# Pomegranate Extract and Its Microbial Metabolite Urolithin A Suppress IBD through Modulation of the Gut Microbiome and T Cell Inflammatory Immune Responses

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2023 · —

## Abstract

The prevalence of inflammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis, is increasing
in Veterans. Diet plays an important role in shaping the intestinal microbiota and has emerged as an important
and actionable modifier of IBD. In addition, metabolites derived from nutrients by gut bacteria have been shown
to modify IBD progression. For example, pomegranate ellagitannins (ET) are broken down to ellagic acid (EA)
and further converted to urolithins by gut bacteria. Both EA and UA were demonstrated to improve symptoms of
IBD in chemically induced mouse models of colitis. We have recently shown that dietary pomegranate extract
(PomX) supplementation reduced colitis markers and downregulated colitis associated inflammatory pathways
in IL-10-/- mice. We also found that PomX and UA reduced pathobionts in wildtype mice. In addition, inter-
individual variations in urolithin production, so called metabotypes (A: only produce UA, B: forms urolithin B (UB),
or isoUA; 0: do not form any urolithins) have been well documented and associated with individual’s metabolic
health. It is our hypothesis that dietary PomX and/or UA suppress IBD pathogenesis by changing the gut
microbiome, strengthening the gut barrier integrity and inhibiting the differentiation of Th1 and Th17 intestinal T
cells and pro-inflammatory cytokine. Therefore, we propose to investigate whether dietary supplementation with
PomX and/or UA will prevent or alleviate colitis and to identify the mechanisms involved in PomX/UA-induced
suppression of colonic inflammatory pathways. The IL-10-/- mouse model, which mirrors the multifactorial nature
of IBD, is ideal to investigate the effect of dietary supplementation on colitis. To accomplish this, in aim 1 we will
investigate the effect of PomX in suppressing spontaneous colitis development in IL-10-/- mice, which either
produce UA (metabotye A) naturally, or lack bacteria forming UA (metabotype 0). We will also evaluate whether
UA will enhance PomX effects in metabotype 0 mice. Last, we will interrogate the potential mechanism of action
of PomX and/or UA supplementation on gut microbiome and host immunity by performing fecal shotgun
metagenomics sequencing, fecal and blood metabolomics, colonic tissue snRNAseq, cytokine RTqPCR, tissue
tight junction analysis and immune cell phenotyping in IL-10-/- mice receiving dietary PomX and/or UA. In aim 2,
we will investigate whether PomX and/or UA induced changes in the gut microbiome are responsible for their
effect on colitis suppression in IL-10-/- mice. Gnotobiotic IL10-/-mice will be colonized with naïve, or PomX,
and/or UA treated gut microbiome from human donors (metabotype A and B), and fed a high fat/high sucrose
(HFHS) diet for 12 weeks. We will investigate the role of donor microbiome metabotype to PomX treatment could
play in colitis susceptibility. In aim 3, we will evaluate the effects of PomX and/or UA on the intestinal T cell-
mediated immune inflammatory pathways...

## Key facts

- **NIH application ID:** 10609810
- **Project number:** 5I01BX005796-02
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Zhaoping Li
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10609810

## Citation

> US National Institutes of Health, RePORTER application 10609810, Pomegranate Extract and Its Microbial Metabolite Urolithin A Suppress IBD through Modulation of the Gut Microbiome and T Cell Inflammatory Immune Responses (5I01BX005796-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10609810. Licensed CC0.

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