Iron-deficiency and associated anemia are the most prevalent nutritional disorders worldwide, shared by nearly a third of the human population. These disorders persist even though the diet often contains sufficient iron. Extensive effort focused on discovering how to improve the bioavailability of dietary iron and supplements. However, little is known about how the complex microbiota within the digestive tract, which take up and process host dietary iron for their own needs, influence the efficiency with which iron is absorbed by the host. At the same time, unmetabolized heme iron from red meat diets that remains in the colon has been associated with the development of colon cancer, with microbial activity postulated to play a key role. Understanding how microbial iron metabolism promotes or ameliorates human disease represents a critical knowledge gap. The long-term goal of this work is to treat iron deficiency and associated iron-related disorders by probiotic therapies and/or engineered manipulation of the gut microbiome, supporting the mission of the NIDDK. In this proposal, we hypothesize that, because bacteria absorb iron for their own needs, the microbiome acts as a sink for dietary iron, increasing its residence time in the gut, altering its chemical speciation, and minimizing fecal excretion. Specifically, we hypothesize that the limited O2 environment of the digestive tract and the varying ability of the resident microbiota to use it are key variables controlling the rate of uptake and ultimate fate of iron. These hypotheses will be tested via two aims.
In Aim 1, we will examine the uptake, heme/non-heme source dependence, and fate of iron supplied to representative gut bacteria and consortia under controlled O2 atmospheres. These ex situ experiments will allow us to predict how bacteria might interact with dietary iron inside the digestive tract of an animal host.
In Aim 2, we will determine how the presence of specific microbes and microbial communities influence the bioavailability and metabolic fate of iron in germ free mice compared to mice with defined microbiomes, including the monocultures and consortia from Aim 1 and complex murine and human microbiomes. Successful completion of this work will provide a first-ever assessment of the bacterial contribution to iron metabolism in an animal host. It will establish working experimental systems and collaborative relationships that will allow for increasingly sophisticated future investigations.

Public Health Relevance

Iron-deficiency and associated anemias are widespread nutritional disorders worldwide, in spite of sufficient iron in many diets. Undigested heme-iron from red meat is likewise associated with the development of colon cancer. The proposed work will show how the metabolism of dietary iron by microbes in the digestive tract ultimately influences host uptake of iron, leading toward the development of probiotic strategies for enhancing absorption of nutritional iron and offsetting disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK114607-01
Application #
9376511
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Maruvada, Padma
Project Start
2017-09-01
Project End
2019-07-31
Budget Start
2017-09-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Montana State University - Bozeman
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717
Choby, Jacob E; Grunenwald, Caroline M; Celis, Arianna I et al. (2018) Staphylococcus aureus HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis. MBio 9: