# Functional interrogation of host-microbial interactions in metabolic diseases

> **NIH NIH R03** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $127,125

## Abstract

PROJECT SUMMARY
 The most common methods to study the human microbiome have involved descriptive studies of bacterial
DNA (metagenomics), RNA (transcriptomics), metabolites (metabolomics) or proteins (proteomics) in patient
cohorts. These “omics” studies have established a strong link between the microbiome and metabolic diseases
such as diabetes and obesity. Unfortunately, little is known about the mechanisms through which commensal
bacteria affect metabolic pathways (i.e. effector functions). Without knowledge of how bacterial DNA and its
encoded proteins/metabolites translate into changes in human biology, “omics” studies are limited to correlative
observations and not mechanisms that define the relationship between microbes and human health. We propose
a shift from descriptive “omics” studies to functional studies of the microbiome to isolate microbial effectors that
shape metabolic outcomes and improve our understanding of disease pathophysiology and treatment.
 It is increasingly clear that the microbiome interacts with human cellular pathways through G-protein-
coupled receptors (GPCRs). As GPCRs are linked to the pathophysiology of metabolic diseases and their
treatment, the identification of GPCR-active microbial effectors presents a strategy to understand how the
microbiome impacts metabolic disease outcomes and to develop microbiome-based therapies (i.e. live
biotherapeutics). In previous work as part of my K08 award, we used functional metagenomics to isolate a family
of bacterial genes that encode for GPCR-active small molecules. One GPCR-active small molecule we identified,
N-acyl serinol (N-AS), is a GPR119 agonist. GPR119 is a metabolic GPCR that is a therapeutic target for the
treatment of diabetes and obesity as GPR119 regulates GLP-1 and insulin release. We demonstrated that
bacteria engineered to produce GPR119-active metabolites can in wild-type mice regulate insulin, GLP-1 and
glucose homeostasis similar to GPR119 agonists in clinical trials. This data supports that the identification of
microbial effectors in vitro informs our understanding of microbiome physiology in vivo and these interactions
can be developed therapeutically. We have since expanded our methods from screening of bacterial DNA to
identify effector genes (K08) to screening of bacterial culture broths to identify GPCR-active metabolites
(functional metabolomics). This work suggests bacteria affect diverse metabolic GPCR beyond GPR119.
 The central hypothesis is that functional interrogation of bacterial culture broths to identify GPCR-active
metabolites (functional metabolomics) will improve our understanding of metabolic disease pathophysiology and
identify novel therapeutic strategies. We will develop this hypothesis by complementing previous methods to
isolate bacterial effector genes (K08) with new methods to isolate effector metabolites (Aim 1) from bacteria
enriched or depleted in patients with metabolic diseases. We will also explore the role of N-AS ...

## Key facts

- **NIH application ID:** 10125150
- **Project number:** 5R03DK124742-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Louis Jared Cohen
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $127,125
- **Award type:** 5
- **Project period:** 2020-03-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125150

## Citation

> US National Institutes of Health, RePORTER application 10125150, Functional interrogation of host-microbial interactions in metabolic diseases (5R03DK124742-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10125150. Licensed CC0.

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