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.
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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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).
Muchowska, K. B., Varma, S. J. & Moran, J. Synthesis and breakdown of universal metabolic precursors promoted by iron. Nature 569, 104–107 (2019).
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).
Knoll, A. H. & Nowak, M. A. The timetable of evolution. Sci. Adv. 3, e1603076 (2017).
Ganz, T. Systemic iron homeostasis. Physiol. Rev. 93, 1721–1741 (2013).
Posey, J. E. & Gherardini, F. C. Lack of a role for iron in the Lyme disease pathogen. Science 288, 1651–1653 (2000).
Fernández-Real, J. M. & Manco, M. Effects of iron overload on chronic metabolic diseases. Lancet Diabetes Endocrinol. 2, 513–526 (2014).
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).
Mayneris-Perxachs, J. et al. Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome. Microbiome 9, 104 (2021).
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).
Seyoum, Y., Baye, K. & Humblot, C. Iron homeostasis in host and gut bacteria — a complex interrelationship. Gut Microbes 13, 1–19 (2021).
Toyokuni, S. Iron and thiols as two major players in carcinogenesis: friends or foes? Front. Pharmacol. 5, 200 (2014).
Shayeghi, M. et al. Identification of an intestinal heme transporter. Cell 122, 789–801 (2005).
Qiu, A. et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127, 917–928 (2006).
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).
Mahroum, N. et al. Ferritin - from iron, through inflammation and autoimmunity, to COVID-19. J. Autoimmun. 126, 102778 (2022).
Cohen, L. A. et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 116, 1574–1584 (2010).
Das, N. K. et al. Microbial metabolite signaling is required for systemic iron homeostasis. Cell Metab. 31, 115–130.e6 (2020).
Wilkinson, N. & Pantopoulos, K. The IRP/IRE system in vivo: insights from mouse models. Front. Pharmacol. 5, 176 (2014).
Volz, K. The functional duality of iron regulatory protein 1. Curr. Opin. Struct. Biol. 18, 106–111 (2008).
Galy, B. et al. Iron regulatory proteins control a mucosal block to intestinal iron absorption. Cell Rep. 3, 844–857 (2013).
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).
Simonsen, K. T. et al. Quantitative proteomics identifies ferritin in the innate immune response of C. elegans. Virulence 2, 120–130 (2011).
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).
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).
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).
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).
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).
Bergamaschi, G. et al. Intestinal expression of genes implicated in iron absorption and their regulation by hepcidin. Clin. Nutr. 36, 1427–1433 (2017).
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).
Yamamoto, K. et al. Interplay of adipocyte and hepatocyte: leptin upregulates hepcidin. Biochem. Biophys. Res. Commun. 495, 1548–1554 (2018).
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).
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).
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).
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).
Pechlaner, R. et al. Inadequate hepcidin serum concentrations predict incident type 2 diabetes mellitus. Diabetes Metab. Res. Rev. 32, 187–192 (2016).
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).
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).
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).
Yang, J. et al. An iron delivery pathway mediated by a lipocalin. Mol. Cell 10, 1045–1056 (2002).
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).
Ratledge, C. & Dover, L. G. Iron metabolism in pathogenic bacteria. Annu. Rev. Microbiol. 54, 881–941 (2000).
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).
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).
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).
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).
Ellison, R. T. The effects of lactoferrin on gram-negative bacteria. Adv. Exp. Med. Biol. 357, 71–90 (1994).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Wang, H. et al. Elevated vitreous Lipocalin-2 levels of patients with proliferative diabetic retinopathy. BMC Ophthalmol. 20, 260 (2020).
Soares, M. P. & Hamza, I. Macrophages and iron metabolism. Immunity 44, 492–504 (2016).
Winn, N. C., Volk, K. M. & Hasty, A. H. Regulation of tissue iron homeostasis: the macrophage ‘ferrostat’. JCI Insight 5, E376–E391 (2020).
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).
Orr, J. S. et al. Obesity alters adipose tissue macrophage iron content and tissue iron distribution. Diabetes 63, 421–432 (2014).
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).
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).
Corna, G. et al. The repair of skeletal muscle requires iron recycling through macrophage ferroportin. J. Immunol. 197, 1914–1925 (2016).
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).
McCance, R. A. & Widdowson, E. M. The absorption and excretion of iron following oral and intravenous administration. J. Physiol. 94, 148–154 (1938).
Dostal, A. et al. Iron modulates butyrate production by a child gut microbiota in vitro. MBio 6, e01453-15 (2015).
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).
Cassat, J. E. & Skaar, E. P. Iron in infection and immunity. Cell Host Microbe 13, 509–519 (2013).
Zhang, Y., Sen, S. & Giedroc, D. P. Iron acquisition by bacterial pathogens: beyond tris-catecholate complexes. ChemBioChem 21, 1955–1967 (2020).
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).
Andrews, S. C., Robinson, A. K. & Rodríguez-Quiñones, F. Bacterial iron homeostasis. FEMS Microbiol. Rev. 27, 215–237 (2003).
Bradley, J. M. et al. Bacterial iron detoxification at the molecular level. J. Biol. Chem. 295, 17602–17623 (2020).
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).
Krewulak, K. D. & Vogel, H. J. Structural biology of bacterial iron uptake. Biochim. Biophys. Acta 1778, 1781–1804 (2008).
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).
Kramer, J., Özkaya, Ö. & Kümmerli, R. Bacterial siderophores in community and host interactions. Nat. Rev. Microbiol. 18, 152–163 (2020).
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).
Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).
Chareyre, S. & Mandin, P. Bacterial iron homeostasis regulation by sRNAs. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.RWR-0010-2017 (2018).
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).
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).
Sivaprakasam, S. et al. Hereditary hemochromatosis promotes colitis and colon cancer and causes bacterial dysbiosis in mice. Biochem. J. 477, 3867–3883 (2020).
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).
Weinberg, E. D. The Lactobacillus anomaly: total iron abstinence. Perspect. Biol. Med. 40, 578–583 (1997).
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).
Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–549 (2011).
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).
Lievin, V. et al. Bifidobacterium strains from resident infant human gastrointestinal microflora exert antimicrobial activity. Gut 47, 646–652 (2000).
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).
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).
Werner, T. et al. Depletion of luminal iron alters the gut microbiota and prevents Crohn’s disease-like ileitis. Gut 60, 325–333 (2011).
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).
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).
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).
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).
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).
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).
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).
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).
Lopez, C. A. & Skaar, E. P. The impact of dietary transition metals on host-bacterial interactions. Cell Host Microbe 23, 737–748 (2018).
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).
Seiwert, N. et al. Chronic intestinal inflammation drives colorectal tumor formation triggered by dietary heme iron in vivo. Arch. Toxicol. 95, 2507–2522 (2021).
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).
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).
Deschemin, J. C. et al. The microbiota shifts the iron sensing of intestinal cells. FASEB J. 30, 252–261 (2016).
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).
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).
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).
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).
Bouglé, D. et al. Influence of short-chain fatty acids on iron absorption by proximal colon. Scand. J. Gastroenterol. 37, 1008–1011 (2002).
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).
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).
Saha, P. et al. Gut microbiota conversion of dietary ellagic acid into bioactive phytoceutical urolithin a inhibits heme peroxidases. PLoS One 11, e0156811 (2016).
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).
Aron-Wisnewsky, J. et al. Major microbiota dysbiosis in severe obesity: fate after bariatric surgery. Gut 68, 70–82 (2019).
Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).
Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).
Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013).
Wang, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).
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).
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).
Fan, Y. & Pedersen, O. Gut microbiota in human metabolic health and disease. Nat. Rev. Microbiol 19, 55–71 (2021).
Chimerel, C. et al. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 9, 1202–1208 (2014).
Perry, R. J. et al. Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature 534, 213–217 (2016).
Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167–177 (2009).
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).
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).
Koh, A. et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell 175, 947–961.e17 (2018).
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).
Chen, G. Y. & Ayres, J. S. Beyond tug-of-war: iron metabolism in cooperative host-microbe interactions. PLoS Pathog. 16, e1008698 (2020).
Weis, S. et al. Metabolic adaptation establishes disease tolerance to sepsis. Cell 169, 1263–1275.e14 (2017).
Jais, A. et al. Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man. Cell 158, 25–40 (2014).
Loomba, R. et al. The commensal microbe veillonella as a marker for response to an FGF19 analog in NASH. Hepatology 73, 126–143 (2021).
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).
Asard, H., Barbaro, R., Trost, P. & Bérczi, A. Cytochromes b 561: ascorbate-mediated trans-membrane electron transport. Antioxid. Redox Signal. 19, 1026–1035 (2013).
Mardinoglu, A. et al. Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD. Mol. Syst. Biol. 13, 916 (2017).
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).
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).
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).
Weinberg, E. D. Survival advantage of the hemochromatosis C282Y mutation. Perspect. Biol. Med. 51, 98–102 (2008).
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).
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).
Quenee, L. E. et al. Hereditary hemochromatosis restores the virulence of plague vaccine strains. J. Infect. Dis. 206, 1050–1058 (2012).
Weinberg, E. D. Microbial pathogens with impaired ability to acquire host iron. Biometals 13, 85–89 (2000).
Parmanand, B. et al. Systemic iron reduction by venesection alters the gut microbiome in patients with haemochromatosis. JHEP Rep. Innov. Hepatol. 2, 100154 (2020).
Aigner, E., Feldman, A. & Datz, C. Obesity as an emerging risk factor for iron deficiency. Nutrients 6, 3587–3600 (2014).
Cheng, H. L. et al. The relationship between obesity and hypoferraemia in adults: a systematic review. Obes. Rev. 13, 150–161 (2012).
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).
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).
Gabrielsen, J. S. et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J. Clin. Invest. 122, 3529–3540 (2012).
Fernández-Real, J. M. & Ricart, W. Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr. Rev. 24, 278–301 (2003).
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).
Janney, A., Powrie, F. & Mann, E. H. Host-microbiota maladaptation in colorectal cancer. Nature 585, 509–517 (2020).
Chi, Y. et al. Cancer cells deploy lipocalin-2 to collect limiting iron in leptomeningeal metastasis. Science 369, 276–282 (2020).
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).
Sestok, A. E., Linkous, R. O. & Smith, A. T. Toward a mechanistic understanding of Feo-mediated ferrous iron uptake. Metallomics 10, 887–898 (2018).
Martins, R. et al. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nat. Immunol. 17, 1361–1372 (2016).
Li, M. et al. The hepatocyte-specific HNF4α/miR-122 pathway contributes to iron overload-mediated hepatic inflammation. Blood 130, 1041–1051 (2017).
Schaible, U. E. & Kaufmann, S. H. E. Iron and microbial infection. Nat. Rev. Microbiol. 2, 946–953 (2004).
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’.
The authors declare no competing interests.
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- 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).
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