# Mechanism and application of sugar-induced phage production by the probiotic gut symbiont Lactobacillus reuteri

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $413,378

## Abstract

While dietary sugars can alter the bacteriophage community in the gut ecosystem, the underlying mechanisms
driving these changes remain elusive. Until we have filled these voids in our knowledge base, we will not be in
a position to comprehend the interplay between dietary sugars, and probiotics and their viruses; this hampers
the development of rational approaches to use diet to promote the efficacy of (engineered) probiotics. The long-
term goals are (i) to unravel the mechanisms that drive the interplay between diet, and probiotic bacteria and
their viruses, and (ii) to develop microbial therapeutics. The objectives of this research program are (1) to eluci-
date the mechanisms by which sucrose promotes phage production in the probiotic gut symbiont Lactobacillus
reuteri, and (2) to exploit diet-induced phage production to promote colonization and the release of therapeutics.
The overarching hypothesis is that sucrose increases phage production, which consequently promotes coloni-
zation and the release of recombinant proteins from engineered probiotics. The rationale of the work proposed
is that its successful completion is expected to result in a paradigm shift of our understanding how diet impacts
phage production, which will open up new and exciting avenues to modulate the gut microbiota composition,
promote probiotic growth, and to tailor therapeutic delivery. The overarching hypothesis will be tested by pursuing
three specific aims: (1) To characterize the sucrose metabolism pathway in relation to phage production; (2) To
determine the role of phage on L. reuteri gut fitness in response to a diet enriched in sucrose; and (3) To use
dietary sugar to control phage-mediated lysis and therapeutic delivery. In the first aim, targeted mutagenesis is
used to dissect the sucrose metabolism pathway and their products to determine the triggers of sucrose-driven
phage production in L. reuteri. Under the second aim, bacterial competition assays in gnotobiotic mice will de-
termine the ecological ramifications of sucrose-driven phage production; isogenic mutants with reduced ability
to metabolize sucrose, and to produce phage, are expected to reveal causation. Under the third aim, L. reuteri
will be engineered to lyse—and release recombinant interleukin-22—in response to metabolism of a specific
sugar. In an animal model of fatty liver disease therapeutic efficacy in response to diet will be investigated. This
research is innovative because an important mutualistic gut symbiont is used to unravel the mechanisms by
which sucrose boosts phage production in the gut ecosystem, which can be applied towards the development of
next-generation probiotics. The research is significant because understanding how a dietary sugar boosts phage
production in the gut ecosystem, and what the ecological ramifications are, opens up previously unexplored
opportunities to alter the composition of the gut microbiota, which may include enrichment and/or engraftment of
probi...

## Key facts

- **NIH application ID:** 10492549
- **Project number:** 5R01AT011202-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Jan-Peter van Pijkeren
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $413,378
- **Award type:** 5
- **Project period:** 2021-09-25 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492549

## Citation

> US National Institutes of Health, RePORTER application 10492549, Mechanism and application of sugar-induced phage production by the probiotic gut symbiont Lactobacillus reuteri (5R01AT011202-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10492549. Licensed CC0.

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