Ironing the Gut

It is well known that iron is not only an essential nutrient for mammals but also serves as a growth factor for most bacteria, including those residing in the intestine, known as the microbiome. Accordingly, intestinal bacteria compete for iron within the gut by different mechanisms. That  provides a growth advantage to those microbes which have more sophisticated strategies to acquire the metal needed for their proliferation and pathogenicity1. In addition, increased iron availability in the intestine severely changes the composition of the gut microbiome with the expansion of more virulent, potentially pathogenic bacteria2. The struggle for iron is now well appreciated as a central mechanism in host pathogen interaction and the outcome of infections3.  In a recent paper published in Cell Metabolism, Das and co-workers (2020) add a new facet to this picture as they provide novel evidence that the gut microbiome affects host iron homeostasis by modulating iron absorption4.  They noted that germ free (GF) but not specific pathogen free C57BL6 mice developed anemia when fed an iron poor diet, which already implied that bacteria in the gut may compete with host iron uptake. Mechanistically, this could be attributed to inhibition of hypoxia inducible factor 2 alpha (HIF2alpha) expression in the intestine by Lactobacilli with subsequent alterations of HIF2alpha mediated effects on transmembrane iron transfer from the intestinal lumen to the circulation.  Das and co-workers found that intestinal microbes sense iron deficiency and produce metabolites, namely, 1,3-diaminopropane (DAP) and reuterin, which block HIF2 heterodimerisation and thus its biological activity resulting in dietary iron accumulation within enterocyte ferritin. These data first suggest, that mice kept under SPF conditions may not be an ideal model to study host iron homeostasis as effects of intestinal microbes and their secreted products will be missed. Secondly, modulation of intestinal bacterial composition may open a new therapeutic avenue, as specific compositions of probiotics  could affect dietary iron absorption in either direction, for treatment of iron overload conditions (more Lactobacilli) or to ameliorate iron absorption (bacteria outcompeting Lactobacilli, antibiotics) in subjects with iron deficiency.    

1.            Skaar EP, Raffatellu M. Metals in infectious diseases and nutritional immunity. Metallomics. 2015;7(6):926-928.

2.            Jaeggi T, Kortman GA, Moretti D, et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut. 2015;64(5):731-742.

3.            Nairz M, Schroll A, Sonnweber T, Weiss G. The struggle for iron – a metal at the host-pathogen interface. Cell Microbiol. 2010;12(12):1691-1702.

4.            Das NK, Schwartz AJ, Barthel G, et al. Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis. Cell Metab. 2020;31(1):115-130 e116.

Günter Weiss, Medical University of Innsbruck, Austria  (guenter.weiss@i-med.ac.at)