Short-Chain Fatty Acids in Colorectal Cancer Mechanisms

Short-chain fatty acids (SCFAs), principally acetate, propionate and butyrate, are microbial fermentation products of dietary fibre in the colon and serve as pivotal regulators of colonic epithelial homeostasis. These metabolites engage diverse molecular pathways to influence colorectal cancer (CRC) initiation and progression. Butyrate, in particular, exerts anti-proliferative and pro-apoptotic effects through inhibition of histone deacetylases (HDACs), thereby altering chromatin structure and gene transcription in cancer cells. SCFAs also modulate immune responses by promoting regulatory T-cell differentiation and by attenuating pro-inflammatory cytokine release via suppression of NF-κB signalling. Recent work has further revealed that butyrate can sensitise CRC cells to ferroptosis, an iron-dependent form of cell death, through down-regulation of the cystine/glutamate antiporter xCT and induction of c-Fos. Moreover, the so-called “butyrate paradox” highlights differential metabolic fates of butyrate in normal versus malignant colonocytes, which underlies selective tumour toxicity. Dysbiosis, characterised by reduced SCFA-producing bacteria, compromises the mucosal barrier and fosters chronic inflammation, thereby elevating CRC risk. Collectively, these insights position SCFAs at the nexus of diet, microbiota and tumour biology, offering avenues for preventive and therapeutic strategies in colorectal cancer.

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Short-Chain Fatty Acids in Colorectal Cancer Mechanisms publication trend

The graph below shows the total number of articles in short-chain fatty acids in colorectal cancer mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Short-chain fatty acids (SCFAs): Fatty acids with fewer than six carbons, produced by bacterial fermentation of dietary fibre in the colon.

Butyrate: A four-carbon SCFA notable for its roles in histone deacetylase inhibition, epithelial energy metabolism and immunomodulation.

Histone deacetylases (HDACs): Enzymes that remove acetyl groups from histone proteins, thereby tightening chromatin and repressing gene transcription.

Ferroptosis: A regulated form of cell death driven by iron-dependent lipid peroxidation and characterised by depletion of glutathione and inactivation of antioxidant systems.

References

1. Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression. Redox Biology (2023).
2. Short-chain fatty acids in cancer pathogenesis. Cancer and Metastasis Reviews (2023).
3. Secondary Bile Acids and Short Chain Fatty Acids in the Colon: A Focus on Colonic Microbiome, Cell Proliferation, Inflammation, and Cancer. International Journal of Molecular Sciences (2019).