PROGRESSION of hepatocellular carcinoma (HCC) accelerated through stress by disrupting the gut microbiome and altering tumour-related immune signalling, according to new preclinical and clinical research.
The study identifies a biological pathway linking psychological stress to liver cancer progression through changes in gut bacteria and their metabolites, suggesting potential new targets for microbiome-based therapeutic strategies.
Stress Linked to Microbiome Disruption Driving Liver Cancer Progression
While stress has previously been associated with worse cancer outcomes, the underlying mechanisms in liver cancer have remained unclear. Researchers used integrated clinical and preclinical models to examine how stress affects tumour biology.
Findings indicated that stress led to marked alterations in gut microbial composition, including a significant reduction in Phocaeicola vulgatus, a bacterial species linked to the production of beneficial metabolites.
Restoring levels of P. vulgatus or administering its key tryptophan-derived metabolite, indole-3-propionic acid, was shown to significantly slow tumour progression in experimental models.
Further analysis revealed that indole-3-propionic acid influenced the tumour microenvironment by reducing expression of JAM2, a protein involved in endothelial signalling. This, in turn, disrupted JAM2–F11R-mediated interactions between endothelial cells and macrophages, which are thought to support tumour growth and immune evasion.
Stress–Gut–Tumour Axis Identified as Potential Therapeutic Target
The findings point to a multi-layered stress–gut–tumour axis in which psychological stress reshapes the microbiome, alters metabolite production, and ultimately influences immune and vascular processes within the tumour microenvironment.
Researchers suggest that targeting this pathway, either by restoring beneficial gut bacteria or using microbial metabolites, could represent a novel therapeutic approach for slowing HCC progression.
They also highlight the potential for microbiome-based interventions to complement existing liver cancer treatments, particularly in patients experiencing chronic stress, which is common in those with advanced malignancy.
While the findings are currently based on experimental models, the authors say they provide a strong rationale for further translational research into gut microbiota modulation as part of cancer management strategies.
Reference
Hu Z et al. Stress accelerates hepatocellular carcinoma progression via a gut microbial-metabolite axis. Front Immunol. 2026;17:1790214. DOI:10.3389/fimmu.2026.1790214.
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