# Lac operon-dependent metabolism in Enterobacteriaceae and its role in liver disease-associated infections

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2024 · $170,520

## Abstract

PROJECT SUMMARY
Dysbiosis, an alteration of the gut microbiome associated with chronic diseases, has been previously described
in patients with cirrhosis. Common features of dysbiosis include reduced bacterial diversity and the outgrowth of
the family of human pathogenic bacteria Enterobacteriaceae, including Escherichia coli. Infectious
complications, namely spontaneous bacterial peritonitis (SBP) and bacteremia, are deadly for patients with
cirrhosis with up to 50% mortality. E. coli is one of the most common causes of these infections, thought to derive
from bacterial translocation across the intestinal epithelium from reduced barrier function. While this suggests a
connection between dysbiosis and disseminated infection, the underlying risk factors of disseminated infection
are not well understood in this population. Lactulose, a simple carbohydrate which is the first line treatment for
the cirrhosis complication hepatic encephalopathy, has been associated with higher abundance of E. coli in the
gut microbiota. Our work demonstrates that lactulose also increases colonization of Enterobacteriaceae, by
overcoming carbon limitation in the colon for these pathogens. My preliminary data show that E. coli acquire
mutations allowing it to utilize lactulose as a carbohydrate source both in culture and in the mouse gut, thus
increasing its fitness. This phenotype is dependent upon constitutive expression of the lactose (lac) operon via
deactivation of the transcriptional regulatory protein LacI, a repressor of the lac operon, which encodes the
lactulose metabolizing enzyme β-galactosidase. I therefore hypothesize that lactulose treatment selects for
mutant Enterobacteriaceae capable of metabolizing lactulose, thereby increasing colonization and the risk of
disseminated infection in patients with liver disease. My objectives in this proposal are to characterize the gain
of function mutations that enable lactulose metabolism by E. coli, determine the competitive advantage imparted
by these mutations, and assess the impact of lactulose on disseminated infection in mice and humans with liver
disease. My hypothesis will be tested through two inter-related Specific Aims that will evaluate the adaptive
mutations and competitive fitness imparted by lactulose treatment to E. coli (Aim 1) and test the impact of
lactulose on disseminated infection (Aim 2). This proposal takes advantage of several innovative techniques
and unique resources including a novel mouse model of disseminated infection in liver disease and creation of
a human disseminated infection strain library. The University of Pennsylvania is an ideal research environment
for these studies given the local expertise in gut microbiome, pathogen biology, and comparative bacterial
genomics. The candidate will acquire critical skills for his career development as an independent investigator,
including in bioinformatics, bacterial genomics, and mouse disease modeling. Successful completion of this
proposa...

## Key facts

- **NIH application ID:** 10985670
- **Project number:** 1K08DK138319-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Aaron L Hecht
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $170,520
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985670

## Citation

> US National Institutes of Health, RePORTER application 10985670, Lac operon-dependent metabolism in Enterobacteriaceae and its role in liver disease-associated infections (1K08DK138319-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10985670. Licensed CC0.

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