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Defining the Quantitative Functional Mechanisms that Underly Gut Microbiome-Diet Interactions Contributing to Human Energy Balance

Award Number: R01DK140328
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Defining the Quantitative Functional Mechanisms that Underly Gut Microbiome-Diet Interactions Contributing to Human Energy Balance - Project Summary The obesity epidemic continues to afflict populations globally. The literature is replete with observational studies purporting a role of the gut microbiome in body weight regulation. The main gap in the development of microbiome-targeted therapeutics to treat obesity is a deep understanding of the causal mechanisms by which microbes impact energy balance in humans. In a first of its kind study, we implemented a quantitative bioenergetics paradigm in which human energy balance was deeply and precisely phenotyped (energy intake, expenditure and fecal energy loss) during an inpatient randomized controlled crossover feeding study. We used diets that delivered minimal (Western Diet; WD) versus high (Microbiome Enhancer Diet; MBD) amounts of microbiota fermentable dietary substrates to the colon to reprogram the gut microbiome within individuals. We uncovered diet-host-microbe interactions that impacted human energy balance via increased fecal energy loss and thus, lower metabolizable energy (ME) that was due in part to an increase in microbial biomass on the MBD as compared to the WD. To advance this work, we need to understand the quantitative and functional mechanisms by which the gut microbiome impacts ME when exposed to different diets. We propose two aims to accomplish this. In Aim 1A, we will determine the amount of fecal energy loss that is due to shunting of energy from the human diet towards biomass expansion (and thus away from the host) to test the hypothesis that the dietary energy diverted from host towards biomass expansion is large enough to promote lower ME (net negative energy balance) on the MBD vs. the WD. In Aim 1B, we will perform absolute quantification of microbial species to determine which ones are the dominant players in biomass expansion and their proportional contribution to fecal biomass energy. In Aim 2A, we will implement a novel integrated multi-omics workflow aimed at determining microbial functions and substrate preferences in vivo. These data will tell us what the microbes “eat”, which specific species compete for the same dietary substrates, and the associated functions of the microbial community when specific dietary substrates are available. These data will be validated in Aim 2B by performing ex vivo experiments to change the absolute abundance of specific microbes that contribute most to biomass by addition of the preferred substrates of those microbes. The overall outcome of this project is that we will have an unprecedented understanding of the quantitative microbial mechanisms that drive human energy balance.


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 = $568,099 )
2025	2025	ADVENTIST HEALTH SYSTEM/SUNBELT INC	601 E ROLLINS ST	ORLANDO	FL	32803	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/15/2025	NON-COMPETING CONTINUATION	$568,099
														Subtotal = $568,099

Issue Date FY: 2024 ( Subtotal = $680,299 )
2024	2024	ADVENTIST HEALTH SYSTEM/SUNBELT INC	601 E ROLLINS ST	ORLANDO	FL	32803	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	7/16/2024	NEW	$0
2024	2024	ADVENTIST HEALTH SYSTEM/SUNBELT INC	601 E ROLLINS ST	ORLANDO	FL	32803	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/10/2024	NEW	$680,299
														Subtotal = $680,299

Grand Total All Awards = $1,248,398

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Defining the Quantitative Functional Mechanisms that Underly Gut Microbiome-Diet Interactions Contributing to Human Energy Balance

Award Number: R01DK140328

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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