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Understanding how heme and iron are metabolized by anaerobic commensal bacteria and host-microbiome communities

Award Number: R35GM136390
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Understanding how heme and iron are metabolized by anaerobic commensal bacteria and host-microbiome communities - PROJECT SUMMARY Little is known about how bacteria prevalent in the digestive tract, most of which are anaerobes, take up and process the host’s dietary iron. How this activity influences the efficiency with which iron is absorbed by the host is also unclear. Closing this gap in the knowledge is of both fundamental and biomedical interest. Iron- deficiency and associated anemia are the most prevalent nutritional disorders worldwide, shared by nearly a third of the human population. At the same time, unmetabolized heme iron from red meat diets that remains in the colon has been associated with the development of diseases ranging from inflammation to colon cancer, with microbial activity postulated to play a key role. The long-term goal of this work is to understand how commensal bacteria commonly found in the healthy mammalian gut metabolize iron under the low/no O2 conditions that are prevalent in this ecosystem. The proposed work focuses our group’s knowledge and infrastructure – accrued over 15 years of studying aerobic heme/iron biochemistry at the level of the catalyst, cell, and ecosystem – on this ambitious long-term goal, which we have divided into two overlapping parts. First, we will examine how common gut microbes, most of which are anaerobic, heme auxotrophic bacteria (HAB), metabolize heme. We are focusing on three experimentally tractable HAB which are abundant in humans and which either require heme for respiration (Bacteroides thetaiotaomicron), are capable of but not dependent on heme-mediated respiration (Lactobacillus rhamnosus), or are obligately fermentative but still have limited uses for heme (Clostridium scindens). We will examine genes (via the generation of knock-outs) and gene products that are predicted to play important roles in heme metabolism in these species, but which belong to metabolic pathways that are typically incomplete. At the same time, we will employ discovery-based approaches to identify members of the heme-proteome, using chemically defined growth media, stable-isotope-labeled heme, and spectroscopic analyses with which we have a depth of expertise. Second, we will define how gut bacterial species work together and with the animal host to metabolize heme iron. As part of our experimental approach, we will use knock-out strains and isotopically labeled heme to examine heme metabolism by co-cultures, using subsets of the three HAB above and a common enteric heme heterotroph (Escherichia coli). Cocultures will be studied both in the flask and in mice with defined (gnotobiotic) microbiomes, in collaboration with Prof. Seth Walk (MSU). Understanding anaerobic heme metabolism by commensal bacteria serves the long-term biomedical goal of manipulating the microbiome to facilitate host metabolism of iron, thereby remediating diseases associated with iron deficiency (anemia) or excess (infection, colitis, inflammation, colon cancer).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $320,884 )
2025	2025	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	001	5	2/19/2025	NON-COMPETING CONTINUATION	$320,884
2025	2024	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	4	11/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $320,884

Issue Date FY: 2024 ( Subtotal = $356,537 )
2024	2024	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	001	4	8/6/2024	NON-COMPETING CONTINUATION	$35,653
2024	2024	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	4	2/15/2024	NON-COMPETING CONTINUATION	$320,884
														Subtotal = $356,537

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	3	5/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $356,537 )
2022	2022	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	001	3	6/22/2022	NON-COMPETING CONTINUATION	$35,657
2022	2022	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	3	2/1/2022	NON-COMPETING CONTINUATION	$320,880
														Subtotal = $356,537

Issue Date FY: 2021 ( Subtotal = $356,537 )
2021	2021	MONTANA STATE UNIVERSITY, INC	211 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	2	2/10/2021	NON-COMPETING CONTINUATION	$356,537
														Subtotal = $356,537

Issue Date FY: 2020 ( Subtotal = $356,537 )
2020	2020	MONTANA STATE UNIVERSITY, INC	307 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	1	4/8/2020	NEW	$356,537
														Subtotal = $356,537

Grand Total All Awards = $1,747,032

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Understanding how heme and iron are metabolized by anaerobic commensal bacteria and host-microbiome communities

Award Number: R35GM136390

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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