Julia Plocica

Background: Colorectal cancer (CRC) is a devastating illness and is ranked as the third most common cancer worldwide¹. Clinical symptoms include, but are not limited to, intestinal obstruction, abdominal masses, anemia, nausea, vomiting, and can often be asymptomatic². Most CRC is diagnosed with endoscopy and is frequently treated by surgical resection. There are many risk factors associated with CRC, but the most notable is a high-fat diet due to its potential to impact bile acid production³. Bile acids (BAs) play an essential biological role in fat and lipid digestion and absorption. However an excess of BAs can act as substrates for the microbial gut flora resulting in production of secondary bile acids (SBA), such as deoxycholic acid (DCA) and lithocholic acid (LCA)³. Previous evidence suggests that SBAs are linked to CRC and promote inflammation, dysbiosis, and tumorigenesis. There are many possible mechanisms for this relationship between SBAs and CRC, but none have been previously described.

Objective: In this narrative review, we explored the possible mechanisms and role SBAs, specifically DCA, play in CRC tumorigenesis.

Search Methods: An online search in the PubMed database and Google Scholar was completed from 2017-2023 using keywords including: “secondary bile acids”, “colorectal cancer”, “colon cancer”, “deoxycholic acid”, and “tumorigenesis”.

Results: Studies indicate that mice fed a DCA-diet had a significantly higher occurrence of CRC tumors than mice given a normal diet. Fecal transplants from DCA-fed mice to healthy mice demonstrated higher occurrences of tumors than mice receiving healthy fecal transplants, indicating the role DCA-induced dysbiosis plays in tumorigenesis. In the same study, protein expression measurements showed increased levels of Wnt signaling molecules in mice receiving fecal transplants from the DCA-fed mice compared to the other treatment groups. The Wnt/β-catenin signaling pathway is known to play a critical role in cell growth and tumorigenesis⁴. Further studies show a novel relationship between the Wnt/β-catenin signaling pathway, SBAs, and the Farnesoid X receptor (FXR). FXR is a bile acid nuclear receptor that plays a role in bile acid homeostasis and regulation⁵. In additional mouse studies, it was found that FXR expression inhibits Wnt/β-catenin signaling molecule expression and further inhibits tumorigenesis, illustrating the reciprocal roles of these pathways⁵. Using human cancerous and noncancerous tissue samples, FXR expression was found to be significantly downregulated in cancerous tissue samples and in the presence of SBA⁶. It is proposed that SBAs may bind to and silence FXR expression, resulting in bile acid dysregulation and enhanced generation of CRC⁶.

Conclusion: Studies have found that high-fat diets contribute to colorectal tumorigenesis by increasing SBA concentration. SBAs, such as DCA, promote Wnt/β-catenin signaling molecule expression contributing to irregular growth and tumorigenesis. In addition, SBAs  lead to bile acid dysregulation by downregulating FXR expression, resulting in a cancer promoting environment and tumorigenesis. These results warrant the consideration of SBAs and FXR as targets for novel CRC therapies to improve the outlook and treatment of CRC.

Works Cited:

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2. Duan B, Zhao Y, Bai J, et al. Colorectal Cancer: An Overview. In: Morgado-Diaz JA, ed. Gastrointestinal Cancers. Brisbane (AU): Exon Publications; September 30, 2022.
3. Zeng H, Umar S, Rust B, Lazarova D, Bordonaro M. Secondary Bile Acids and Short Chain Fatty Acids in the Colon: A Focus on Colonic Microbiome, Cell Proliferation, Inflammation, and Cancer. Int J Mol Sci. 2019;20(5):1214. Published 2019 Mar 11. doi:10.3390/ijms20051214
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6. Ma Y, Zhang Y, Qu R, et al. Promotion of Deoxycholic Acid Effect on Colonic Cancer Cell Lines In Vitro by Altering the Mucosal Microbiota. Microorganisms. 2022;10(12):2486. Published 2022 Dec 15. doi:10.3390/microorganisms10122486