Sasha Kadamba

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide, and its development is attributed to a variety of genetic and environmental factors including microbial exposures in the gut.¹ Streptococcus gallolyticus subsp. gallolyticus (Sgg) is a gut pathobiont associated with septicemia, endocarditis, and colorectal cancer.¹ Recent research has found that Sgg promotes tumorigenesis through a variety of mechanisms that disrupt the homeostasis of the gut epithelium.¹ Thus, mechanisms by which the bacteria manipulate epithelial cell behavior is an area of active research with the potential for improving treatment and management of colorectal cancer.

Objective: In this narrative review, we explored the mechanisms by which Streptococcus gallolyticus subs. gallolyticus promotes colorectal tumorigenesis through disruption of intestinal epithelial homeostasis.

Search Methods: An online search in the PubMed database was conducted for studies reported between 2018 to 2026 using the following keywords: “Streptococcus gallolyticus subs. gallolyticus”, “colorectal cancer”, and “gut epithelium”.

Results: Experimental studies have demonstrated that Streptococcus gallolyticus subsp. gallolyticus (Sgg) promotes colon cancer cell proliferation through a variety of mechanisms that disrupt intestinal epithelial homeostasis. Specifically, Sgg utilizes a specialized type VII secretion system (T7SS) which secretes protein substrates such as EsxA that facilitate bacterial adherence to human colorectal cancer cells and stimulates epithelial cell proliferation.¹ Deletion of the T7SS locus reduced the capacity of the bacteria to colonize mouse colon and impaired colon tumor growth.¹ Additionally, transcriptomic profiling revealed that exposure of colonic epithelial cells to Sgg induced extensive transcriptomic changes, resulting in a pro-tumoral shift in the cells.² Another study found that Sgg upregulates collagen (specifically type VI collagen), components of the extracellular matrix, in human CRC cells (HT29 and HCT116 cells). Knockdown of collagen VI reduced cell proliferation induced by Sgg.³ Sgg also upregulates cytochrome P450 (CYP) family proteins through the Aryl hydrocarbon receptor (AhR) in in vitro cultured CRC cells and in a mouse model. ⁴ AhR activation by Sgg led to increased sensitivity to DNA damaging agents in CRC cells. Furthermore, Sgg exhibited tannase activity, enabling protection of CRC cells from the anti-tumor effects of tannic acid, a type of plant polyphenol with antioxidant and antimicrobial properties.⁵

Conclusion: Studies indicate that Streptococcus gallolyticus subsp. gallolyticus (Sgg) contributes to colon cancer cell proliferation through various mechanisms that disrupt intestinal epithelial homeostasis. Among these mechanisms are the Type VII Secretion System, induction of pro-tumor transcriptomic changes, manipulation of extracellular matrix composition, activation of AhR and upregulation of CYP1, and protection against tannic acid. However, the incorporation of these findings in the development of strategies for prevention and therapeutic intervention of colorectal cancer remain limited. Such data on the specific mechanisms by which Sgg contributes to tumor development can help inform future work on therapeutic strategies that include Sgg as a clinical target for treating colorectal cancer.¹

Works Cited:

1. Taylor JC, Gao X, Xu J, et al. A type VII secretion system of Streptococcus gallolyticus subsp. gallolyticus contributes to gut colonization and the development of colon tumors. PLoS Pathog. 2021;17(1):e1009182. Published 2021 Jan 6. doi:10.1371/journal.ppat.1009182
2. Pasquereau-Kotula E, du Merle L, Sismeiro O, et al. Transcriptome profiling of human colonic cells exposed to the gut pathobiont Streptococcus gallolyticus subsp. gallolyticus. PLoS One. 2023;18(11):e0294868. Published 2023 Nov 30. doi:10.1371/journal.pone.0294868
3. Kumar R, Taylor JC, Jain A, Jung SY, Garza V, Xu Y. Modulation of the extracellular matrix by Streptococcus gallolyticus subsp. gallolyticus and importance in cell proliferation. PLoS Pathog. 2022;18(10):e1010894. Published 2022 Oct 3. doi:10.1371/journal.ppat.1010894
4. Taddese R, Roelofs R, Draper D, et al. Streptococcus gallolyticus Increases Expression and Activity of Aryl Hydrocarbon Receptor-Dependent CYP1 Biotransformation Capacity in Colorectal Epithelial Cells. Front Cell Infect Microbiol. 2021;11:740704. Published 2021 Oct 27. doi:10.3389/fcimb.2021.740704
5. Oehmcke-Hecht S, Mandl V, Naatz LT, et al. Streptococcus gallolyticus abrogates anti-carcinogenic properties of tannic acid on low-passage colorectal carcinomas. Sci Rep. 2020;10(1):4714. Published 2020 Mar 13. doi:10.1038/s41598-020-61458-5