# Identifying the active factor of an anti-inflammatory chemopreventive bacterium

> **NIH NIH R21** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $235,927

## Abstract

Project Abstract/Summary
Colorectal cancer (CRC) remains a major public health issue, with approximately 145,000 new cases and 51,000
deaths from this disease per year in the US alone. Alterations in the composition of the gut microbiota and
elevated inflammation are established risk factors for CRC. We made the novel observation that the normal gut
bacterium Parabacteroides distasonis (Pd) suppresses colorectal inflammation and tumor formation in mice.
Importantly, we show that Pd suppresses the activation of the pro-inflammatory, pro-tumorigenic TLR4 signaling
pathway. The objectives of this application are to determine whether blocking TLR4 is required for the ant-tumor
effects of Pd, to identify the active factor of Pd and its host target and finally to define how Pd influences immune
cell populations in the colon. Based on our robust data, we hypothesize that the chemopreventive effect of Pd is
achieved by the suppression of pro-inflammatory TLR4 signaling and the recruitment of inflammation quelling T
regulatory (Treg) cells to the colon. The specific aims of the study are to: 1) To identify anti-inflammatory factor of
Pd; 1A) To test whether the anti-TLR4 function of Pd is required for its chemopreventive effect; 1B) To identify
the molecular target of the Pd anti-inflammatory molecule and 2) To define how Pd influences immune cell
populations in the colonic mucosa. The aims of this study will be addressed by comparing the ability of various
closely-related bacterial species to inhibit TLR4 signaling in vitro followed by comparative genomics to identify
genes common to inhibitory species but without homologs in non-inhibitory species. The function of candidates
will be evaluated by expressing them in E.coli Nissle 1917 (EcN) and mutating them in Pd. To evaluate whether
TLR4 inhibition is required for chemoprevention by Pd we will compare the ability of Pd and Pd lacking anti-TLR4
function to suppress colon tumorigenesis with EcN and EcN expressing Pd anti-TLR4 genes. Host target proteins
will be identified by co-immunoprecipitation with the recombinant tagged Pd protein. Finally, the influence of Pd
on colonic immune cells will be evaluated by comparing specific cancer and microbiota relevant immune cell
populations between Pd fed and control mice over time. Understanding Pd’s mechanism of action and identifying
its active and target molecules will pave the way for this bacterium, or its active component, to be utilized in the
prevention of CRC. Our long-term goal is to identify bacteria with chemopreventive properties and to understand
their mechanisms of action. Importantly, Pd appears to be compatible with other microbial therapies and does
not disrupt the resident microbiota. These studies are highly worthwhile because although a few agents show
promise as chemopreventive agents in pre-clinical studies, aspirin (a drug developed over 100 years ago)
remains the only agent for which we have compelling evidence of efficacy and its detrime...

## Key facts

- **NIH application ID:** 10600457
- **Project number:** 7R21CA253392-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Jimmy W Crott
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $235,927
- **Award type:** 7
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10600457

## Citation

> US National Institutes of Health, RePORTER application 10600457, Identifying the active factor of an anti-inflammatory chemopreventive bacterium (7R21CA253392-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10600457. Licensed CC0.

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