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The interplay between nutrient availability and secondary bile acid metabolism in commensal Clostridia mediates colonization resistance against C. difficile

Award Number: R35GM149222
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/24/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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The interplay between nutrient availability and secondary bile acid metabolism in commensal Clostridia mediates colonization resistance against C. difficile - Project Summary/Abstract In the Theriot laboratory we apply cutting-edge technology and high-throughput methods to analyze the gut microbiome and metabolome using a range of experimental techniques and animal models. We leverage many approaches that span diverse fields including bacterial genetics, bacterial physiology, protein engineering, biochemistry, and apply a variety of omic approaches (microbiomics, transcriptomics, proteomics, and metabolomics) in vitro and in vivo to define the mechanisms behind how the gut microbiota provides colonization resistance against C. difficile. One of the many essential functions of the indigenous gut microbiota is its ability to maintain colonization resistance and to prevent establishment and growth of pathogens in the gut. There has been a great deal of research in this area trying to define the mechanisms by which the gut microbiota mediates colonization resistance. Potential mechanisms include competition for nutrients, taking up physical space or biomass, production of inhibitory products, and shaping the host immune response. A popular model organism used to interrogate these mechanisms is Clostridioides difficile due to its exquisite sensitivity to changes in the gut microbiota structure and function. C. difficile is an anaerobic, spore-forming, Gram-positive bacterium first isolated in 1935 and the causative agent for C. difficile infection (CDI). Unlocking how C. difficile is able to benefit from the loss of colonization resistance in the gut has major implications for development of therapeutics for prevention and treatment of CDI. My long-term goal is to understand how the gut microbiota mediates colonization resistance against C. difficile. The overall objective of this application is to determine the relationship between nutrient availability (amino acids) and bile acid metabolism in the context of colonization resistance against C. difficile. Based on preliminary data our hypothesis is that amino acid availability influences secondary bile acid production by commensal Clostridia, which will alter colonization resistance against C. difficile. In order to investigate this hypothesis, we plan to alter amino acid abundances in defined and rich media in vitro, and use defined diets in vivo to understand how this impacts secondary bile acid production of commensal Clostridia. Leveraging our robust and reproducible germfree and antibiotic treated mouse models of CDI, we will determine how these metabolic processes affect the establishment and growth of C. difficile, as well as the surrounding gut microbial community. Using novel platforms like LC-IMS-MS and Protein-SIP, we will define the gut metabolome and metaproteome in the context of colonization resistance. The contribution of the proposed research is significant as it seeks to move away from untargeted therapies like FMT and move toward a targeted approach, whereby we can use diet (amino acids) to control secondary bile acid production by commensal Clostridia, restoring colonization resistance against C. difficile. The findings in this proposal will advance understanding of microbe-microbe interactions, host-microbe interactions, and improve microbiome-based therapeutics. Beyond C. difficile it has the potential to allow us to intelligently design customized therapeutic interventions to target human health conditions in the complex ecological environment of the human intestine.


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: 2026 ( Subtotal = $380,000 )
2026	2026	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	4	4/7/2026	NON-COMPETING CONTINUATION	$380,000
														Subtotal = $380,000

Issue Date FY: 2025 ( Subtotal = $380,000 )
2025	2025	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	001	3	4/7/2025	NON-COMPETING CONTINUATION	$380,000
2025	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	2	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $380,000

Issue Date FY: 2024 ( Subtotal = $380,000 )
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	001	2	6/21/2024	NON-COMPETING CONTINUATION	$38,000
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	2	3/28/2024	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $380,000

Issue Date FY: 2023 ( Subtotal = $380,000 )
2023	2023	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Biomedical Research and Research Training	000	1	4/24/2023	NEW	$380,000
														Subtotal = $380,000

Grand Total All Awards = $1,520,000

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The interplay between nutrient availability and secondary bile acid metabolism in commensal Clostridia mediates colonization resistance against C. difficile

Award Number: R35GM149222

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/24/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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