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Microbial regulation of intestinal lipid metabolism and its physiological consequences

Award Number: R01DK131742
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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ABSTRACT Intestinal microbiota are known to promote absorption of dietary fat and to confer susceptibility to diet-induced obesity. However, there exist fundamental gaps in our knowledge of the underlying mechanisms. Our long-term goal is to understand the mechanisms underlying host-microbe interactions and lipid metabolism in the intestine and how they contribute to human physiology and disease. Our preliminary studies in gnotobiotic and conventional mice and zebrafish reveal that microbiota specifically suppress mitochondrial fatty acid oxidation (FAO) in intestinal epithelial cells (IECs), and identify potential upstream microbial and transcriptional regulatory mechanisms. Our genetic analysis in conventional mice also establishes that blocking FAO specifically in IECs promotes dietary fat absorption and modulates intestinal and systemic energy metabolism. The overall objectives of this project are to understand how microbiota regulate FAO in IECs, and define the impact of intestinal FAO on intestinal and systemic physiology. The proposed research will test the central hypothesis that specific bacterial products downregulate FAO in IECs by suppressing FAO gene transcription, which in turn modulates IEC fuel selection and differentiation and promotes positive energy balance. Our rationale is that an improved understanding of how microbes influence intestinal FAO, and how FAO contributes to intestinal physiology and systemic energy metabolism could lead to new strategies for controlling fat metabolism and energy balance in humans and other animals. In Specific Aim 1, we will identify the host and microbial mechanisms by which microbiota suppress FAO in the intestinal epithelium. In Specific Aim 2, we will define the roles of intestinal FAO in fuel selection and differentiation of IECs, and in mediating the influence of the gut microbiota on systemic energy balance. The expected outcomes will vertically advance the field in several ways. First, they will establish intestinal FAO as a major determinant of intestinal and systemic energy balance. Second, they will provide definitive new evidence that intestinal epithelial FAO is a major target of microbial regulation. Third, they will show that the striking resistance of germ-free mice to diet-induced obesity is mediated by intestinal FAO. Finally, they will provide a novel bacteria-host signaling pathway governing intestinal FAO. These results are expected to have a significant impact because they are likely to lead to new microbe- and host-targeted strategies to control energy balance in the context of obesity and malnutrition by manipulating FAO and associated gene expression networks and metabolic pathways in the gut.


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 = $648,968 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/24/2023	NON-COMPETING CONTINUATION	$608,408
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/15/2024	NON-COMPETING CONTINUATION	$40,560
														Subtotal = $648,968

Issue Date FY: 2023 ( Subtotal = $683,874 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/10/2023	NON-COMPETING CONTINUATION	$683,874
														Subtotal = $683,874

Issue Date FY: 2022 ( Subtotal = $722,838 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/2/2021	NEW	$722,838
														Subtotal = $722,838

Grand Total All Awards = $2,055,680

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Microbial regulation of intestinal lipid metabolism and its physiological consequences

Award Number: R01DK131742

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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