# Targeting Gut Microbiota Metabolites to Prevent Liver Cancer

> **NIH NIH F31** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2022 · $40,854

## Abstract

PROJECT SUMMARY/ABSTRACT
Hepatocellular carcinoma (HCC) has emerged as a leading cause of cancer-related
deaths globally and in the United States. Metagenomic studies are unveiling that gut
microbiota dysbiosis may possess diagnostic potential for HCC patients. Intriguingly, our
previous Cell publication highlights that a diet enriched with the fermentable fiber inulin
can act as the trigger to induce HCC in mice with preexisting gut dysbiosis. Ablation of
the gut microbiota through antibiotics and germ-free conditions completely eradicated
inulin-induced HCC, which leads to question HOW does the gut microbiota contribute to
HCC and, on the therapeutic standpoint, WHAT within the gut microbiota can be
specifically targeted to impede HCC. Accordingly, we first found this HCC phenotype in
genetically altered mice but for this proposal we have generated gut dysbiotic wild-type
(WTDYS) mice through extensive breeding and cross fostering to study specifically the role
of gut microbiota in inulin-induced HCC. Through 16S rRNA sequencing, we found that
WTDYS mice recapitulated the HCC-associated microbiota, which includes an overgrowth
of short chain fatty acid (SCFA)- and secondary bile acid (2° BA)-producing Clostridia
species and opportunistic pathogens like γ-Proteobacteria. While the fecal and serum
contents from WTDYS mice fed on inulin containing diet are in the process for
metabolomics analysis, we expect to have a striking elevation of SCFA and 2° BA based
on the associated bacterial blooms, which would be analogous to our original model with
genetic deficiency. Intriguingly, both gut metabolites have been recently delineated in the
literature to cause a severe reduction of invariant natural killer T (iNKT) cells but expand
regulatory T (Treg) cell abundance, which would downregulate anti-tumor responses and
favor immunosuppression, respectively. From this recent insight, we performed hepatic
immune cell isolation and characterization via flow cytometry in WTDYS mice and identified
mitigated levels of iNKT but overpopulated Treg cells. Our previous study and preliminary
data lead us to the central hypothesis that gut microbiota-dependent immunosuppression
is a main contributor to inulin-induced HCC. In Aim 1, we will implement pharmacologic
and genetic interventions to blockade SCFA production and activation of SCFA receptors,
while Aim 2 will apply pharmacologic and dietary interventions to inhibit 2° BA production,
which we posit will be two independent, but inter-related, approaches to abate inulin-
induced HCC by restoring anti-tumor immunosurveillance.

## Key facts

- **NIH application ID:** 10386414
- **Project number:** 1F31CA260842-01A1
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** Rachel M. Golonka
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $40,854
- **Award type:** 1
- **Project period:** 2022-01-13 → 2025-01-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386414

## Citation

> US National Institutes of Health, RePORTER application 10386414, Targeting Gut Microbiota Metabolites to Prevent Liver Cancer (1F31CA260842-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10386414. Licensed CC0.

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