Sunday, July 6, 2025 7/6/2025

Bile Acids

Award Number: F31AT010981
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/15/2020
PERIOD OF PERFORMANCE END DATE: 03/18/2023

Group Awards By:

View Award Description

Bile Acids - This proposal aims to elucidate how proanthocyanidin-rich extracts of grape polyphenols (GPs) modulate bile acid (BA) signaling to farnesoid X-receptor (FXR) resulting in improved glucose metabolism. Using intestine- specific (FxrΔIE) and liver-specific (FxrΔL) FXR knockout mice and derived ileal organoids, we will investigate whether GP-induced glycemic improvements are due to inhibition of intestinal and/or hepatic FXR signaling. We will also determine if GPs directly sequester secondary bile acids (SBAs) or indirectly leads to their depletion. Consumption of polyphenol-rich foods is associated with reduced risk of chronic disease; however, many dietary polyphenols are poorly absorbed raising questions about their mechanism(s) of action. Metabolic benefits of polyphenols are likely driven by changes in the gut microbiota. Prior work showed that GPs improved glucose metabolism in high-fat diet (HFD)-fed wild type (WT) mice due to GP-induced changes in the gut microbiota that correlated with attenuated body weight, metabolic endotoxemia (i.e. lower serum lipopolysaccharide (LPS)), tissue inflammation, as well as increased tight junction protein expression. Our recent data showed that GP supplementation mitigated hyperglycemia in diabetic db/db mice independent of changes in obesity, gut barrier integrity, and inflammation. Rather, GP-induced changes in the gut microbiota of db/db mice promoted a BA profile that suppressed intestinal FXR activity and FXR responsive pathways. Selective inhibition of intestinal FXR has been correlated with improved glucose metabolism and decreased ceramide synthesis in mice treated with antidiabetic drug, metformin. Metformin altered the gut microbiota and BA pool, reduced ceramide production, and lowered expression of hepatic gluconeogenic markers [Sun et al., 2018]. Dual antagonism of FXR in liver and intestine may promote cholestasis [Kong et al., 2012], therefore differentiating tissue specific effects of GPs on FXR activity is important. 16S rRNA V4 amplicon sequencing showed that GP supplementation depleted genera implicated in secondary BA (SBAs) metabolism concomitant with a dramatic decrease in serum SBAs and an increase in primary BAs (PBAs). Intestinal and liver tissues of mice supplemented with GPs had: 1) decreased gene expression of Shp and Fgf15, markers of FXR activity; 2) lowered expression of Smpd3, Cers4, and Sptlc2 , FXR responsive genes critical for ceramide synthesis; and 3) increased expression of Cyp7a1, an enzyme responsible for PBA synthesis. Gut organoids were used to differentiate the direct effects of BAs on intestinal FXR activation and ceramide synthesis and revealed GP-induced a BA profile antagonistic to intestinal FXR. We propose to 1) investigate glucoregulatory effect of GP supplementation in FxrΔIE and FxrΔL to uncover if GPs are antagonistic to liver FXR signaling mechanisms and distinguish the ability of GPs to sequester SBAs agonistic to FXR within the ileum. 2) Use ileal gut organoids derived from FXR∆IE to determine the requirement of intestinal FXR for GP-mediated regulation of ceramide biosynthesis and 3) directly determine whether anaerobic cultures of ileal content collected from GP supplemented mice lack ability to produce SBAs.


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 = -$34,031 )
2024	2022	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Research and Training in Complementary and Integrative Health	000	3	12/28/2023	NON-COMPETING CONTINUATION	-$34,031
														Subtotal = -$34,031

Issue Date FY: 2023 ( Subtotal = -$6,888 )
2023	2022	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Research and Training in Complementary and Integrative Health	000	3	9/20/2023	NON-COMPETING CONTINUATION	-$6,888
														Subtotal = -$6,888

Issue Date FY: 2022 ( Subtotal = $42,795 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Research and Training in Complementary and Integrative Health	000	3	5/20/2022	NON-COMPETING CONTINUATION	$42,796
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Research and Training in Complementary and Integrative Health	001	3	5/24/2022	NON-COMPETING CONTINUATION	-$1
														Subtotal = $42,795

Issue Date FY: 2021 ( Subtotal = $42,079 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Research and Training in Complementary and Integrative Health	000	2	5/21/2021	NON-COMPETING CONTINUATION	$42,079
														Subtotal = $42,079

Issue Date FY: 2020 ( Subtotal = $41,563 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Research and Training in Complementary and Integrative Health	000	1	4/2/2020	NEW	$41,563
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Research and Training in Complementary and Integrative Health	001	1	4/2/2020	NEW	$0
														Subtotal = $41,563

Grand Total All Awards = $85,518

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Bile Acids

Award Number: F31AT010981

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/15/2020

PERIOD OF PERFORMANCE END DATE: 03/18/2023

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer