Gut microbiota metabolites positively impacts chemotherapy effects in colorectal cancer

TL;DR

This study shows that gut microbiota metabolites can boost the effectiveness of chemotherapy in colorectal cancer.

Contribution

The first report demonstrating that physiologically relevant SCFA combinations improve 5-FU chemotherapy in CRC.

Findings

SCFAs enhance the antitumor effects of low-dose 5-FU in CRC cell models.

Combined SCFA and 5-FU treatment significantly reduces tumor size in the CAM assay.

SCFAs inhibit CRC cell growth, proliferation, survival, and migration.

Abstract

Colorectal cancer (CRC) remains one of the leading causes of cancer-related deaths worldwide, largely due to late-stage diagnosis and limited efficacy of current therapies. 5-Fluorouracil (5-FU) is the standard chemotherapeutic agent used in CRC treatment; however, its effectiveness is often hampered by resistance, toxicity, and suboptimal outcomes in advanced-stage tumors. Recent evidence suggests that gut microbiota-derived short-chain fatty acids (SCFAs) exert anticancer effects and may hold promise as therapeutic adjuvants. In this study, we investigated the potential of a physiologically relevant mixture of SCFAs to enhance the efficacy of 5-FU against CRC. Using a combination of 2D monolayer cultures, 3D models, and the in vivo chicken chorioallantoic membrane (CAM) assay, we demonstrated that SCFAs positively affect the antitumor effects of low-dose 5-FU. SCFAs contributed to the inhibition of CRC cell growth, proliferation, survival, and migration, with an overall increase of the anti-tumour effects observed across the different models. The combined treatment led to a significant reduction in tumour size in the CAM assay, contributing for an improvement of the effects of 5-FU alone. To our knowledge, this is the first report showing that physiologically relevant SCFA combinations can be harnessed to improve the therapeutic index of 5-FU in CRC, in a context-dependent manner. These findings support the development of microbiota-targeted co-adjuvant strategies to optimize CRC chemotherapy, reduce treatment toxicity, and improve patient outcomes, which is important given the clinical interest in microbiome-chemotherapy interactions.

The online version contains supplementary material available at 10.1007/s10565-026-10147-6.

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