# Mining the Gut Microbial Metabolome for Immunomodulatory Molecules that Contribute to Health or Disease

> **NIH NIH F32** · HARVARD MEDICAL SCHOOL · 2020 · $51,657

## Abstract

Project Summary/Abstract
Inflammatory Bowel Disease (IBD), is increasingly linked with disruption of the normal gut
microbial community. While many studies correlate disease with increases or decreases of certain
microbes, the role of these microbes in IBD is currently unknown. Microbes largely sense and
respond to their environment through metabolites and small molecules. This study’s premise is
that members of the gut microbiome produce molecules which exacerbate or diminish
inflammatory signals, thereby progressing or retarding inflammation and tissue damage in
patients. In preliminary studies, patient-derived bacteria were grown and separated into fractions
which were screened for molecules that promote inflammation. This effort identified several initial
hits, one being a lipidic molecule from Bifidobacterium breve. Projects proposed in Aim 1 of this
grant will identify and characterize this molecule and its mechanism of action. The success of this
preliminary work prompted us to propose a screen of an entire library of gut microbial fractions to
identify potent immunomodulatory molecules in Aim 2. To this end, three screens will be
performed on: 1) wild-type, 2) TLR2-/- TLR4-/-, and 3) LPS-stimulated mouse dendritic cells. While
the wild-type cells provide a broad view of all inflammatory antigens, the TLR2-/- TLR4-/- cells,
which lack the common receptors TLR2 and TLR4, reveal only molecules that act through less-
studied pathways. The LPS-stimulation assay will identify anti-inflammatory molecules (i.e.
molecules that inhibit the LPS response). In Aim 3, hit fractions from all assays will be confirmed
and characterized structurally and functionally via an array of analytical techniques. Molecules
that are highly potent, purified, and with a solved structure, will undergo secondary assays to
probe their mechanism of action. Initial secondary assays will include ELISAs with deletion cell
lines (lacking specific immune receptors) to identify which signaling pathways are responsible for
the bioactivity. This research will be performed primarily at Harvard Medical School which houses
state of the art facilities and equipment for performing chemical analysis (e.g. NMR, HPLC, MS).
Some aspects of this work will also be performed at the Broad Institute which provides access to
bacterial isolates, mouse strains, as well as an array of equipment and resources for
immunological and secondary assays. The training plan for the applicant will include frequent
communication with mentors about the project progress and career plans. Pertinent courses,
workshops, and conferences will be attended by the applicant to develop networking and
presentation skills, as well as help in rigorous assessment of the science in this proposal.
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## Key facts

- **NIH application ID:** 9987924
- **Project number:** 1F32AT010415-01A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** CHELSI Danielle CASSILLY
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $51,657
- **Award type:** 1
- **Project period:** 2020-05-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987924

## Citation

> US National Institutes of Health, RePORTER application 9987924, Mining the Gut Microbial Metabolome for Immunomodulatory Molecules that Contribute to Health or Disease (1F32AT010415-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9987924. Licensed CC0.

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