# Novel synthetic analogue of microbial metabolite, Urolithin A, mitigates inflammatory bowel diseases

> **NIH NIH P20** · UNIVERSITY OF LOUISVILLE · 2022 · $207,267

## Abstract

Project Summary/Abstract 
 Inflammatory Bowel Diseases (IBDs), which include f ulcerative colitis and Crohn’s disease, affect as 
many as 1.4 million people in the USA. Chronic inflammation and microbial dysbiosis are major features of IBDs. 
Beneficial effects rendered by healthy dietary practices are not uniform among individuals and are attributed to 
variations in gut microbiota and their active metabolites. To overcome the challenge of inter-individual differences 
in gut microbiota, their metabolites and poor bioavailability, here we propose direct usage of microbial 
metabolites to maintain gut immune homeostasis to mitigate IBDs. Urolithin A (UroA) is one of such beneficial 
microbial metabolite derived from ellagic acid and ellagitannins, major polyphenolic components of berries and 
pomegranate. Based on UroA structure, we developed novel potent structural analogue, UAS03, which exhibited 
increased anti-inflammatory and gut barrier functional activities compared to parent UroA compound. The 
current proposal investigates the molecular and cellular mechanisms of UAS03 and its therapeutic efficacies in 
IBD pre-clinical models. 
 Our preliminary results showed that the oral administration of UAS03 mitigated colitis in dextran sodium 
sulphate (DSS)- or 2,4,6-Trinitrobenzenesulfonic acid (TNBS) induced murine colitis even at 10 fold lower dose 
compared to UroA. UAS03 significantly inhibited lipopolysaccharide (LPS)-induced increase in inflammatory 
mediators in immune cells and epithelial cells with 10 fold higher efficacy than UroA. Further, treatment with 
UAS03 reduced intestinal permeability by up-regulating junctional proteins through activation of nuclear factor 
(erythroid-derived 2)-like 2 (Nrf2)-hemoxygenase (HO1) pathways in epithelial cells. Based on these results, we 
propose two-pronged beneficial activities of UAS03 and UroA, where these compounds protect the host from 
external challenges by protecting gut barrier function and dampening inflammatory activities. In this proposal we 
will test the hypothesis that ‘treatment with UAS03, an effective analogue of a microbial metabolite, protects 
from IBD development by reducing barrier dysfunction and inflammation. In Aim 1, we will investigate how 
USA03/UroA increase gut barrier function in a Nrf2-dependent manner by upregulating junctional proteins as 
well as molecular events involved anti-inflammatory activities of UAS03. In Aim 2, therapeutic efficacies of 
UAS03 and UroA will be examined in acute, chronic and spontaneous IBD pre-clinical models. In Aim 3, we 
propose to identify the bacteria responsible for UroA production and test their pro-biotic activities in colitis models. 
The successful completion of proposed studies will allow understanding of UAS03 and UroA mechanisms of 
actions, and establishes the basis for therapeutic usage in IBDs.

## Key facts

- **NIH application ID:** 10349569
- **Project number:** 5P20GM125504-05
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Venkatakrishna Rao Jala
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $207,267
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10349569

## Citation

> US National Institutes of Health, RePORTER application 10349569, Novel synthetic analogue of microbial metabolite, Urolithin A, mitigates inflammatory bowel diseases (5P20GM125504-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10349569. Licensed CC0.

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