Lalita Kunamneni

Background: Colorectal cancer (CRC) is the second deadliest and third most common cancer globally.¹ Although the mortality rate for CRC has decreased over the past two decades, there is a rising incidence in individuals under 50, well below the median age of onset at 67 years. ¹,²,³ Approximately 20% of CRC cases are metastatic, significantly impacting survival rates with a 14% 5-year metastatic survival rate compared to around 90% 5 year survival rate for non-metastatic Stage II cases. ³ Risk factors for CRC include inflammatory bowel disease, Lynch syndrome, and lifestyle factors such as red meat consumption, high-fat diets, obesity, alcohol and tobacco use, and long-term antibiotic use in early to middle adulthood. ⁴^,⁵ Of the two main types of CRC, distal and proximal, proximal CRC is more challenging to diagnose early, which impacts survival outcomes. ³ African Americans face health disparities with CRC, being more likely to have early onset and proximal tumors, which could partially be attributed to differences in ancestral gut microbiome composition, such as higher levels of Fusobacterium nucleatum (F. nucleatum). ² F. Nucleatum is an anaerobic gram-negative bacteria usually affiliated with the oral cavity, and when present in the gut microbiome, has significant impact on the progression of CRC. ²

Objective(s): This narrative review explores how the presence of F. Nucleatum in the gut microbiome alters the progression of CRC and the cellular mechanisms of inflammation, suppressed immune response, and increased metastasis involved.^6,7,8,9

Search Methods: An online search in the PubMed database was conducted from 2019 to 2024 using the following searches: (“Colorectal Neoplasms”[Mesh] OR “Colorectal Cancer”[Mesh]) AND (“Microbiota”[Mesh] OR “Dysbiosis”[Mesh]) AND (“Inflammation”[Mesh] OR “Lymphangiogenesis”[Mesh] OR “Lymphatic System”[Mesh]) and “Fusobacterium nucleatum” AND (“Colorectal Neoplasms”[Mesh] OR “Colorectal Cancer”[Mesh]).

Results: F. Nucleatum impacts CRC by increasing cell proliferation and inflammation through the Wnt/beta catenin pathway by up regulating CDK5, which causes increased transcription of genes such as Myc, that is not present in other pathogenic bacteria like E. Coli.⁸ Upregulation of CDK5 was also shown to significantly increase the rate of migration in cells as well, increasing metastases.⁸ Increased metastasis was also caused by F. Nucleatum’s upregulation of pro-inflammatory and pro-metastatic cytokines IL8 and CXCL1 binding Fap2 that cause both infected and noninfected cells to migrate.⁹ F. Nucleatum also suppresses natural killer cell activity which was measured through a significant decrease in IFN-gamma levels, and the loss of this early defense mechanism is associated with increased cancer risk.⁷ F. Nucleatum changes the totality of the gut microbiome by downregulating probiotic bacteria and enriching pro-inflammatory bacteria pathogenic bacteria.⁶ F. Nucleatum causes overexpression of TLR4, nuclear factor-kappaB, and FABP1, which cause hyperactivation of the immune system and is associated with chronic inflammation, tumor growth, and poor prognosis because they contribute to the epithelial-mesenchymal transition and reduced E cadherin expression.⁶ Although it is possible to target specific gene mechanisms to create treatments to minimize CRC metastases and improve outcomes, a holistic downregulation of F. Nucleatum could prove to be incredibly effective.^10,11 In a study that followed the effects of diet and Vitamin D sufficiency on CRC, while not sufficient to prove causation, the inverse relationship between serum levels of Vitamin D and post-treatment concentration of F. Nucleatum was of note.^10,11 Additionally, Vitamin D deficiency may partially contribute to poor CRC outcomes and health disparities in African American populations.¹²

Conclusion: F. Nucleatum influences CRC outcomes through a variety of mechanisms such as increased CDK5, IL8, and CXCL1 expression, decreased natural killer cell activity, and altered microbiota and the epithelial mesenchymal transition.^6,7,8,9 Further research is needed to determine the use of Vitamin D as a prophylactic measure to reduce incidence of F. Nucleatum and subsequent severity of CRC. ^10,11

Works CIted:

1.  Quaglio AEV, Grillo TG, De Oliveira ECS, Di Stasi LC, Sassaki LY. Gut microbiota, inflammatory bowel disease and colorectal cancer. World J Gastroenterol. 2022;28(30):4053-4060. doi:10.3748/wjg.v28.i30.4053
2. Ahmad S, Ashktorab H, Brim H, Housseau F. Inflammation, microbiome and colorectal cancer disparity in African-Americans: Are there bugs in the genetics?. World J Gastroenterol. 2022;28(25):2782-2801. doi:10.3748/wjg.v28.i25.2782
3. Biller LH, Schrag D. Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA. 2021;325(7):669-685. doi:10.1001/jama.2021.0106
4. Xing C, Du Y, Duan T, et al. Interaction between microbiota and immunity and its implication in colorectal cancer. Front Immunol. 2022;13:963819. Published 2022 Jul 29. doi:10.3389/fimmu.2022.963819
5. Patel SG, Karlitz JJ, Yen T, Lieu CH, Boland CR. The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection. Lancet Gastroenterol Hepatol. 2022;7(3):262-274. doi:10.1016/S2468-1253(21)00426-X
6. Wu N, Feng YQ, Lyu N, Wang D, Yu WD, Hu YF. Fusobacterium nucleatum promotes colon cancer progression by changing the mucosal microbiota and colon transcriptome in a mouse model. World J Gastroenterol. 2022;28(18):1981-1995. doi:10.3748/wjg.v28.i18.1981
7. Kim YJ, Kim BK, Park SJ, Kim JH. Impact of Fusobacterium nucleatum in the gastrointestinal tract on natural killer cells. World J Gastroenterol. 2021;27(29):4879-4889. doi:10.3748/wjg.v27.i29.4879
8. Li X, Huang J, Yu T, et al. Fusobacterium nucleatum Promotes the Progression of Colorectal Cancer Through Cdk5-Activated Wnt/β-Catenin Signaling. Front Microbiol. 2021;11:545251. Published 2021 Jan 6. doi:10.3389/fmicb.2020.545251
9. Casasanta MA, Yoo CC, Udayasuryan B, et al. Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration. Sci Signal. 2020;13(641):eaba9157. Published 2020 Jul 21. doi:10.1126/scisignal.aba9157
10. Serrano D, Pozzi C, Guglietta S, et al. Microbiome as Mediator of Diet on Colorectal Cancer Risk: The Role of Vitamin D, Markers of Inflammation and Adipokines. Nutrients. 2021;13(2):363. Published 2021 Jan 25. doi:10.3390/nu13020363
11. Bellerba F, Serrano D, Johansson H, et al. Colorectal cancer, Vitamin D and microbiota: A double-blind Phase II randomized trial (ColoViD) in colorectal cancer patients. Neoplasia. 2022;34:100842. doi:10.1016/j.neo.2022.100842
12. Ames BN, Grant WB, Willett WC. Does the High Prevalence of Vitamin D Deficiency in African Americans Contribute to Health Disparities?. Nutrients. 2021;13(2):499. Published 2021 Feb 3. doi:10.3390/nu13020499