Friday, May 9, 2025
5/9/2025
Targeting Gut Microbiota Metabolites to Prevent Liver Cancer - 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.
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