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Gut microbial fermentation products of muscle-derived lactate as mediators of exercise and metabolism

Award Number: R01DK129850
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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PROJECT SUMMARY/ABSTRACT The gut microbiome makes significant contributions to whole-body glucose metabolism and insulin sensitivity, in part, through production of short chain fatty acids (SCFA). Recent evidence suggests that microbial SCFA production may be increased by exercise training, and that SCFA may be important positive regulators of exercise performance and skeletal muscle metabolism and function. However, it is not known how gut microbes could regulate SCFA production in response to exercise. Our work identifies lactate utilizing bacteria (LU-Bac), which can convert lactate to SCFA, as potential sources of SCFA during exercise. As circulating lactate levels increase during moderate to high intensity exercise, combining LU-Bac supplementation with exercise may result in higher levels of circulating SCFA, thus enhancing the metabolic benefits of exercise. Individuals with impaired glucose tolerance have lower gut LU-Bac content, and blunted metabolic and aerobic improvements in response to exercise training. Thus, in addition to improving metabolic health, LU-Bac supplementation may enhance the health benefits of exercise by ameliorating the metabolic defects that lead to impaired training response. We hypothesize that lactate produced by muscle with regular exercise is used by LU-Bac to generate SCFA, which then act on skeletal muscle to improve metabolism and function. We propose this novel gut-muscle axis leads to improved metabolic health and exercise response. One aim of this proposal is to test LU-Bac supplementation as a treatment for impaired glucose tolerance and low response to exercise in mouse models of metabolic disease that partially reflect the pathologies of type 1 and type 2 diabetes. A second aim is to determine the specific contribution of lactate fermentation by LU-Bac to circulating and tissue SCFA levels with exercise, and whether LU-Bac-derived SCFA contribute to the health benefits of exercise training. Our third aim is to define the mechanisms in skeletal muscle by which SCFA lead to enhanced exercise performance and metabolic health. Specifically, we will determine whether SCFA receptors and transporters in muscle are necessary for the positive effects of SCFA on muscle metabolism and function. This work will have a broad impact on the fields of exercise, metabolism, and microbiology by determining the mechanisms by which the microbiome can enhance muscle metabolism and adaptation to exercise. We anticipate our results will lead to development of a live biotherapeutic to improve exercise response and metabolic health.


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 = $560,231 )
2024	2024	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/22/2024	NON-COMPETING CONTINUATION	$560,231
														Subtotal = $560,231

Issue Date FY: 2023 ( Subtotal = $634,993 )
2023	2023	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/23/2023	NON-COMPETING CONTINUATION	$634,993
														Subtotal = $634,993

Issue Date FY: 2022 ( Subtotal = $588,659 )
2022	2022	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/21/2022	NEW	$588,659
														Subtotal = $588,659

Grand Total All Awards = $1,783,883

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Gut microbial fermentation products of muscle-derived lactate as mediators of exercise and metabolism

Award Number: R01DK129850

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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