Gut microbiota regulates systemic iron homeostasis in mice by modulating intestinal HIF-2α activity

Seminar Details
Wednesday, September 6, 2017 - 9:00am to 10:00am


Nupur K. Das MBBS, PhD
Postdoctoral Research Fellow, Yatrik Shah Lab
Department of Molecular and Integrative Physiology
University of Michigan


5623 Med. Sci. II  (Wheeler Seminar Room)


Iron is essential for survival of all living organisms. Dietary acquisition and intestinal absorption in humans (and other mammals) is the only way by which systemic iron requirement is fulfilled. In addition, we harbor a diverse group of microbial population in our intestines that also rely on host diet for their iron. It is unclear if and how our gut commensal microbiota compete with the host intestinal iron absorption pathways. The germ free (GF) and specific pathogen free (SPF) mice fed with iron-sufficient (350 ppm), moderately iron-containing (35 ppm) and iron-deficient (< 5ppm or FD) diets for 2 weeks demonstrated a significant resistance to iron deficiency anemia in the GF compared to SPF mice.  This provides the first evidence of a reciprocal competition between host and commensals for limiting dietary iron. Interestingly commensals have an active inhibitory mechanism that leads to a decrease in host iron transport system. The GF mice on all three iron diets (350, 35 and <5 ppm) exhibited significant induction of duodenal iron transporters, divalent metal transporter 1(DMT1), duodenal cytochrome ferric reductase (Dcytb1), and ferroportin (Fpn1). The expressions of DMT1, Dcytb1 and Fpn1 are maximally induced during iron deficiency (<5 ppm diet), but GF mice on iron deficient diet showed even higher level of duodenal expression of these three transporters. The resistance to anemia and commensal-induced modulation of host iron transporters could be recapitulated in mice administered broad-spectrum antibiotics, demonstrating this is not due to developmental defects in GF mice. All three transporters are regulated by the hypoxic transcription factor HIF-2a. Intestinal HIF-2a knockout mice do not have an increase in iron transporters following antibiotic treatment as observed in wild-type mice, suggesting that gut microbiota suppresses the basal HIF-2α activity.To further understand the mechanism by which gut microbiota inhibit intestinal HIF-2a signaling, metabolites (aqueous and organic phases) from GF and SPF fecal samples were extracted, and HCT116 colon cancer cells were treated in presence of HIF-2a inducing agents (hypoxia or iron chelation). Interestingly, organic phase of the fecal metabolites from SPF significantly suppressed HIF-2a induction while the organic phase fecal metabolites from GF mice did not suppress. This data demonstrates that one or more gut microbial metabolite plays a dominant role in physiological suppression of intestinal HIF-2a expression and activity. Moreover, the microbial community analysis by 16sRNA sequencing in SPF fecal and duodenal isolates revealed that iron deficient diet favored growth of Lactobacillus species, L. johnsonii and L. reuteri being the most abundant. Current studies are aimed at identifying the bacterial species, the metabolite(s) and delineation of the specific mechanisms leading to commensal-mediated modulation of the host iron response.

Sponsored by the Host Microbiome Initiative