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Elucidating the role of the microbiome in inducing gut permeability and inflammation

Award Number: R00DK128503
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Elucidating the role of the microbiome in inducing gut permeability and inflammation - Project Summary/Abstract Background – The microbiome affects host metabolism predominantly via metabolites synthesized or modified by gut bacteria. The identity of these metabolites and their mechanisms of action in the host remain largely unknown. Overarching metabolomic analyses have offered a glimpse into classes of microbial molecules and how they associate with disease. Two such types of molecules, bile acids and folates have been shown in recent years to differentially modulate cell signaling pathways. However, the mechanisms of how distinct bile acids and folates induce gut permeability and inflammation, the hallmarks of metabolic syndrome remain largely evasive. Research – Targeted metabolomic analyses in human patient and rodent models of inflammatory diseases will identify bile acid and folate metabolites that differ compared to healthy controls. Preliminary data suggests that microbial unconjugated bile acids induce intestinal permeability, inhibition of which protects against development of Non-Alcoholic Steatohepatitis (NASH). Bile acids are deconjugated by gut bacteria. The K99 phase of the proposal will identify mechanisms of how unconjugated bile acids induce intestinal permeability, and if chronic inhibition of gut bacterial bile acid deconjugation is an effective strategy to rescue gut permeability and NASH. There is sufficient evidence to suggest that bacterially produced polyglutamylated (glu) folates can activate host folate receptor (FR) signaling, which in turn induces the MAP kinase pathway. The K99/R00 transition phase of the proposal will identify and quantify individual folate molecules in diseased cohorts that activate FR. The diseased samples include rodent and human bariatric surgery, NASH, and Inflammatory Bowel Disease (IBD) intestinal contents. A compound library of folates will be generated for high-throughput screening. Inflammatory folate producing bacteria will be isolated to establish causal relationships between strains and gut inflammation. Multiple IBD patient ileal biopsies show an upregulation of the folate hydrolase (FOLH1) gene, the only known purpose of which is to deconjugate poly-glu folates to mono-glu form. In the R00 phase, the mechanism of folate- mediated upregulation of FOLH1 in IBD will be studied. Further, the role of poly-glu folate deconjugation will be studied in the context of intestinal inflammation and metabolism. Alterations in mitochondrial dynamics, one- carbon metabolism, and energy status will be measured following activation or inhibition of the folate/FR/FOLH1 axis. This study will also utilize high-throughput screening to identify molecules that can rescue gut inflammation. Impact on Public Health – Bacteria in the gut encounter bile and dietary nutrients prior to their absorption in the body. Approximately 50% of bile acids and folates absorbed from the intestine is microbially derived. Therefore, studying microbiome-derived metabolites and their activity is important not only for intestinal, but organismal homeostasis. Bile acids are one of the most abundant molecules in the gut, present in millimolar concentrations. Folate concentrations, also high in the gut, vary widely based on folate fortification policies imposed by different countries. Therefore, the study of these metabolites in disease prognosis will reveal strategies for amelioration.


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 = $235,721 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/3/2025	NON-COMPETING CONTINUATION	$235,721
														Subtotal = $235,721

Issue Date FY: 2025 ( Subtotal = $242,477 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/12/2025	NON-COMPETING CONTINUATION	$24,248
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/20/2024	NON-COMPETING CONTINUATION	$218,229
														Subtotal = $242,477

Issue Date FY: 2024 ( Subtotal = $283,206 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/30/2023	EXTENSION WITH OR WITHOUT FUNDS	$249,000
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	2/20/2024	EXTENSION WITH OR WITHOUT FUNDS	$34,206
														Subtotal = $283,206

Grand Total All Awards = $761,404

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Elucidating the role of the microbiome in inducing gut permeability and inflammation

Award Number: R00DK128503

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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