The impact of gut microbial short-chain fatty acids on colorectal cancer development and prevention

Abstract

Cancer is a long-term illness that involves an imbalance in cellular and immune functions. It can be caused by a range of factors, including exposure to environmental carcinogens, poor diet, infections, and genetic alterations. Maintaining a healthy gut microbiome is crucial for overall health, and short-chain fatty acids (SCFAs) produced by gut microbiota play a vital role in this process. Recent research has established that alterations in the gut microbiome led to decreased production of SCFA's in lumen of the colon, which associated with changes in the intestinal epithelial barrier function, and immunity, are closely linked to colorectal cancer (CRC) development and its progression. SCFAs influence cancer progression by modifying epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNA functions thereby affecting tumor initiation and metastasis. This suggests that restoring SCFA levels in colon through microbiota modulation could serve as an innovative strategy for CRC prevention and treatment. This review highlights the critical relationship between gut microbiota and CRC, emphasizing the potential of targeting SCFAs to enhance gut health and reduce CRC risk.

Keywords: CRC prevention; Short chain fatty acids; gut microbiome; immune modulation.

Figure 1.

Pathways responsible for the biosynthesis of short-chain fatty acids (SCFAs) derived from indigestible dietary fiber and carbohydrate fermentation by gut microbiota. The primary SCFAs include acetate, generated through the wood–Ljungdahl pathway or from acetyl-CoA; butyrate, formed from two acetyl-CoA molecules; and propionate, produced from phosphoenolpyruvate via either the acrylate or succinate pathway or through propanediol pathway.

Figure 2.

SCFAs primarily act on target cells through three mechanisms. (i) The first mechanism involves the binding of SCFAs to GPCRs on the cell membrane, such as GPR109A, GPR43, and GPR41. This binding can inhibit downstream pathways, including PLC, MAPK, Nf-κB, and others. (ii) SCFAs can enter the cell with the help of transporters on the cell membrane, then move into the cell nucleus where they inhibit HDAC and activate HAT. This results in increased histone acetylation, the gradual loosening of dense chromosomes, and ultimately, increased gene (LHR, XIAP or IDO-1) expression. (iii) Another mechanism of action is that SCFAs enter the cell with the help of AhR, then move to the nucleus. Nuclear receptors, such as AhR and ARNT, can bind to DNA, which suppresses gene expression involved in detoxification, metabolism, cell development, and the essential role of cellular sensors for xenobiotics, coordinating the body response.

Figure 3.

The intestinal microbiota contributes to the epigenetic regulation of colorectal cancer by producing SCFAs, which serve as both substrates and regulators that influence chromatin-modifying enzymes. The mechanisms by which this occurs is the inhibition of histone deacetylase activity, leading to chromatin alterations typically linked to the upregulation of target gene expression in a variety of different cancer cell lines.