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The role of iron in host–microbiota crosstalk and its effects on systemic glucose metabolism

Abstract

Iron is critical for the appearance and maintenance of life on Earth. Almost all organisms compete or cooperate for iron acquisition, demonstrating the importance of this essential element for the biological and physiological processes that are key for the preservation of metabolic homeostasis. In humans and other mammals, the bidirectional interactions between the bacterial component of the gut microbiota and the host for iron acquisition shape both host and microbiota metabolism. Bacterial functions influence host iron absorption, whereas the intake of iron, iron deficiency and iron excess in the host affect bacterial biodiversity, taxonomy and function, resulting in changes in bacterial virulence. These consequences of the host–microbial crosstalk affect systemic levels of iron, its storage in different tissues and host glucose metabolism. At the interface between the host and the microbiota, alterations in the host innate immune system and in circulating soluble factors that regulate iron (that is, hepcidin, lipocalin 2 and lactoferrin) are associated with metabolic disease. In fact, patients with obesity-associated metabolic dysfunction and insulin resistance exhibit dysregulation in iron homeostasis and alterations in their gut microbiota profile. From an evolutionary point of view, the pursuit of two important nutrients — glucose and iron — has probably driven human evolution towards the most efficient pathways and genes for human survival and health.

Key points

  • Circulating levels of crucial soluble proteins for body iron homeostasis are altered in individuals with obesity, insulin resistance and/or type 2 diabetes mellitus.

  • Macrophages exert a key role in tissue iron homeostasis, specifically in those tissues involved in systemic insulin action.

  • Intestinal iron availability shapes the gut bacterial ecosystem; iron deficiency and iron overload are associated with specific gut microbiota profiles in humans and rodents.

  • The gut microbiota has a relevant role in the absorption of iron in the intestine and bacteria-derived metabolites are implicated in the regulation of body iron homeostasis.

  • The bidirectional interaction between iron homeostasis and the gut microbiota affects systemic glucose metabolism and the development of hepatic steatosis.

  • Host–microbiota crosstalk in the acquisition of glucose and iron has possible evolutionary implications in the selection of the most efficient pathways and genes critical for human survival.

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Fig. 1: Pathways involved in host iron homeostasis.
Fig. 2: Bacterial iron homeostasis in Gram-negative bacteria.
Fig. 3: Regulation of host systemic iron homeostasis by the gut microbiota.
Fig. 4: Crosstalk between the gut microbiota, iron and glucose metabolism.
Fig. 5: A model of how iron and glucose acquisition might drive human evolution.

References

  1. Wade, J., Byrne, D. J., Ballentine, C. J. & Drakesmith, H. Temporal variation of planetary iron as a driver of evolution. Proc. Natl Acad. Sci. USA 118, e2109865118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Muchowska, K. B., Varma, S. J. & Moran, J. Synthesis and breakdown of universal metabolic precursors promoted by iron. Nature 569, 104–107 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Weiss, M. C., Preiner, M., Xavier, J. C., Zimorski, V. & Martin, W. F. The last universal common ancestor between ancient Earth chemistry and the onset of genetics. PLoS Genet. 14, e1007518 (2018).

    PubMed  PubMed Central  Google Scholar 

  4. Knoll, A. H. & Nowak, M. A. The timetable of evolution. Sci. Adv. 3, e1603076 (2017).

    PubMed  PubMed Central  Google Scholar 

  5. Ganz, T. Systemic iron homeostasis. Physiol. Rev. 93, 1721–1741 (2013).

    CAS  PubMed  Google Scholar 

  6. Posey, J. E. & Gherardini, F. C. Lack of a role for iron in the Lyme disease pathogen. Science 288, 1651–1653 (2000).

    CAS  PubMed  Google Scholar 

  7. Fernández-Real, J. M. & Manco, M. Effects of iron overload on chronic metabolic diseases. Lancet Diabetes Endocrinol. 2, 513–526 (2014).

    PubMed  Google Scholar 

  8. Fernandez-Real, J. M., Mcclain, D. & Manco, M. Mechanisms linking glucose homeostasis and iron metabolism toward the onset and progression of type 2 diabetes. Diabetes Care 38, 2169–2176 (2015).

    CAS  PubMed  Google Scholar 

  9. Mayneris-Perxachs, J. et al. Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome. Microbiome 9, 104 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858 (2017).

    CAS  PubMed  Google Scholar 

  11. Seyoum, Y., Baye, K. & Humblot, C. Iron homeostasis in host and gut bacteria — a complex interrelationship. Gut Microbes 13, 1–19 (2021).

    CAS  PubMed  Google Scholar 

  12. Toyokuni, S. Iron and thiols as two major players in carcinogenesis: friends or foes? Front. Pharmacol. 5, 200 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. Shayeghi, M. et al. Identification of an intestinal heme transporter. Cell 122, 789–801 (2005).

    CAS  PubMed  Google Scholar 

  14. Qiu, A. et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127, 917–928 (2006).

    CAS  PubMed  Google Scholar 

  15. Muckenthaler, M. U., Galy, B. & Hentze, M. W. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu. Rev. Nutr. 28, 197–213 (2008).

    CAS  PubMed  Google Scholar 

  16. Mahroum, N. et al. Ferritin - from iron, through inflammation and autoimmunity, to COVID-19. J. Autoimmun. 126, 102778 (2022).

    CAS  PubMed  Google Scholar 

  17. Cohen, L. A. et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 116, 1574–1584 (2010).

    CAS  PubMed  Google Scholar 

  18. Das, N. K. et al. Microbial metabolite signaling is required for systemic iron homeostasis. Cell Metab. 31, 115–130.e6 (2020).

    CAS  PubMed  Google Scholar 

  19. Wilkinson, N. & Pantopoulos, K. The IRP/IRE system in vivo: insights from mouse models. Front. Pharmacol. 5, 176 (2014).

    PubMed  PubMed Central  Google Scholar 

  20. Volz, K. The functional duality of iron regulatory protein 1. Curr. Opin. Struct. Biol. 18, 106–111 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Galy, B. et al. Iron regulatory proteins control a mucosal block to intestinal iron absorption. Cell Rep. 3, 844–857 (2013).

    CAS  PubMed  Google Scholar 

  22. Schade, A. L. & Caroline, L. Raw hen egg white and the role of iron in growth inhibition of Shigella dysenteriae, Staphylococcus aureus, Escherichia coli and Saccharomyces cerevisiae. Science 100, 14–15 (1944).

    CAS  PubMed  Google Scholar 

  23. Simonsen, K. T. et al. Quantitative proteomics identifies ferritin in the innate immune response of C. elegans. Virulence 2, 120–130 (2011).

    PubMed  Google Scholar 

  24. Lou, D. Q. et al. Iron- and inflammation-induced hepcidin gene expression in mice is not mediated by Kupffer cells in vivo. Hepatology 41, 1056–1064 (2005).

    CAS  PubMed  Google Scholar 

  25. Nemeth, E. et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113, 1271–1276 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Arezes, J. et al. Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe 17, 47–57 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Prentice, S. et al. Hepcidin mediates hypoferremia and reduces the growth potential of bacteria in the immediate post-natal period in human neonates. Sci. Rep. 9, 16596 (2019).

    PubMed  PubMed Central  Google Scholar 

  28. Gulec, S., Anderson, G. J. & Collins, J. F. Mechanistic and regulatory aspects of intestinal iron absorption. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G397–G409 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bergamaschi, G. et al. Intestinal expression of genes implicated in iron absorption and their regulation by hepcidin. Clin. Nutr. 36, 1427–1433 (2017).

    CAS  PubMed  Google Scholar 

  30. Arndt, S. et al. Iron-induced expression of bone morphogenic protein 6 in intestinal cells is the main regulator of hepatic hepcidin expression in vivo. Gastroenterology 138, 372–382 (2010).

    CAS  PubMed  Google Scholar 

  31. Yamamoto, K. et al. Interplay of adipocyte and hepatocyte: leptin upregulates hepcidin. Biochem. Biophys. Res. Commun. 495, 1548–1554 (2018).

    CAS  PubMed  Google Scholar 

  32. Moreno-Navarrete, J. M. et al. Hepatic iron content is independently associated with serum hepcidin levels in subjects with obesity. Clin. Nutr. 36, 1434–1439 (2017).

    CAS  PubMed  Google Scholar 

  33. Stoffel, N. U. et al. The effect of central obesity on inflammation, hepcidin, and iron metabolism in young women. Int. J. Obes. 44, 1291–1300 (2020).

    CAS  Google Scholar 

  34. Del Giudice, E. M. et al. Hepcidin in obese children as a potential mediator of the association between obesity and iron deficiency. J. Clin. Endocrinol. Metab. 94, 5102–5107 (2009).

    PubMed  Google Scholar 

  35. Moreno-Navarrete, J. M. et al. Increased small intestine expression of non-heme iron transporters in morbidly obese patients with newly diagnosed type 2 diabetes. Mol. Nutr. Food Res. https://doi.org/10.1002/mnfr.201700301 (2018).

    Article  PubMed  Google Scholar 

  36. Pechlaner, R. et al. Inadequate hepcidin serum concentrations predict incident type 2 diabetes mellitus. Diabetes Metab. Res. Rev. 32, 187–192 (2016).

    CAS  PubMed  Google Scholar 

  37. Aregbesola, A., Voutilainen, S., Virtanen, J. K., Aregbesola, A. & Tuomainen, T. P. Serum hepcidin concentrations and type 2 diabetes. World J. Diabetes 6, 978 (2015).

    PubMed  PubMed Central  Google Scholar 

  38. Suárez-Ortegón, M. F. et al. Circulating hepcidin in type 2 diabetes: a multivariate analysis and double blind evaluation of metformin effects. Mol. Nutr. Food Res. 59, 2460–2470 (2015).

    PubMed  Google Scholar 

  39. Wang, H. et al. Hepcidin is directly regulated by insulin and plays an important role in iron overload in streptozotocin-induced diabetic rats. Diabetes 63, 1506–1518 (2014).

    CAS  PubMed  Google Scholar 

  40. Yang, J. et al. An iron delivery pathway mediated by a lipocalin. Mol. Cell 10, 1045–1056 (2002).

    CAS  PubMed  Google Scholar 

  41. Devireddy, L. R., Gazin, C., Zhu, X. & Green, M. R. A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 123, 1293–1305 (2005).

    CAS  PubMed  Google Scholar 

  42. Ratledge, C. & Dover, L. G. Iron metabolism in pathogenic bacteria. Annu. Rev. Microbiol. 54, 881–941 (2000).

    CAS  PubMed  Google Scholar 

  43. Goetz, D. H. et al. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol. Cell 10, 1033–1043 (2002).

    CAS  PubMed  Google Scholar 

  44. Liu, Z. et al. Regulation of mammalian siderophore 2,5-DHBA in the innate immune response to infection. J. Exp. Med. 211, 1197–1213 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang, Y. et al. Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans. Clin. Chem. 53, 34–41 (2007).

    CAS  PubMed  Google Scholar 

  46. Moreno-Navarrete, J. M. et al. Metabolic endotoxemia and saturated fat contribute to circulating NGAL concentrations in subjects with insulin resistance. Int. J. Obes. 34, 240–249 (2010).

    CAS  Google Scholar 

  47. Ellison, R. T. The effects of lactoferrin on gram-negative bacteria. Adv. Exp. Med. Biol. 357, 71–90 (1994).

    CAS  PubMed  Google Scholar 

  48. Ward, P. P., Mendoza-Meneses, M., Cunningham, G. A. & Conneely, O. M. Iron status in mice carrying a targeted disruption of lactoferrin. Mol. Cell. Biol. 23, 178–185 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Guo, C. et al. Recombinant human lactoferrin attenuates the progression of hepatosteatosis and hepatocellular death by regulating iron and lipid homeostasis in ob/ob mice. Food Funct. 11, 7183–7196 (2020).

    CAS  PubMed  Google Scholar 

  50. Singh, A. et al. Whey protein and its components lactalbumin and lactoferrin affect energy balance and protect against stroke onset and renal damage in salt-loaded, high-fat fed male spontaneously hypertensive stroke-prone rats. J. Nutr. 150, 763–774 (2020).

    PubMed  Google Scholar 

  51. Ling, C. J. et al. Lactoferrin promotes bile acid metabolism and reduces hepatic cholesterol deposition by inhibiting the farnesoid X receptor (FXR)-mediated enterohepatic axis. Food Funct. 10, 7299–7307 (2019).

    CAS  PubMed  Google Scholar 

  52. Li, Y. C. & Hsieh, C. C. Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model. PLoS One 9, e97341 (2014).

    PubMed  PubMed Central  Google Scholar 

  53. Zapata, R. C., Singh, A., Pezeshki, A., Nibber, T. & Chelikani, P. K. Whey protein components — lactalbumin and lactoferrin — improve energy balance and metabolism. Sci. Rep. 7, 9917 (2017).

    PubMed  PubMed Central  Google Scholar 

  54. Xiong, L., Ren, F., Lv, J., Zhang, H. & Guo, H. Lactoferrin attenuates high-fat diet-induced hepatic steatosis and lipid metabolic dysfunctions by suppressing hepatic lipogenesis and down-regulating inflammation in C57BL/6J mice. Food Funct. 9, 4328–4339 (2018).

    CAS  PubMed  Google Scholar 

  55. Min, Q. Q. et al. Effects of metformin combined with lactoferrin on lipid accumulation and metabolism in mice fed with high-fat diet. Nutrients 10, 1628 (2018).

    PubMed Central  Google Scholar 

  56. Ono, T. et al. Potent anti-obesity effect of enteric-coated lactoferrin: decrease in visceral fat accumulation in Japanese men and women with abdominal obesity after 8-week administration of enteric-coated lactoferrin tablets. Br. J. Nutr. 104, 1688–1695 (2010).

    CAS  PubMed  Google Scholar 

  57. Moreno-Navarrete, J. M., Ortega, F. J., Bassols, J., Ricart, W. & Fernández-Real, J. M. Decreased circulating lactoferrin in insulin resistance and altered glucose tolerance as a possible marker of neutrophil dysfunction in type 2 diabetes. J. Clin. Endocrinol. Metab. 94, 4036–4044 (2009).

    CAS  PubMed  Google Scholar 

  58. Mohamed, W. A. & Schaalan, M. F. Antidiabetic efficacy of lactoferrin in type 2 diabetic pediatrics; controlling impact on PPAR-γ, SIRT-1, and TLR4 downstream signaling pathway. Diabetol. Metab. Syndr. 10, 89 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Moreno-Navarrete, J. M. et al. Association of circulating lactoferrin concentration and 2 nonsynonymous LTF gene polymorphisms with dyslipidemia in men depends on glucose-tolerance status. Clin. Chem. 54, 301–309 (2008).

    CAS  PubMed  Google Scholar 

  60. Catalán, V. et al. Peripheral mononuclear blood cells contribute to the obesity-associated inflammatory state independently of glycemic status: involvement of the novel proinflammatory adipokines chemerin, chitinase-3-like protein 1, lipocalin-2 and osteopontin. Genes Nutr. 10, 460 (2015).

    PubMed  Google Scholar 

  61. Auguet, T. et al. Upregulation of lipocalin 2 in adipose tissues of severely obese women: positive relationship with proinflammatory cytokines. Obesity 19, 2295–2300 (2011).

    CAS  PubMed  Google Scholar 

  62. Ong, K. L. et al. Relationships of adipocyte-fatty acid binding protein and lipocalin 2 with risk factors and chronic complications in type 2 diabetes and effects of fenofibrate: a fenofibrate Intervention and event lowering in diabetes sub-study. Diabetes Res. Clin. Pract. 169, 108450 (2020).

    CAS  PubMed  Google Scholar 

  63. Veiga, G. et al. NGAL and SMAD1 gene expression in the early detection of diabetic nephropathy by liquid biopsy. J. Clin. Pathol. 73, 713–721 (2020).

    CAS  PubMed  Google Scholar 

  64. Eilenberg, W. et al. Neutrophil gelatinase associated lipocalin (NGAL) is elevated in type 2 diabetics with carotid artery stenosis and reduced under metformin treatment. Cardiovasc. Diabetol. 16, 98 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang, H. et al. Elevated vitreous Lipocalin-2 levels of patients with proliferative diabetic retinopathy. BMC Ophthalmol. 20, 260 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Soares, M. P. & Hamza, I. Macrophages and iron metabolism. Immunity 44, 492–504 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Winn, N. C., Volk, K. M. & Hasty, A. H. Regulation of tissue iron homeostasis: the macrophage ‘ferrostat’. JCI Insight 5, E376–E391 (2020).

    Google Scholar 

  68. Winn, N. C., Wolf, E. M., Cottam, M. A., Bhanot, M. & Hasty, A. H. Myeloid-specific deletion of ferroportin impairs macrophage bioenergetics but is disconnected from systemic insulin action in adult mice. Am. J. Physiol. Endocrinol. Metab. 321, E376–E391 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Orr, J. S. et al. Obesity alters adipose tissue macrophage iron content and tissue iron distribution. Diabetes 63, 421–432 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Hubler, M. J., Erikson, K. M., Kennedy, A. J. & Hasty, A. H. MFe hi adipose tissue macrophages compensate for tissue iron perturbations in mice. Am. J. Physiol. Cell Physiol. 315, C319–C329 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Varghese, J. et al. Development of insulin resistance preceded major changes in iron homeostasis in mice fed a high-fat diet. J. Nutr. Biochem. 84, 108441 (2020).

    CAS  PubMed  Google Scholar 

  72. Corna, G. et al. The repair of skeletal muscle requires iron recycling through macrophage ferroportin. J. Immunol. 197, 1914–1925 (2016).

    CAS  PubMed  Google Scholar 

  73. Ikeda, Y. et al. Deletion of H-ferritin in macrophages alleviates obesity and diabetes induced by high-fat diet in mice. Diabetologia 63, 1588–1602 (2020).

    CAS  PubMed  Google Scholar 

  74. McCance, R. A. & Widdowson, E. M. The absorption and excretion of iron following oral and intravenous administration. J. Physiol. 94, 148–154 (1938).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Dostal, A. et al. Iron modulates butyrate production by a child gut microbiota in vitro. MBio 6, e01453-15 (2015).

    PubMed  PubMed Central  Google Scholar 

  76. Jaeggi, T. et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut 64, 731–742 (2015).

    CAS  PubMed  Google Scholar 

  77. Cassat, J. E. & Skaar, E. P. Iron in infection and immunity. Cell Host Microbe 13, 509–519 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhang, Y., Sen, S. & Giedroc, D. P. Iron acquisition by bacterial pathogens: beyond tris-catecholate complexes. ChemBioChem 21, 1955–1967 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Raymond, K. N., Dertz, E. A. & Kim, S. S. Enterobactin: an archetype for microbial iron transport. Proc. Natl Acad. Sci. USA 100, 3584–3588 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Andrews, S. C., Robinson, A. K. & Rodríguez-Quiñones, F. Bacterial iron homeostasis. FEMS Microbiol. Rev. 27, 215–237 (2003).

    CAS  PubMed  Google Scholar 

  81. Bradley, J. M. et al. Bacterial iron detoxification at the molecular level. J. Biol. Chem. 295, 17602–17623 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kronstad, J. W. & Caza, M. Shared and distinct mechanisms of iron acquisition by bacterial and fungal pathogens of humans. Front. Cell. Infect. Microbiol. 4, 80 (2013).

    Google Scholar 

  83. Krewulak, K. D. & Vogel, H. J. Structural biology of bacterial iron uptake. Biochim. Biophys. Acta 1778, 1781–1804 (2008).

    CAS  PubMed  Google Scholar 

  84. Wilson, B. R., Bogdan, A. R., Miyazawa, M., Hashimoto, K. & Tsuji, Y. Siderophores in iron metabolism: from mechanism to therapy potential. Trends Mol. Med. 22, 1077–1090 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Kramer, J., Özkaya, Ö. & Kümmerli, R. Bacterial siderophores in community and host interactions. Nat. Rev. Microbiol. 18, 152–163 (2020).

    CAS  PubMed  Google Scholar 

  86. Golonka, R., Yeoh, B. S. & Vijay-Kumar, M. The iron tug-of-war between bacterial siderophores and innate immunity. J. Innate Immun. 11, 249–262 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).

    CAS  PubMed  Google Scholar 

  88. Chareyre, S. & Mandin, P. Bacterial iron homeostasis regulation by sRNAs. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.RWR-0010-2017 (2018).

    Article  PubMed  Google Scholar 

  89. Kortman, G. A. M., Raffatellu, M., Swinkels, D. W. & Tjalsma, H. Nutritional iron turned inside out: intestinal stress from a gut microbial perspective. FEMS Microbiol. Rev. 38, 1202–1234 (2014).

    CAS  PubMed  Google Scholar 

  90. Buhnik-Rosenblau, K., Moshe-Belizowski, S., Danin-Poleg, Y. & Meyron-Holtz, E. G. Genetic modification of iron metabolism in mice affects the gut microbiota. BioMetals 25, 883–892 (2012).

    CAS  PubMed  Google Scholar 

  91. Sivaprakasam, S. et al. Hereditary hemochromatosis promotes colitis and colon cancer and causes bacterial dysbiosis in mice. Biochem. J. 477, 3867–3883 (2020).

    CAS  PubMed  Google Scholar 

  92. Santacruz, A. et al. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br. J. Nutr. 104, 83–92 (2010).

    CAS  PubMed  Google Scholar 

  93. Weinberg, E. D. The Lactobacillus anomaly: total iron abstinence. Perspect. Biol. Med. 40, 578–583 (1997).

    CAS  PubMed  Google Scholar 

  94. Anderson, R. C., Cookson, A. L., McNabb, W. C., Kelly, W. J. & Roy, N. C. Lactobacillus plantarum DSM 2648 is a potential probiotic that enhances intestinal barrier function. FEMS Microbiol. Lett. 309, 184–192 (2010).

    CAS  PubMed  Google Scholar 

  95. Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–549 (2011).

    CAS  PubMed  Google Scholar 

  96. Coconnier, M. H., Liévin, V., Bernet-Camard, M. F., Hudault, S. & Servin, A. L. Antibacterial effect of the adhering human Lactobacillus acidophilus strain LB. Antimicrob. Agents Chemother. 41, 1046–1052 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Lievin, V. et al. Bifidobacterium strains from resident infant human gastrointestinal microflora exert antimicrobial activity. Gut 47, 646–652 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Knight, L. C., Wang, M., Donovan, S. M. & Dilger, R. N. Early-life iron deficiency and subsequent repletion alters development of the colonic microbiota in the pig. Front. Nutr. 6, 120 (2019).

    PubMed  PubMed Central  Google Scholar 

  99. Dostal, A. et al. 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, 271–277 (2012).

    CAS  PubMed  Google Scholar 

  100. Werner, T. et al. Depletion of luminal iron alters the gut microbiota and prevents Crohn’s disease-like ileitis. Gut 60, 325–333 (2011).

    CAS  PubMed  Google Scholar 

  101. Ellermann, M. et al. Dietary iron variably modulates assembly of the intestinal microbiota in colitis-resistant and colitis-susceptible mice. Gut Microbes 11, 32–50 (2020).

    CAS  PubMed  Google Scholar 

  102. Dostal, A., Fehlbaum, S., Chassard, C., Zimmermann, M. B. & Lacroix, C. Low iron availability in continuous in vitro colonic fermentations induces strong dysbiosis of the child gut microbial consortium and a decrease in main metabolites. FEMS Microbiol. Ecol. 83, 161–175 (2013).

    CAS  PubMed  Google Scholar 

  103. Fischbach, M. A., Lin, H., Liu, D. R. & Walsh, C. T. How pathogenic bacteria evade mammalian sabotage in the battle for iron. Nat. Chem. Biol. 2, 132–138 (2006).

    CAS  PubMed  Google Scholar 

  104. Raffatellu, M. et al. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe 5, 476–486 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Zimmermann, M. B. et al. The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Côte d’Ivoire. Am. J. Clin. Nutr. 92, 1406–1415 (2010).

    CAS  PubMed  Google Scholar 

  106. Krebs, N. F. et al. Effects of different complementary feeding regimens on iron status and enteric microbiota in breastfed infants. J. Pediatr. 163, 416–423 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Constante, M., Fragoso, G., Calvé, A., Samba-Mondonga, M. & Santos, M. M. Dietary heme induces gut dysbiosis, aggravates colitis, and potentiates the development of adenomas in mice. Front. Microbiol. 8, 1809 (2017).

    PubMed  PubMed Central  Google Scholar 

  108. Fang, S., Zhuo, Z., Yu, X., Wang, H. & Feng, J. Oral administration of liquid iron preparation containing excess iron induces intestine and liver injury, impairs intestinal barrier function and alters the gut microbiota in rats. J. Trace Elem. Med. Biol. 47, 12–20 (2018).

    CAS  PubMed  Google Scholar 

  109. Lopez, C. A. & Skaar, E. P. The impact of dietary transition metals on host-bacterial interactions. Cell Host Microbe 23, 737–748 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Moreno-Navarrete, J. M. et al. Increased adipose tissue heme levels and exportation are associated with altered systemic glucose metabolism. Sci. Rep. 7, 5305 (2017).

    PubMed  PubMed Central  Google Scholar 

  111. Seiwert, N. et al. Chronic intestinal inflammation drives colorectal tumor formation triggered by dietary heme iron in vivo. Arch. Toxicol. 95, 2507–2522 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Kortman, G. A. M. et al. Microbial metabolism shifts towards an adverse profile with supplementary iron in the TIM-2 in vitro model of the human colon. Front. Microbiol. 6, 1481 (2016).

    PubMed  PubMed Central  Google Scholar 

  113. Reddy, B. S., Pleasants, J. R. & Wostmann, B. S. Effect of intestinal microflora on iron and zinc metabolism, and on activities of metalloenzymes in rats. J. Nutr. 102, 101–107 (1972).

    CAS  PubMed  Google Scholar 

  114. Deschemin, J. C. et al. The microbiota shifts the iron sensing of intestinal cells. FASEB J. 30, 252–261 (2016).

    CAS  PubMed  Google Scholar 

  115. Taylor, M. et al. Hypoxia-inducible factor-2α mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology 140, 2044–2055 (2011).

    CAS  PubMed  Google Scholar 

  116. Qi, B. & Han, M. Microbial siderophore enterobactin promotes mitochondrial iron uptake and development of the host via interaction with ATP synthase. Cell 175, 571–582.e11 (2018).

    CAS  PubMed  Google Scholar 

  117. Shanmugam, N. K. N., Trebicka, E., Fu, L., Shi, H. N. & Cherayil, B. J. Intestinal inflammation modulates expression of the iron-regulating hormone hepcidin depending on erythropoietic activity and the commensal microbiota. J. Immunol. 193, 1398–1407 (2014).

    CAS  PubMed  Google Scholar 

  118. Salovaara, S., Sandberg, A. S. & Andlid, T. Combined impact of pH and organic acids on iron uptake by Caco-2 cells. J. Agric. Food Chem. 51, 7820–7824 (2003).

    CAS  PubMed  Google Scholar 

  119. Bouglé, D. et al. Influence of short-chain fatty acids on iron absorption by proximal colon. Scand. J. Gastroenterol. 37, 1008–1011 (2002).

    PubMed  Google Scholar 

  120. Hoppe, M., Önning, G., Berggren, A. & Hulthén, L. Probiotic strain Lactobacillus plantarum 299v increases iron absorption from an iron-supplemented fruit drink: a double-isotope cross-over single-blind study in women of reproductive age. Br. J. Nutr. 114, 1195–1202 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Venegas, D. P. et al. Short chain fatty acids (SCFAs)mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front. Immunol. 10, 277 (2019).

    CAS  Google Scholar 

  122. Saha, P. et al. Gut microbiota conversion of dietary ellagic acid into bioactive phytoceutical urolithin a inhibits heme peroxidases. PLoS One 11, e0156811 (2016).

    PubMed  PubMed Central  Google Scholar 

  123. Thingholm, L. B. et al. Obese individuals with and without type 2 diabetes show different gut microbial functional capacity and composition. Cell Host Microbe 26, 252–264.e10 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Aron-Wisnewsky, J. et al. Major microbiota dysbiosis in severe obesity: fate after bariatric surgery. Gut 68, 70–82 (2019).

    CAS  PubMed  Google Scholar 

  125. Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).

    PubMed  Google Scholar 

  126. Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013).

    CAS  PubMed  Google Scholar 

  128. Wang, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).

    PubMed  Google Scholar 

  129. Mayneris-Perxachs, J. & Fernández-Real, J. M. Exploration of the microbiota and metabolites within body fluids could pinpoint novel disease mechanisms. FEBS J. 287, 856–865 (2020).

    CAS  PubMed  Google Scholar 

  130. Canfora, E. E., Meex, R. C. R., Venema, K. & Blaak, E. E. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat. Rev. Endocrinol. 15, 261–273 (2019).

    CAS  PubMed  Google Scholar 

  131. Fan, Y. & Pedersen, O. Gut microbiota in human metabolic health and disease. Nat. Rev. Microbiol 19, 55–71 (2021).

    CAS  PubMed  Google Scholar 

  132. Chimerel, C. et al. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 9, 1202–1208 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Perry, R. J. et al. Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature 534, 213–217 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167–177 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Parmanand, B. A. et al. A decrease in iron availability to human gut microbiome reduces the growth of potentially pathogenic gut bacteria; an in vitro colonic fermentation study. J. Nutr. Biochem. 67, 20–27 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Siegert, I. et al. Ferritin-mediated iron sequestration stabilizes hypoxia-inducible factor-1α upon LPS activation in the presence of ample oxygen. Cell Rep. 13, 2048–2055 (2015).

    CAS  PubMed  Google Scholar 

  137. Koh, A. et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell 175, 947–961.e17 (2018).

    CAS  PubMed  Google Scholar 

  138. Sanchez, K. K. et al. Cooperative metabolic adaptations in the host can favor asymptomatic infection and select for attenuated virulence in an enteric pathogen. Cell 175, 146–158.e15 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Chen, G. Y. & Ayres, J. S. Beyond tug-of-war: iron metabolism in cooperative host-microbe interactions. PLoS Pathog. 16, e1008698 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Weis, S. et al. Metabolic adaptation establishes disease tolerance to sepsis. Cell 169, 1263–1275.e14 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Jais, A. et al. Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man. Cell 158, 25–40 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Loomba, R. et al. The commensal microbe veillonella as a marker for response to an FGF19 analog in NASH. Hepatology 73, 126–143 (2021).

    CAS  PubMed  Google Scholar 

  143. Zhu, L. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57, 601–609 (2013).

    CAS  PubMed  Google Scholar 

  144. Asard, H., Barbaro, R., Trost, P. & Bérczi, A. Cytochromes b 561: ascorbate-mediated trans-membrane electron transport. Antioxid. Redox Signal. 19, 1026–1035 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Mardinoglu, A. et al. Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD. Mol. Syst. Biol. 13, 916 (2017).

    PubMed  PubMed Central  Google Scholar 

  146. Manuel Fernández-Real, J. et al. Adipose tissue R2* signal is increased in subjects with obesity: a preliminary MRI study. Obesity 24, 352–358 (2016).

    Google Scholar 

  147. Zhang, Z. et al. Adipocyte iron levels impinge on a fat-gut crosstalk to regulate intestinal lipid absorption and mediate protection from obesity. Cell Metab. 33, 1624–1639.e9 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Blasco, G. et al. The gut metagenome changes in parallel to waist circumference, brain iron deposition, and cognitive function. J. Clin. Endocrinol. Metab. 102, 2962–2973 (2017).

    PubMed  Google Scholar 

  149. Weinberg, E. D. Survival advantage of the hemochromatosis C282Y mutation. Perspect. Biol. Med. 51, 98–102 (2008).

    PubMed  Google Scholar 

  150. Olakanmi, O., Schlesinger, L. S. & Britigan, B. E. Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages. J. Leukoc. Biol. 81, 195–204 (2007).

    CAS  PubMed  Google Scholar 

  151. Wright, A. C., Simpson, L. M. & Oliver, J. D. Role of iron in the pathogenesis of Vibrio vulnificus infections. Infect. Immun. 34, 503–507 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Quenee, L. E. et al. Hereditary hemochromatosis restores the virulence of plague vaccine strains. J. Infect. Dis. 206, 1050–1058 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Weinberg, E. D. Microbial pathogens with impaired ability to acquire host iron. Biometals 13, 85–89 (2000).

    CAS  PubMed  Google Scholar 

  154. Parmanand, B. et al. Systemic iron reduction by venesection alters the gut microbiome in patients with haemochromatosis. JHEP Rep. Innov. Hepatol. 2, 100154 (2020).

    Google Scholar 

  155. Aigner, E., Feldman, A. & Datz, C. Obesity as an emerging risk factor for iron deficiency. Nutrients 6, 3587–3600 (2014).

    PubMed  PubMed Central  Google Scholar 

  156. Cheng, H. L. et al. The relationship between obesity and hypoferraemia in adults: a systematic review. Obes. Rev. 13, 150–161 (2012).

    CAS  PubMed  Google Scholar 

  157. Teng, I. C. et al. Can diet-induced weight loss improve iron homoeostasis in patients with obesity: a systematic review and meta-analysis. Obes. Rev. 21, e13080 (2020).

    PubMed  Google Scholar 

  158. Moreno-Navarrete, J. M. et al. Obesity is associated with gene expression and imaging markers of iron accumulation in skeletal muscle. J. Clin. Endocrinol. Metab. 101, 1282–1289 (2016).

    CAS  PubMed  Google Scholar 

  159. Gabrielsen, J. S. et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J. Clin. Invest. 122, 3529–3540 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Fernández-Real, J. M. & Ricart, W. Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr. Rev. 24, 278–301 (2003).

    PubMed  Google Scholar 

  161. Huang, J. et al. Iron overload and diabetes risk: a shift from glucose to fatty acid oxidation and increased hepatic glucose production in a mouse model of hereditary hemochromatosis. Diabetes 60, 80–87 (2011).

    CAS  PubMed  Google Scholar 

  162. Janney, A., Powrie, F. & Mann, E. H. Host-microbiota maladaptation in colorectal cancer. Nature 585, 509–517 (2020).

    CAS  PubMed  Google Scholar 

  163. Chi, Y. et al. Cancer cells deploy lipocalin-2 to collect limiting iron in leptomeningeal metastasis. Science 369, 276–282 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Richard, K. L., Kelley, B. R. & Johnson, J. G. Heme uptake and utilization by gram-negative bacterial pathogens. Front. Cell. Infect. Microbiol. 9, 81 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Sestok, A. E., Linkous, R. O. & Smith, A. T. Toward a mechanistic understanding of Feo-mediated ferrous iron uptake. Metallomics 10, 887–898 (2018).

    CAS  PubMed  Google Scholar 

  166. Martins, R. et al. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nat. Immunol. 17, 1361–1372 (2016).

    CAS  PubMed  Google Scholar 

  167. Li, M. et al. The hepatocyte-specific HNF4α/miR-122 pathway contributes to iron overload-mediated hepatic inflammation. Blood 130, 1041–1051 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Schaible, U. E. & Kaufmann, S. H. E. Iron and microbial infection. Nat. Rev. Microbiol. 2, 946–953 (2004).

    CAS  PubMed  Google Scholar 

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Acknowledgements

J.M.F.-R. acknowledges the support of funding from the Instituto de Salud Carlos III (Madrid, Spain) through projects PI15/01934, PI18/01022 and PI21/01361. J.M.-P. acknowledges the support of the Instituto de Salud Carlos III (ISCIII) through project PI20/01090 co-funded by the European Union under the European Regional Development Fund (FEDER) ‘A way to make Europe’ and project CP18/00009 co-funded by the European Union under the European Social Fund (FSE) ‘Investing in your Future’.

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Glossary

Great oxygenation event

Also called the Oxygen Catastrophe or Oxygen Crisis, this period was a time interval when the Earth’s atmosphere and the superficial ocean first experienced an increase in the amount of oxygen, approximately 2.4–2.0 Ga (billion years ago).

Neoproterozoic oxygenation event

An oxygenation event sometime during 850 to 541 Ma (million years ago) in the Neoproterozoic era that supposedly led to the diversification of complex animal life during the Cambrian period (541–485.4 Ma).

Cheating

A bacterial behavioural strategy to exploit cooperative interactions, whereby the cheater (which does not cooperate) increases its own fitness at the expense of the fitness of a cooperating partner.

Haem iron

The form of iron found in blood and muscle haem proteins such as haemoglobin and myoglobin.

Colonic fermentation studies

These studies are designed to evaluate the production of short-chain fatty acids in the colon as a consequence of microbial activity.

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Mayneris-Perxachs, J., Moreno-Navarrete, J.M. & Fernández-Real, J.M. The role of iron in host–microbiota crosstalk and its effects on systemic glucose metabolism. Nat Rev Endocrinol 18, 683–698 (2022). https://doi.org/10.1038/s41574-022-00721-3

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