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Relating impacts of antibiotics on the gut metabolome and microbiome to host physiology and weight

Award Number: R01DK125382
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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In the US, the obesity crisis is severe—approximately 40% of American adults and 18.5% of American children are clinically obese. Robust evidence suggests that antibiotic overuse may be one contributing factor. The human gut microbiome is a key determinant of health and one crucial function of this community is to regulate host metabolism by fermenting host-indigestible dietary components. A significant body of work also indicates that in both humans and animals, antibiotic use – and especially the use of penicillins and other β-lactams – is strongly associated with obesity. The mechanism of this antibiotic-associated weight gain is not fully understood, although many theories exist, ranging from the induction of systemic inflammation to the reduction of pathogen burden. Understanding how antibiotic-induced perturbations of the microbiome lead to complications such as obesity is an essential step towards alleviating this problem. The proposed work will contribute to this goal by defining the impacts of antibiotics on the metabolic environment of the murine gut, host metabolite availability, and weight gain. Antibiotics can disrupt the microbiome, but what is less appreciated is that this perturbation is associated with a disruption of the metabolic capacity of gut bacteria and a concomitant perturbation of the gut metabolome. The Belenky Lab has defined the impacts of several clinically-relevant antibiotics on the composition and transcriptional response of the murine microbiome. This previous work identified that antibiotics, specifically amoxicillin, change the composition, transcriptional activity, and the metabolome of the murine cecal microbiome. The resulting microbial community is metabolically deficient, enriched for Bacteroidetes, and devoid of Firmicutes. These changes are associated with reduced cecal glucose, reduced butyrate, elevated blood glucose, systemic inflammation, and weight gain. The core hypothesis of this work is that β-lactam antibiotics contribute to inflammation and obesity by eliminating critical bacteria in the Firmicutes phylum, subsequently inducing metabolic dysfunction. The resulting metabolically-deficient gut microbiome is unable to provide critical nutrients and signaling molecules to reduce inflammation and regulate host metabolism. This hypothesis will be tested in the following three aims: Aim 1 – Determine the impact of clinically-relevant antibiotics on the metabolome and taxonomic composition of the murine gut, host physiology, and weight gain. Aim 2 – Utilize microbial consortia to determine if microbial composition associated with antibiotic therapy is linked to the detected metabolite shifts and host impacts. Aim 3 – Microbiome restoration and diet modulation to reduce antibiotic-induced perturbations of the gut metabolome and weight gain. The insight gained from this work will help to identify methodologies that reduce antibiotic-mediated microbiome disruption and may help to combat the obesity crisis. Antibiotics have been miracle drugs, but now that we understand the significant cost to microbiome function, we must find better ways to use them.


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: 2024 ( Subtotal = $579,101 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/27/2024	NON-COMPETING CONTINUATION	$479,718
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	5/30/2024	SUPPLEMENT FOR EXPANSION	$99,383
														Subtotal = $579,101

Issue Date FY: 2023 ( Subtotal = $602,502 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/5/2023	SUPPLEMENT FOR EXPANSION	$99,383
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/26/2023	NON-COMPETING CONTINUATION	$503,119
														Subtotal = $602,502

Issue Date FY: 2022 ( Subtotal = $517,405 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/17/2022	NON-COMPETING CONTINUATION	$517,405
														Subtotal = $517,405

Issue Date FY: 2021 ( Subtotal = $515,919 )
2021	2021	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/12/2021	NON-COMPETING CONTINUATION	$515,919
														Subtotal = $515,919

Issue Date FY: 2020 ( Subtotal = $500,504 )
2020	2020	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/7/2020	NEW	$500,504
														Subtotal = $500,504

Grand Total All Awards = $2,715,431

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Relating impacts of antibiotics on the gut metabolome and microbiome to host physiology and weight

Award Number: R01DK125382

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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