# Defining Host-Microbial Interactions Using Functional Metagenomics

> **NIH NIH K08** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $34,085

## Abstract

PROJECT SUMMARY
 The trillions of bacteria that make up the human microbiome are believed to encode functions that are
important to human health; however, little is known about the specific effectors that commensal bacteria use to
interact with the human host. The inability to culture many commensal bacteria renders these microbes
incompatible with the most heavily relied upon techniques for characterizing effector molecules. To solve this
problem requires the application of methods where bacterial effectors can be isolated and observed to interact
with human biology. In functional metagenomic studies fragments of DNA extracted from an environmental
sample are cloned into a model bacterial host, and the resulting metagenomic clones are examined for
phenotypes of interest. This approach circumvents the culture barrier allowing for the simultaneous identification
of effectors from both cultured and uncultured microbes.
 In a recently submitted manuscript we demonstrated the use of functional metagenomic techniques to
isolate commensal effector molecules. In this study we created three metagenomic libraries from DNA isolated
from phenotypically diverse patient stool samples. High content imaging of a human reporter cell line was used
to identify effector molecules produced by metagenomic clones that activate human cellular NFκB pathways.
This study led to the discovery of 26 biosynthetic commensal effector genes and a small molecule, N-acyl-3OH-
palmitoyl-glycine which structurally mimics endogenous signaling molecules in humans and modulates immune
cell functions. The central hypothesis is that our functional metagenomic screening method can be broadly
applied to the human microbiome to discover effector molecules by expanding our metagenomic library collection
and repertoire of human cellular reporters (Aim 1). Once metagenomic clones are isolated that interact with
human cells it is straightforward to identify each effector gene and molecule (Aim 2) and explore the chemical
diversity of similar molecules produced by other commensals (Aim 3). The rationale that underlies this proposal
is that the isolation of bioactive molecules creates a strong foundation for future research to understand how
commensal effector functions dictate host physiology and to target these host-microbial interactions for
therapeutic development.
 To achieve these aims I will be supported by a primary mentor who is a scientific leader in the application
of functional metagenomic research methods, Dr. Sean Brady (Rockefeller University). The mentor will help me
complete the individual aims of this project and develop the skills required to pursue my long term goal to
understand how commensal effector molecules define host-microbial interactions.

## Key facts

- **NIH application ID:** 10386268
- **Project number:** 3K08DK109287-05S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Louis Jared Cohen
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $34,085
- **Award type:** 3
- **Project period:** 2016-07-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386268

## Citation

> US National Institutes of Health, RePORTER application 10386268, Defining Host-Microbial Interactions Using Functional Metagenomics (3K08DK109287-05S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10386268. Licensed CC0.

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