# Bile Acids

> **NIH NIH F31** · RUTGERS, THE STATE UNIV OF N.J. · 2021 · $42,079

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10147609
- **Project number:** 5F31AT010981-02
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** Kevin Michael Tveter
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $42,079
- **Award type:** 5
- **Project period:** 2020-06-15 → 2023-06-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147609

## Citation

> US National Institutes of Health, RePORTER application 10147609, Bile Acids (5F31AT010981-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10147609. Licensed CC0.

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