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

Nature Reviews Endocrinology volume 18, pages 683–698 (2022)Cite this article

Subjects

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.

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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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  1. Department of Diabetes, Endocrinology and Nutrition, Institut d’Investigació Biomèdica de Girona (IDIBGI), Girona, Spain

    Jordi Mayneris-Perxachs, José María Moreno-Navarrete & José Manuel Fernández-Real

  2. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain

    Jordi Mayneris-Perxachs, José María Moreno-Navarrete & José Manuel Fernández-Real

  3. Department of Medicine, Universitat de Girona, Girona, Spain

    José Manuel Fernández-Real

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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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