.

    “Reduced inflow of cytosolic iron decreases intra‐vacuolar iron, so reducing iron‐catalysed ROS production and originating a more amenable intra‐phagosomal environment, which facilitates Salmonella survival and replication. 27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Lim D, Kim KS, Jeong J‐H, Marques O, Kim H‐J, Song M et al The hepcidin‐ferroportin axis controls the iron content of Salmonella‐containing vacuoles in macrophages. Nat Commun 2018; 9: 1– 12. 29844422 PMC5974375 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HAMP can induce the degradation of phagosomal membrane FPN as well as FPN in the plasma membrane.

    “Recent work suggests that HAMP can induce the degradation of phagosomal membrane FPN as well as FPN in the plasma membrane. 27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Lim D, Kim KS, Jeong J‐H, Marques O, Kim H‐J, Song M et al The hepcidin‐ferroportin axis controls the iron content of Salmonella‐containing vacuoles in macrophages. Nat Commun 2018; 9: 1– 12. 29844422 PMC5974375 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IRP, ferritin and the siderophore-binding protein lipocalin 2 play pivotal roles in preventing and regulating intracellular infection, underscoring iron's key role in determining the outcome of pathogen invasion.

    “IRP, Ft and the siderophore‐binding protein lipocalin 2 (LCN2) play pivotal roles in preventing and regulating intracellular infection, underscoring iron’s key role in determining the outcome of pathogen invasion. 94 , 95”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [94] Nairz M, Schroll A, Haschka D, Dichtl S, Sonnweber T, Theurl I et al Lipocalin‐2 ensures host defense against Salmonella Typhimurium by controlling macrophage iron homeostasis and immune response. Eur J Immunol 2015; 45: 3073– 86. 10.1002/eji.201545569 26332507 PMC4688458 source

      Not checked in the free run.

    • cites [95] Nairz M, Ferring‐Appel D, Casarrubea D, Sonnweber T, Viatte L, Schroll A et al Iron regulatory proteins mediate host resistance to Salmonella infection. Cell Host Microbe 2015; 18: 254– 61. 26190773 PMC4666941 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Independent work proposed a role for the Spi-C transcription factor and FPN-expressing macrophages in protection against dextran sodium sulphate-driven colitis.

    “Independent work proposed a role for the Spi‐C transcription factor and FPN‐expressing macrophages in protection against dextran sodium sulphate‐driven colitis. 108”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Kayama H, Kohyama M, Okuzaki D, Motooka D, Barman S, Okumura R et al Heme ameliorates dextran sodium sulfate‐induced colitis through providing intestinal macrophages with noninflammatory profiles. Proc Natl Acad Sci USA 2018; 115: 8418– 23. 30061415 PMC6099887 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exposure to low iron evokes a stress response in C. difficile, with many of the differentially expressed genes exhibiting binding sites for Fur.

    “Similarly to Salmonella, exposure to low iron evokes a stress response in C. difficile, with many of the differentially expressed genes exhibiting binding sites for Fur. 90”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Ho TD, Ellermeier CD. Ferric uptake regulator fur control of putative iron acquisition systems in Clostridium difficile. J Bacteriol 2015; 197: 2930– 40. 26148711 PMC4542176 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron depletion revealed significant up-regulation of C. difficile genes associated with virulence, including polyamine and histidine biosynthesis and uptake, as well as several flagella-associated genes, which represent well-known factors involved in adherence.

    “Moreover, iron depletion revealed significant up‐regulation of C. difficile genes associated with virulence, including polyamine and histidine biosynthesis and uptake, as well as several flagella‐associated genes, which represent well‐known factors involved in adherence. 92”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Hastie JL, Hanna PC, Carlson PE. Transcriptional response of Clostridium difficile to low iron conditions. Pathog Dis 2018; 76: fty009 10.1093/femspd/fty009 PMC6251574 29390127 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many bacteria are unaffected by host responses elicited by endogenous or therapeutic HAMP, which may be partly explained by their capacity to obtain iron from diverse sources in vivo, such as haem.

    “However, many bacteria are unaffected by host responses elicited by endogenous (or therapeutic) HAMP, which may be partly explained by their capacity to obtain iron from diverse sources in vivo, such as haem. 100”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Stefanova D, Raychev A, Arezes J, Ruchala P, Gabayan V, Skurnik M et al Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non‐transferrin‐bound iron. Blood 2017; 130: 245– 57. 28465342 PMC5520472 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron depletion inhibits bacterial growth and pathogenicity, and low manganese levels decrease the resistance of microbes to oxidative stress.

    “Iron depletion inhibits bacterial growth and pathogenicity, and low manganese levels decrease the resistance of microbes to oxidative stress. 114”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Cunrath O, Bumann D. Host resistance factor SLC11A1 restricts Salmonella growth through magnesium deprivation. Science 2019; 366: 995– 9. 31753999 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S. Typhimurium hemA mutants were avirulent in mice, and their exposure to hydrogen peroxide resulted in extensive iron-mediated DNA damage and cell death.

    “It was previously shown that S. Typhimurium hemA mutants were avirulent in mice, 89 and their exposure to hydrogen peroxide resulted in extensive iron‐mediated DNA damage and cell death. 87”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] Benjamin WH, Hall P, Briles DE. A hemA mutation renders Salmonella typhimurium avirulent in mice, yet capable of eliciting protection against intravenous infection with S. typhimurium. Microb Pathog 1991; 11: 289– 95. 1813780 source

      Not checked in the free run.

    • cites [87] Elgrably‐Weiss M, Park S, Schlosser‐Silverman E, Rosenshine I, Imlay J, Altuvia S. A Salmonella enterica Serovar Typhimurium hemA mutant is highly susceptible to oxidative DNA damage. J Bacteriol 2002; 184: 3774– 84. 12081946 PMC135181 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The haem biosynthetic pathway branches out into two distinct pathways related to the synthesis of sirohaem and of cobalamin.

    “It also branches out into two distinct pathways related to the synthesis of sirohaem (a substrate in cysteine biosynthesis) and of cobalamin (or vitamin B12, a cofactor to many different enzymes). 87”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Elgrably‐Weiss M, Park S, Schlosser‐Silverman E, Rosenshine I, Imlay J, Altuvia S. A Salmonella enterica Serovar Typhimurium hemA mutant is highly susceptible to oxidative DNA damage. J Bacteriol 2002; 184: 3774– 84. 12081946 PMC135181 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In C. difficile, glucose metabolism by pyruvate formate-lyase, formate dehydrogenase and [FeFe]-hydrogenase, ferredoxin-dependent amino acid fermentation, and cell motility are all suppressed by iron deficiency.

    “Specifically, glucose metabolism by pyruvate formate‐lyase, formate dehydrogenase and [FeFe]‐hydrogenase, ferredoxin‐dependent amino acid fermentation, and cell motility are all suppressed by iron deficiency.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Ho TD, Ellermeier CD. Ferric uptake regulator fur control of putative iron acquisition systems in Clostridium difficile. J Bacteriol 2015; 197: 2930– 40. 26148711 PMC4542176 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Failure to sequester iron locally resulted in dysbiosis, increased microbial translocation across the mucosa, persistent gut inflammation and failure to recover weight.

    “Failure to sequester iron locally resulted in dysbiosis, increased microbial translocation across the mucosa, persistent gut inflammation and failure to recover weight 107 (Fig. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Bessman NJ, Mathieu JRR, Renassia C, Zhou L, Fung TC, Fernandez KC et al Dendritic cell–derived hepcidin sequesters iron from the microbiota to promote mucosal healing. Science 2020; 368: 186– 9. 32273468 PMC7724573 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fur can itself be regulated by the peroxide sensor OxyR, with ROS-mediated induction of Fur probably preventing oxidation of biomolecules by reducing intracellular iron concentration and subsequent formation of hydroxyl radicals.

    “Fur can also itself be regulated by the peroxide sensor OxyR, with ROS‐mediated induction of Fur probably preventing oxidation of biomolecules by reducing intracellular iron concentration and subsequent formation of hydroxyl radicals. 82”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Varghese S, Wu A, Park S, Imlay KRC, Imlay JA. Submicromolar hydrogen peroxide disrupts the ability of Fur protein to control free‐iron levels in Escherichia coli. Mol Microbiol 2007; 64: 822– 830. 17462026 PMC3048849 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Haem biosynthesis is exquisitely regulated, with haem negatively regulating the activity of the rate-limiting biosynthetic enzyme HemA.

    “In addition to Fur‐mediated iron sensing, haem biosynthesis is also exquisitely regulated, with haem negatively regulating the activity of the rate‐limiting biosynthetic enzyme HemA. 85 , 86”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [85] Jones AM, Elliott T. A purified mutant HemA protein from Salmonella enterica serovar Typhimurium lacks bound heme and is defective for heme‐mediated regulation in vivo. FEMS Microbiol Lett 2010; 307: 41– 7. 20412302 source

      Not checked in the free run.

    • cites [86] Choby JE, Skaar EP. Heme synthesis and acquisition in bacterial pathogens. J Mol Biol 2016; 428: 3408– 28. 27019298 PMC5125930 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Positive selection on primate Tf indicates evolutionary pressure on the host to deprive pathogens of iron and the importance of Tf for host defence.

    “Primate Tf shows evidence of positive evolutionary selection at amino acid residues bound by bacterial Tf receptors, indicating the evolutionary pressure on the host to deprive pathogens of iron and the importance of Tf for host defence. 123”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Barber MF, Elde NC. Escape from bacterial iron piracy through rapid evolution of transferrin. Science 2014; 346: 1362– 6. 25504720 PMC4455941 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    By sensing low haem concentrations, HsmR activates expression of the operon hsmRA; this prompts the binding of haem to the membrane-bound HsmA, which shields the bacterium from redox-active species.

    “By sensing low haem concentrations, HsmR activates expression of the operon hsmRA; this prompts the binding of haem to the membrane‐bound HsmA, which, due to haem’s reactivity, is able to shield the bacterium from redox‐active species.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Knippel RJ, Zackular JP, Moore JL, Celis AI, Weiss A, Washington MK et al Heme sensing and detoxification by HatRT contributes to pathogenesis during Clostridium difficile infection. PLoS Pathog 2018; 14: e1007486. 30576368 PMC6303022 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tf and Lf target free Fe3+ and can reduce its availability.

    “Both target free Fe3+, 122 and can therefore reduce its availability.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Legrand D, Elass E, Pierce A, Mazurier J. Lactoferrin and host defence: an overview of its immuno‐modulating and anti‐inflammatory properties. Biometals 2004; 17: 225– 9. 15222469 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The genome of C. difficile encodes several ferritin-, ferric-, and siderophore-bound iron uptake systems, which are almost exclusively Fur-regulated and highly responsive to iron fluctuations.

    “The genome of C. difficile encodes several ferritin‐, ferric‐, and siderophore‐bound iron uptake systems, which are almost exclusively Fur‐regulated and highly responsive to iron fluctuations. 91 , 135”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [91] Berges M, Michel A‐M, Lassek C, Nuss AM, Beckstette M, Dersch P et al Iron regulation in Clostridioides difficile. Front Microbiol 2018; 9: 3183 10.3389/fmicb.2018.03183 30619231 PMC6311696 source

      Not checked in the free run.

    • cites [135] Cernat RC, Scott KP. Evaluation of novel assays to assess the influence of different iron sources on the growth of Clostridium difficile. Anaerobe 2012; 18: 298– 304. 22554901 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Haemoglobin or spontaneously dissociated haem/haemin may be captured directly by bacterial cell surface-associated haemoglobin/haem-binding transporters, or acquired indirectly via small soluble high-affinity haem-binding proteins called haemophores.

    “Haemoglobin – or spontaneously dissociated haem/haemin – may be captured directly by bacterial cell surface‐associated haemoglobin/haem‐binding transporters, or acquired indirectly via small soluble high‐affinity haem‐binding proteins called haemophores. 138”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Richard KL, Kelley BR, Johnson JG. Heme uptake and utilization by gram‐negative bacterial pathogens. Front Cell Infect Microbiol 2019; 9: 81 10.3389/fcimb.2019.00081 30984629 PMC6449446 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron deprivation induces expression of putative ferric hydroxamate uptake and sulphonate ABC transporter systems in C. difficile, which might facilitate iron uptake during iron-poor conditions.

    “Moreover, iron deprivation also induced expression of putative ferric hydroxamate uptake and sulphonate ABC transporter systems, which might facilitate iron uptake during iron‐poor conditions. 91 , 92”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [91] Berges M, Michel A‐M, Lassek C, Nuss AM, Beckstette M, Dersch P et al Iron regulation in Clostridioides difficile. Front Microbiol 2018; 9: 3183 10.3389/fmicb.2018.03183 30619231 PMC6311696 source

      Not checked in the free run.

    • cites [92] Hastie JL, Hanna PC, Carlson PE. Transcriptional response of Clostridium difficile to low iron conditions. Pathog Dis 2018; 76: fty009 10.1093/femspd/fty009 PMC6251574 29390127 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The iron-induced skew and associated gut inflammation were particularly strong in low- to middle-income country cohorts, probably because relatively poor sanitary conditions increase the risk of underlying colonization by pathogenic microorganisms, the proliferation of which may be facilitated by extra iron availability.

    “This skew and associated gut inflammation were particularly strong in low‐ to middle‐income country cohorts, probably because relatively poor sanitary conditions increase the risk of underlying colonization by pathogenic microorganisms, the proliferation of which may be facilitated by extra iron availability. 156”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Paganini D, Zimmermann MB. The effects of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review. Am J Clin Nutr 1688S; 106: 1688S– 93. PMC5701709 29070552 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cholera toxin was recently shown to produce a growth-enhancing effect on Vibrio cholerae growth in the gut lumen by facilitating iron acquisition.

    “however, cholera toxin was recently shown to produce a growth‐enhancing effect on Vibrio cholerae growth in the gut lumen by facilitating iron acquisition. 147”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Rivera‐Chávez F, Mekalanos JJ. Cholera toxin promotes pathogen acquisition of host‐derived nutrients. Nature 2019; 572: 244– 8. 31367037 PMC6727848 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C. difficile catecholate precursor spermidine biosynthetic and transport genes (speAHEB and potABCD) and the catecholate siderophore import system YclNOPQ are Fur-regulated and highly induced under iron-limiting conditions.

    “Previously, it was shown that the catecholate’s precursor spermidine biosynthetic‐ and transport‐coding genes (speAHEB and potABCD, respectively), as well as the catecholate siderophore import system YclNOPQ, are Fur‐regulated and highly induced in C. difficile grown under iron‐limiting conditions. 91 , 136”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [91] Berges M, Michel A‐M, Lassek C, Nuss AM, Beckstette M, Dersch P et al Iron regulation in Clostridioides difficile. Front Microbiol 2018; 9: 3183 10.3389/fmicb.2018.03183 30619231 PMC6311696 source

      Not checked in the free run.

    • cites [136] Lopez CA, Beavers WN, Weiss A, Knippel RJ, Zackular JP, Chazin W et al The immune protein calprotectin impacts Clostridioides difficile metabolism through zinc limitation. mBio 2019; 10: e02289‐19 10.1128/mBio.02289-19 31744916 PMC6867894 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FPN-mediated effluxes of iron favour the growth of S. Typhimurium, conferring on them an advantage in the invasion of epithelial cells.

    “FPN‐mediated effluxes of iron were shown to favour the growth of S. Typhimurium, conferring on them an advantage in the invasion of epithelial cells. 81 , 159”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [81] Kortman GAM, Boleij A, Swinkels DW, Tjalsma H. Iron availability increases the pathogenic potential of Salmonella typhimurium and other enteric pathogens at the intestinal epithelial interface. PLoS One 2012; 7: e29968. 22272265 PMC3260200 source

      Not checked in the free run.

    • cites [159] Chlosta S, Fishman DS, Harrington L, Johnson EE, Knutson MD, Wessling‐Resnick M et al The iron efflux protein ferroportin regulates the intracellular growth of Salmonella enterica. Infect Immun 2006; 74: 3065– 7. 16622252 PMC1459754 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some bacteria produce siderophores, small molecules with extremely high affinity for Fe3+, to hijack iron from host glycoproteins and scavenge residual free iron.

    “As an alternative to directly taking up Tf or Lf, some bacteria produce siderophores; these are small molecules with extremely high affinity for Fe3+, frequently employed as a tool to hijack iron from host glycoproteins (such as Lf, Tf and Ft), and to scavenge residual free iron from the external milieu.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Kramer J, Özkaya Ö, Kümmerli R. Bacterial siderophores in community and host interactions. Nat Rev Microbiol 2020; 18: 152– 63. 31748738 PMC7116523 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Concepts of manipulating commensal-pathogen competition for nutrients such as iron may also prove relevant to C. difficile infection, where faecal microbial transfer has had therapeutic success through normalization of the commensal microbiota.

    “These concepts of manipulating commensal–pathogen competition for nutrients, such as iron, may also prove relevant to C. difficile infection, where faecal microbial transfer has had therapeutic success through normalization of the commensal microbiota. 149 , 176”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [149] Bäumler AJ, Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature 2016; 535: 85– 93. 27383983 PMC5114849 source

      Not checked in the free run.

    • cites [176] Seekatz AM, Young VB. Clostridium difficile and the microbiota. J Clin Invest 2014; 124: 4182– 9. 25036699 PMC4191019 source

      Not checked in the free run.

    • Rests on an assumption: It is possible to target bacteria-specific iron acquisition and promote commensal iron uptake while optimizing iron availability to the host without unacceptable harm.

  • May combine two claims.

    Premisecitation

    The microbiota-enforced status quo protects against gastrointestinal infection, as demonstrated by antibiotic therapy increasing the risk of C. difficile and Salmonella infections, whereas limitation of nutrient availability by the microbiota also plays a role.

    “The microbiota‐enforced status quo protects against gastrointestinal infection, as demonstrated by antibiotic therapy increasing the risk of C. difficile and Salmonella infections, whereas limitation of nutrient availability by the microbiota also plays a role. 149”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Bäumler AJ, Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature 2016; 535: 85– 93. 27383983 PMC5114849 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron uptake in the face of host and commensal defences is a major requirement for pathogen virulence, with iron acquisition systems being ubiquitous features of pathogenicity islands within genomes of virulent bacteria.

    “Iron uptake in the face of host and commensal defences is a major requirement for pathogen virulence, with iron acquisition systems being ubiquitous features of pathogenicity islands within genomes of virulent bacteria. 172”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [172] Schmidt H, Hensel M. Pathogenicity islands in bacterial pathogenesis. Clin Microbiol Rev 2004; 17: 14– 56. 14726454 PMC321463 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The non-pathogenic E. coli strain Nissle has complex iron acquisition pathways and can secrete and utilize enterobactin, LCN2-resistant salmochelin, yersiniabactin and aerobactin to effectively acquire iron at the expense of Salmonella.

    “The non‐pathogenic E. coli strain Nissle has complex iron acquisition pathways and can secrete and utilize not only enterobactin, but also LCN2‐resistant salmochelin, yersiniabactin and aerobactin to effectively acquire iron at the expense of Salmonella. 17 , 168 , 169”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Glover J, Jacobs A. Observations on iron in the jejunal lumen after a standard meal. Gut 1971; 12: 369– 71. 4255818 PMC1411612 source

      Not checked in the free run.

    • cites [168] Valdebenito M, Crumbliss AL, Winkelmann G, Hantke K. Environmental factors influence the production of enterobactin, salmochelin, aerobactin, and yersiniabactin in Escherichia coli strain Nissle 1917. Int J Med Microbiol 2006; 296: 513– 20. 17008127 source

      Not checked in the free run.

    • cites [169] Deriu E, Liu JZ, Pezeshki M, Edwards RA, Ochoa RJ, Contreras H et al Probiotic bacteria reduce Salmonella Typhimurium intestinal colonization by competing for iron. Cell Host Microbe 2013; 14: 26– 37. 23870311 PMC3752295 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Improving host nutritional immunity through immunization against enterobactins reduced the severity of experimental gastrointestinal Salmonella infection, systemic dissemination and infection-associated dysbiosis.

    “Improving host nutritional immunity through immunization against enterobactins reduced the severity of experimental gastrointestinal Salmonella infection, systemic dissemination and infection‐associated dysbiosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [174] Sassone‐Corsi M, Chairatana P, Zheng T, Perez‐Lopez A, Edwards RA, George MD et al Siderophore‐based immunization strategy to inhibit growth of enteric pathogens. Proc Natl Acad Sci USA 2016; 113: 13462– 7. 27821741 PMC5127304 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Although pathogens seem to suffer from iron deprivation, the dependence of innate and adaptive cellular immunity on iron makes therapeutically targeting iron availability problematic.

    “However, although pathogens seem to suffer from iron deprivation, the dependence of innate and adaptive cellular immunity on iron makes therapeutically targeting iron availability problematic. 173”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [173] Collins HL, Kaufmann SHE, Schaible UE. Iron chelation via deferoxamine exacerbates experimental salmonellosis via inhibition of the nicotinamide adenine dinucleotide phosphate oxidase‐dependent respiratory burst. J Immunol 2002; 168: 3458– 63. 11907105 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    1,3-Diaminopropane production by lactobacilli was specifically enhanced during dietary iron deficiency, highlighting how the microbiota modulates local host iron homeostasis and luminal iron availability.

    “1,3‐Diaminopropane production by lactobacilli was specifically enhanced during dietary iron deficiency, highlighting how the microbiota modulates local host iron homeostasis and luminal iron availability. 166”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Das NK, Schwartz AJ, Barthel G, Inohara N, Liu Q, Sankar A et al Microbial metabolite signaling is required for systemic iron homeostasis. Cell Metab 2020; 31: 115– 30.e6. 31708445 PMC6949377 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Increasing iron availability in the gastrointestinal tract probably alters both the composition and metabolic activity of the gut microbiota, creating a niche through which pathogenic microorganisms can enter and cause disease.

    “Although the picture is in no way clear‐cut, it seems that increasing iron availability in the gastrointestinal tract probably alters both the composition and metabolic activity of the gut microbiota, creating a niche through which pathogenic microorganisms can enter and cause disease.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from animal models and in vitro systems about iron, microbiota, and infection can be generalized to human enteric infections.
68 of 68

  • The paper relies on this without support.

    The gastrointestinal system is home to more than 10^14 bacteria.

    “However, as the gastrointestinal system is also home to >1014 bacteria, all of which engage in their own programmes of iron homeostasis, the gut represents an anatomical location where the inter‐kingdom fight for iron is never‐ending.”

  • The paper relies on this without support.

    All bacteria engage in their own programmes of iron homeostasis.

    “However, as the gastrointestinal system is also home to >1014 bacteria, all of which engage in their own programmes of iron homeostasis, the gut represents an anatomical location where the inter‐kingdom fight for iron is never‐ending.”

  • The paper relies on this without support.

    Iron deprivation acts as a sensory cue in bacterial pathogens, triggering the coordinated regulation of iron acquisition and virulence genes.

    “Iron deprivation acts as a sensory cue in bacterial pathogens, triggering the coordinated regulation of iron acquisition and virulence genes.”

  • The paper relies on this without support.

    The capacity to acquire sufficient iron to support proliferation, in the presence of iron-limiting host defence mechanisms, is an important determinant of pathogenicity.

    “The capacity to acquire sufficient iron to support proliferation, in the presence of iron‐limiting host defence mechanisms, is an important determinant of pathogenicity.”

  • The paper relies on this without support.

    Most iron acquisition strategies employed by bacterial pathogens are regulated by members of the Fur or DtxR superfamilies.

    “Indeed, most iron acquisition strategies employed by bacterial pathogens are regulated by members of the Fur or DtxR superfamilies.”

  • The paper relies on this without support.

    Manganese deprivation is the major NRAMP1-mediated Salmonella resistance mechanism.

    “Recent results suggest manganese deprivation is the major NRAMP1‐mediated Salmonella resistance mechanism.”

  • The paper relies on this without support.

    Findings from animal models and in vitro systems about iron, microbiota, and infection can be generalized to human enteric infections.

    “Experiments in animal models and in vitro fermentation systems broadly support the claims that iron supplementation remodels the gut microbiota, 161 , 162 potentially skewing towards a dysbiotic phenotype.”

  • The paper relies on this without support.

    It is possible to target bacteria-specific iron acquisition and promote commensal iron uptake while optimizing iron availability to the host without unacceptable harm.

    “Targeting bacteria‐specific iron acquisition apparatus and promoting commensal iron uptake at the expense of pathogens, while optimizing iron availability to the host, may together foster improved therapeutic approaches to gastrointestinal infectious and inflammatory disorders.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Several metals including Mn and host metal-containing molecules such as haem can be detrimental to bacterial survival at high concentrations.

    “Although not discussed at length below, several metals including Mn and host metal- containing molecules such as haem can be detrimental to bacterial survival at high concentrations 31,144 .”

    From Nutritional immunity: the battle for nutrient metals at the host–pathogen interface (2022) · cites this paper as [144]

    In “Extraction and capture of haem” (page unavailable), the paper describes a bacterial system that exports haem when intracellular levels become toxic. It does not say that high Mn concentrations harm bacterial survival; its discussion of Mn instead concerns the effects of manganese deprivation. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Opposite claims about Fe2+ and Fe3+ solubility

    Minor

    The bacterial-iron section describes Fe2+ as less soluble than Fe3+, whereas the earlier account says oxidation to Fe3+ causes dietary iron to precipitate and describes Fe2+ as the form available for uptake.

1 of 1

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Authors
Sousa Gerós, A., Simmons, A., Drakesmith, H., Aulicino, A., & Frost, J. N.
Affiliations
  • MRC Human Immunology Unit Weatherall Institute of Molecular Medicine University of Oxford Oxford UK
  • John Radcliffe Hospital (GB)
  • University of Oxford (GB)
Corresponding author
  • Aulicino, Anna
  • Frost, Joe N.
ORCID
Venue
Immunology
Publisher
Wiley
Published
2020-08-11
Volume
161
Issue
3
Pages
186-199
ISSN
  • 0019-2805 (ISSN-L)
  • 1365-2567
DOI
10.1111/imm.13236
PMC
PMC7576875
OpenAlex
W3040806694
Cited by
58
References
189
Citations by year
2026: 5 · 2025: 5 · 2024: 6 · 2023: 22 · 2022: 8 · 2021: 9 · 2020: 3
FWCI
1.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Medical Research Council (MC_UU_12010/10)
  • National Institute for Health Research
  • Bristol-Myers Squibb
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords
iron homeostasis, host-pathogen interaction, gastrointestinal infections, nutritional immunity, Salmonella, Clostridium, gut microbiota, dietary iron absorption, iron toxicity, host defense against infection
MeSH terms
Clostridiaceae, Animals, Gastrointestinal Diseases, Homeostasis, Humans, Iron, Salmonella, Salmonella Infections, Gram-Positive Bacterial Infections, Microbiota

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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