Andrew Talcott

Background: Colorectal cancer (CRC) ranks as both the third highest diagnosed cancer and cause of cancer-related death for both men and women in the United States.¹ CRC originates in intestinal epithelial cells of the colon and has been shown to be closely associated with gut microbiome dysbiosis.^2,3,6 Current treatment for CRC consists primarily of surgical resection.^2,5 Enterotoxigenic Bacteroides Fragilis (ETBF) is a common member of the gut microbiome identified frequently in the stool samples of individuals with CRC.² ETBF secretes a single pathogenic factor, Bacteroides Fragilis Toxin (BFT), which can mediate colonic inflammation and CRC.^2,3,6 BFT induces an upregulation of IL-8 secretion by intestinal epithelial cells through GPR35 and the E-Cadherin/β-Catenin/NF-κB pathway.^6,7 Upregulation of IL-8 has been reported throughout the progression of CRC.⁸ These findings demonstrate another potential method of treatment for CRC.

Objective(s): In this review, the mechanism through which BFT induces secretion of IL-8 from intestinal epithelial cells was explored, along with potential treatment methods that could effectively target BFT and increased IL-8 levels to suppress progression of CRC.

Search Methods: An online search was conducted utilizing the PubMed database from 2017-2023 with the key terms: “Colorectal Cancer”, “Bacteroides Fragilis”, and “IL-8”.

Results: GPR35 was identified as a candidate receptor for BFT action.⁷ GPR35 shRNA knockdown in human epithelial HT29/C1 cells demonstrated a reduction in E-cadherin cleavage and lowered secretion of IL-8 when treated with BFT.⁷ IL-8 levels and E-cadherin cleavage was reduced in the presence of BFT and the GPR35 inhibitor, ML145, compared to those treated with BFT alone.⁷ In vivo, murine studies demonstrated GPR35 knockout led to a significant increase in survival rate after colonization of ETBF.⁷ E-cadherin knockout cells were unable to secrete IL-8 in response to BFT.⁶ Knockout of the β-Catenin gene (CTNNB1) resulted in a decrease in IL-8 levels.⁶ β -Catenin knockout had no impact on BFT mediated E-Cadherin cleavege.⁶ NF-kB transcriptional activity in the β-Catenin knockout cells did not increase after addition of BFT.⁶ Both IL-8 and the IL-8 receptors (IL-8RA and IL-8RB) demonstrated an increase in fluorescent intensity in adenoma and CRC epithelial patient samples.⁸ Q-PCR quantified a significant increase in IL-8 mRNA levels within adenoma and CRC samples.⁸ A dose-dependent allosteric inhibition of BFT-3 proteolytic activity was identified after treatment with three different FDA pre-approved drugs.⁹ Treatment of BFT on HT29/C1 alongside the inhibitory compounds demonstrated reduced E-Cadherin cleavage.⁹ HuMax-IL8 is a monoclonal antibody designed to target IL-8.¹⁰ A phase 1 trial of HuMax-IL8 conducted on 15 patients with metastatic or unresectable solid tumors demonstrated no dose limiting toxicities when administered intravenously at four varying doses every two weeks for 52-weeks maximum.¹⁰ Treatment resulted in significantly reduced IL-8 serum levels in 10/15 patients.¹⁰ The best outcome of HuMax-IL8 treatment was disease stabilization.¹⁰

Conclusion: Studies have shown that BFT induces secretion of IL-8, which is seen in high levels through the progression of CRC.^6,8 Targeting BFT with FDA pre-approved drugs or reducing IL-8 levels through HuMax-IL8 could therefore serve as therapeutic treatments to suppress the progression of CRC.

Works Cited:

1.  Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48.
2. Clay SL, Fonseca-Pereira D, Garrett WS. Colorectal cancer: the facts in the case of the microbiota. J Clin Invest. 2022;132(4).
3. Dalal N, Jalandra R, Bayal N, et al. Gut microbiota-derived metabolites in CRC progression and causation. J Cancer Res Clin Oncol. 2021;147(11):3141-3155.
4. Li J, Huang L, Zhao H, Yan Y, Lu J. The Role of Interleukins in Colorectal Cancer. Int J Biol Sci. 2020;16(13):2323-2339.
5. Thanikachalam K, Khan G. Colorectal Cancer and Nutrition. Nutrients. 2019;11(1).
6. Lee CG, Hwang S, Gwon SY, et al. Bacteroides fragilis Toxin Induces Intestinal Epithelial Cell Secretion of Interleukin-8 by the E-Cadherin/β-Catenin/NF-κB Dependent Pathway. Biomedicines. 2022;10(4).
7. Boleij A, Fathi P, Dalton W, et al. G-protein coupled receptor 35 (GPR35) regulates the colonic epithelial cell response to enterotoxigenic Bacteroides fragilis. Commun Biol. 2021;4(1):585.
8. Cui G, Li G, Pang Z, Florholmen J, Goll R. The presentation and regulation of the IL-8 network in the epithelial cancer stem-like cell niche in patients with colorectal cancer. Biomed Pharmacother. 2022;152:113252.
9. Jimenez-Alesanco A, Eckhard U, Asencio Del Rio M, et al. Repositioning small molecule drugs as allosteric inhibitors of the BFT-3 toxin from enterotoxigenic Bacteroides fragilis. Protein Sci. 2022;31(10):e4427.
10. Bilusic M, Heery CR, Collins JM, et al. Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. J Immunother Cancer. 2019;7(1):240.