# Development of Engineered Native Bacteria as a Tool for Functional Manipulation of the Gut Microbiome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $788,553

## Abstract

PROJECT SUMMARY/ABSTRACT
 Most therapies that target microbiome composition do not have a detectable impact on the gut microbiome
and are not robust to the interpersonal diversity and plasticity of the community in human hosts. To develop a
better mechanistic understanding of the microbe-host relationship and more effective microbiome-mediated
therapies, approaches based on functional modulation of the gut microbiome are necessary. However, these
approaches have been difficult to develop. Attaining long-term engraftment in the luminal environment has
proven to be quite difficult, and even once engraftment has been achieved, a change in physiology or
improvement of pathologic phenotype has not yet been demonstrated. There is a critical need for a tool that will
allow investigators to “knock-in” functions into the gut microbiome and investigate their effects on the luminal
milieu and, ultimately, physiology in conventionally-raised hosts in non-sterile conditions. The investigators
propose a novel approach to address this need by using native bacteria as chassis for the introduction of specific
functions into the luminal environment. The proposal's innovation is a new strategy that allows the quick and
effective “knock-in” of a beneficial function in a sustained manner into conventional hosts. To date they have
demonstrated that tractable native bacteria can be engineered to express a beneficial function ex vivo,
reintroduced to the host, engraft the entire gut of the host, and deliver an intended beneficial function. These
functions can affect host physiology, help determine the effect of specific bacterial functions and potentially
alleviate disease. The central hypothesis of this proposal is that long-term colonization and functional change in
the gut microbiome of a conventional host can be performed effectively with engineered native bacteria.
 In the next five years, the investigators will continue the development of this technology and better
understand the chassis-host interactions that will aid in the development of live bacterial therapeutics for clinical
use. First, the investigators will engineer regulatory systems for the transgene of interest, including a sense and
control, protein secretion, and biocontainment circuit. They will test whether these systems function in vivo in
hosts that are in a non-sterile environment. In addition, they will assess the natural biocontainment of engineered
native bacteria among co-housed hosts. Second, they will determine how the niche for a bacterial chassis affects
function delivery and whether multiple functions can be delivered by the same chassis or whether different
chassis are necessary for the delivery of multiple functions. Finally, the investigators will determine the role of
microbial community in amplifying the effects of a transgene of interest in gnotobiotic mice. The expected
outcome of the proposed studies is attainment of fundamental biological knowledge of how the gut microbiome
can ...

## Key facts

- **NIH application ID:** 10737475
- **Project number:** 1R01AI163483-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** JEFF M HASTY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $788,553
- **Award type:** 1
- **Project period:** 2023-06-20 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10737475

## Citation

> US National Institutes of Health, RePORTER application 10737475, Development of Engineered Native Bacteria as a Tool for Functional Manipulation of the Gut Microbiome (1R01AI163483-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10737475. Licensed CC0.

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