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Enteroendocrine cells sense gut bacteria and activate a gut-brain pathway

Award Number: K01DK125527
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/20/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Enteroendocrine cells sense gut bacteria and activate a gut-brain pathway - PROJECT SUMMARY Microorganisms residing in the intestinal lumen have a significant impact on brain function and behavior. Perturbation of microbe-gut-brain communication is believed to be involved in the pathogenesis of well-known gut-brain disorders such as irritable bowel syndrome (IBS) and related functional GI disorders. However, there is lack of understanding of the precise microbial mechanisms and the cellular pathways that allow gut microbes to communicate with the brain. To address this critical knowledge gap, the applicant has pioneered the zebrafish system for the study of microbe-gut-brain communication. Using in vivo real-time measurements of cell activity in zebrafish, the applicant’s recent research revealed that specific gut bacteria directly activate specialized sensory cells in the intestine epithelium, enteroendocrine cells (EECs), through the receptor transient receptor potential ankyrin A1 (Trpa1). Microbial, pharmacological, or optogenetic activation of Trpa1+EECs directly activates enteric neurons and stimulates vagal sensory ganglia. Preliminary studies identified a distinct subset of bacterial derived tryptophan catabolites as novel agonists that potently activate Trpa1. The objective of the proposed research is to determine the precise molecular mechanism by which enteric bacteria activate the EEC- vagal sensory pathway to modulate brain activity. The central hypothesis is that bacterial secreted tryptophan catabolites stimulate Trpa1 in EECs to activate vagal sensory neurons through a novel EEC secreted signal peptide, pituitary adenylate cyclase activating polypeptide (Pacap). To test this, the applicant will first use molecular microbiology and zebrafish gnotobiotic approaches to define the microbial pathway and mechanism that activates EEC Trpa1 signaling. Second, the applicant will use in vivo vagal calcium imaging, optochemical and genetic manipulation to identify the specific subtype of EECs that transmit enteric bacterial information to the vagus. Finally, the applicant will use pharmaceutical, genetic and cell transplantation approaches to define the EEC signaling peptide that transmits bacterial information from the gut lumen to the vagus. The proposed research is expected to make a significant new contribution to our understanding of the molecular mechanisms and cellular pathways by which enteric bacteria communicate with the brain. The interdisciplinary experimental approach together with the comprehensive career development plan will extend the applicant’s training from gastroenterology into vagal and brain physiology as well as molecular microbiology. A diverse team of established investigators at Duke University and UNC Chapel Hill, with expertise ranging from host-microbe interaction to gut-brain physiology to bacteriology, will oversee the applicant’s career development during the award period by contributing intellectually to her research training, providing mentorship, and offering career advice. This 5-year career development award will provide the applicant with the necessary professional and scientific skills to be an independent and successful microbiota-gut-brain scientist.


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 = $0 )
2026	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/8/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $150,482 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/8/2025	NON-COMPETING CONTINUATION	$150,482
														Subtotal = $150,482

Issue Date FY: 2024 ( Subtotal = $150,482 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/29/2024	NON-COMPETING CONTINUATION	$150,482
														Subtotal = $150,482

Issue Date FY: 2023 ( Subtotal = $150,482 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	5/4/2023	NON-COMPETING CONTINUATION	$150,482
2023	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	11/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$86,739
2023	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/29/2022	NEW	-$86,739
														Subtotal = $150,482

Issue Date FY: 2022 ( Subtotal = $150,482 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$150,482
2022	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/8/2022	NEW	$0
														Subtotal = $150,482

Issue Date FY: 2021 ( Subtotal = $126,892 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/20/2021	NEW	$126,892
														Subtotal = $126,892

Grand Total All Awards = $728,820

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Enteroendocrine cells sense gut bacteria and activate a gut-brain pathway

Award Number: K01DK125527

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/20/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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