# Establishing the feasibility of editing the human gut microbiome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $403,750

## Abstract

PROJECT SUMMARY
Definitive links between the remarkable inter-individual genotypic variation in the human microbiome and
disease are still limited due to the lack of generalizable methods to precisely remove microbial genes from
complex microbial communities in situ. Not only would such a technology help transform the microbiome field
from a descriptive to a mechanistic discipline, but it would also have immediate clinical applications. The goal
of this Focused Technology Research and Development (PAR-19-253) application is to establish a
generalizable toolkit to program the endogenous CRISPR-Cas systems in human gut bacteria to
knockout genes of interest with unprecedented precision. CRISPR-Cas is a bacterial immune system,
composed of RNA-guided nucleases, that protect the cell against bacteriophage and other foreign DNA.
Endogenous CRISPR-Cas systems can be programmed to target their own genomic DNA using custom guide
RNAs (gRNAs) homologous to a gene of interest. As an initial proof-of-principle we will target a single gut
bacterial gene that we discovered is responsible for the inactivation of the cardiac drug digoxin, but if
successful this approach could be readily extended to the numerous bacterial species that have now been
implicated in host physiology and the predisposition to and treatment of disease. We will pursue the following
Specific Aims: (Aim I) the functional validation of a novel CRISPR-Cas system in Eggerthella lenta, a prevalent
gut Actinobacterium with multiple links to metabolism and microbial pathogenesis; (Aim II) the isolation and
rebooting of bacteriophages that infect human gut bacteria; and (Aim III) the engineering of bacteriophage to
program an endogenous gut bacterial CRISPR-Cas system. Our long-term goal is to establish the first
modular tools for engineering the gut microbiome to delete one gene, combinations of genes, or even entire
metabolic pathways. Importantly, by focusing on endogenous CRISPR-Cas systems, we anticipate that along
the way we will uncover basic insights into the diversity, regulation, and function of these systems, with broad
implications for our understanding of the complex interactions between bacteriophages, their bacterial hosts,
and their shared mammalian habitat. While our early results provide support for feasibility, this high-risk, high-
reward technology development plan would have broad implications for the study of microbial communities and
host-microbiome interactions while bringing the promise of microbiome-based therapeutics within reach.

## Key facts

- **NIH application ID:** 10048547
- **Project number:** 1R01AT011117-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Peter James Turnbaugh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,750
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048547

## Citation

> US National Institutes of Health, RePORTER application 10048547, Establishing the feasibility of editing the human gut microbiome (1R01AT011117-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10048547. Licensed CC0.

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