Oral Bacteria and the Risk of Colorectal Cancer

Oral Bacteria and the Risk of Colorectal Cancer

The relationship of oral infection and inflammation to certain systemic diseases has been a focus of intense study over the past 30 years. The oral disease of primary interest is periodontitis, as studies suggest that periodontitis has an adverse effect on certain noncommunicable chronic diseases (NCDs), primarily cardiovascular disease (CVD), diabetes mellitus (DM) and respiratory diseases (RD). Further, reports of some 40 other associations have appeared in the literature, albeit without the expansive body of research published for CVD, DM and RD.

The majority of published studies have reported associations, generally cross-sectional in nature, examining the presence of periodontitis and the presence of specific systemic diseases and disorders. There have been a few longitudinal studies, which are more challenging to conduct but offer the possibility of defining the temporal relationship of periodontitis to the NCD. Further, treatment studies have reported on the effect of conservative periodontal therapy on measures of health for persons with NCDs. The best example is provided by studies examining the effect of conservative periodontal treatment on a surrogate marker of the risk of DM progression [glycated hemoglobin (HbA1c)]. A definitive review concluded that periodontal treatment was associated with a statistically and clinically significant reduction in HbA1c, which is a surrogate marker for metabolic control in persons with DM, and a risk factor for development of clinical complications of this disease1Simpson TC, Clarkson JE, Worthington HV, MacDonald L, Weldon JC, Needleman I, et al. Treatment of periodontitis for glycaemic control in people with diabetes mellitus. Cochrane Database Syst Rev. 2022;4(4):CD004714..

Other studies have examined large private and public insurance databases to determine if conservative periodontal treatment/preventive dental care had an effect on health outcomes. These databases contained both medical and dental treatment data collected over a number of years. Again, focusing on DM, these longitudinal studies have consistently shown that accessing preventive dental care is associated with improved health outcomes, specifically reduced hospitalizations, spending on hospital services and total health care expenditures 2Nasseh K, Vujicic M, Glick M. The Relationship between Periodontal Interventions and Healthcare Costs and Utilization. Evidence from an Integrated Dental, Medical, and Pharmacy Commercial Claims Database. Health Econ. 2017;26(4):519-27.^,3Blaschke K, Hellmich M, Samel C, Listl S, Schubert I. The impact of periodontal treatment on healthcare costs in newly diagnosed diabetes patients: Evidence from a German claims database. Diabetes Res Clin Pract. 2021;172:108641.^,4Lamster IB MK, DiMura PM, Cheng B, Wagner VL, Matson JM, Proj A, Xi Y, Abel SN and Alfano MC (2022) Preventive dental care is associated with improved healht care outcomes and reduced costs for Medicaid members with diabetes. Front. Dent. Med 3:952182..

These clinical studies are both exciting and intriguing, as establishing the importance of periodontal treatment as a necessary therapy for persons with both periodontitis and specific NCDs will alter patient management. However, these relationships are strengthened by basic research that defines specific, molecular aspects that help explain the adverse effects of periodontal disease on specific systemic disorders. Such studies have begun to appear in the literature 5Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, et al. Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019;5(1):eaau3333.. Recently, a study was published in Nature, reporting on the role of the periodontal microbial pathogen Fusobacterium nucleatum (FN) in the pathogenesis of colorectal cancer (CRC;6Zepeda-Rivera M, Minot SS, Bouzek H, Wu H, Blanco-Miguez A, Manghi P, et al. A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche. Nature. 2024;628(8007):424-32.).

CRC is cancer that occurs in the large intestine and rectum at the terminal end of the gastrointestinal track. In the United States, CRC is the fourth most common cancer and second most common cancer affecting both sexes (7U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; https://www.cdc.gov/cancer/dataviz, released in June 2024. Accessed on September 21, 2024.; Figure 1). Classical risk factors for CRC include a close relative with a history of CRC (genetic/familial risk), inflammatory bowel disease, including ulcerative colitis and Crohn’s disease and certain genetic syndromes, such as familial adenomatous polyposis8cancer.org/cancer/types/colon-rectal-cancer.html. Accessed on September 15, 2024..

Symptoms that suggest the need for a screening test include any significant change in bowel habits, blood in or on stool, abdominal discomfort that does not abate and unexplained weight loss. As for all cancers, early detection is key to a favorable outcome, and at-risk individuals may need increased frequency of screening tests and procedures. In general, screening for CRC should begin at age 458cancer.org/cancer/types/colon-rectal-cancer.html. Accessed on September 15, 2024..

There are a number of screening procedures and tests for CRC. The most familiar is colonoscopy, in which a flexible tube provides visualization of any polyps and other suspicious lesions in the rectum and large intestine. A biopsy is needed to confirm the diagnosis. A virtual colonoscopy is also available, which is computer tomographic imaging of the colon. Tests that analyze stool samples are also used, including a guaiac-based test for occult blood, the fecal immunochemistry test and a combination fecal immunochemistry plus DNA test (where both blood and altered DNA characteristic of CRC are evaluated). These tests would be followed by a colonoscopy8cancer.org/cancer/types/colon-rectal-cancer.html. Accessed on September 15, 2024..

Treatment of diagnosed CRC depends on the stage of the cancer, but usually includes surgery, and also radiation therapy and chemotherapy. Treatment decisions are based in part on the system for classifying CRC (stages 0 to IV, with 0 being a cancer that has not spread beyond the inner layer of the colon/rectum, and IV being a cancer that has spread to other organs or tissues including lymph nodes, the peritoneum, lung and/or liver.

Implicated Oral Microorganism: Fusobacterium nucleatum

FN is a Gram-negative anaerobic bacterium that can exist as a commensal organism (existing without harming the host), as well as an opportunistic pathogen. In the oral cavity, FN has been associated with the development of periodontitis. Further, while FN has been identified in a number of locations in the body, the oral cavity is the major reservoir. This organism is essential to oral biofilm development and exists in that complex environment where the different bacterial species interact metabolically. FN also has a role in the development of the pathogenic oral biofilm due to its role in promoting bacterial adhesion, which includes aggregation of the other important periodontal pathogens Porphyromonas gingivalis and Treponema denticola. Further, FN has been shown to interact with the host inflammatory and immune systems, triggering the release of pro-inflammatory mediators. Of particular importance here, FN can influence the development of certain cancers, in particular CRC9Brennan CA, Garrett WS. Fusobacterium nucleatum - symbiont, opportunist and oncobacterium. Nat Rev Microbiol. 2019;17(3):156-66..

The relationship of microbial organisms to cancer has been the subject of considerable controversy. An extensive review provides an excellent introduction to this topic10Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science. 2021;371(6536).. The review notes that the role of infection in development, progression and even regression of cancer has been examined for centuries, with the importance of this relationship waxing and waning over time. The discovery of the potential role of the Rous Sarcoma Virus in development of malignancy in domestic birds restarted the search for other viruses, fungi and bacteria that have a role in cancer. However, the search for microbial agents directly involved in cancer development has yielded only a few specific examples, but their ability to influence development of certain cancers has been expanding. The most notable examples are the relationship of hepatitis C to liver cancer11Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006;25(27):3834-47., the human papilloma virus to cervical and oropharyngeal cancers12Szymonowicz KA, Chen J. Biological and clinical aspects of HPV-related cancers. Cancer Biol Med. 2020;17(4):864-78. and the bacterium Helicobacter pylori to stomach cancer13Bakhti SZ, Latifi-Navid S. Interplay and cooperation of Helicobacter pylori and gut microbiota in gastric carcinogenesis. BMC Microbiol. 2021;21(1):258..

The importance of the intestinal microbiota in the development of gastrointestinal cancers has attracted significant attention, and implicated bacteria include FN, Streptococcus bovis, Bacteroides fragilis, Enterococcus faecalis, Escherichia coli, and Peptostreptococcus anaerobius. Among the mechanisms identified are enhanced inflammation, release of virulence factors from specific bacteria, oxidative stress and the adverse effect of various microbial metabolites14Cheng Y, Ling Z, Li L. The Intestinal Microbiota and Colorectal Cancer. Front Immunol. 2020;11:615056..

A number of reviews have examined the relationship of cancers of the GI tract to FN.15Alon-Maimon T, Mandelboim O, Bachrach G. Fusobacterium nucleatum and cancer. Periodontol 2000. 2022;89(1):166-80. In the oral cavity, this organism is found in the subgingival biofilm as well as other mucosal surfaces. These authors note that while FN is found in the oral cavity when periodontitis is present, it is not regularly found in the microflora of the gastrointestinal track. However, a number of studies have found proportionally larger concentrations of FN in CRC samples as compared to normal tissues. This was determined by DNA/RNA analysis. This initial finding was a surprise, since as noted this organism is not generally part of the gut microflora.

Studies have confirmed that FN found in CRC samples were derived from the oral cavity. Samples were collected from the cancers and saliva from patients. PCR analysis indicated concurrence in 75% of the patients16Komiya Y SY, Higurashi T, et al. Patients with colorectal cancer have identical strains of Fusobacterium nucleatum in their colorectal cancer and oral cavity. Gut 2019;68:1335-1337.. Other studies have found similar results17Abed J, Maalouf N, Manson AL, Earl AM, Parhi L, Emgard JEM, et al. Colon Cancer-Associated Fusobacterium nucleatum May Originate From the Oral Cavity and Reach Colon Tumors via the Circulatory System. Front Cell Infect Microbiol. 2020;10:400.. The next question was how do bacteria from the oral cavity appear in the gastrointestinal track? Animal studies have examined two potential routes of transmission:

1. passage through the gastrointestinal track (swallowing),
2. spread via the hematological route, specifically related to subgingival ulceration and local access to the systemic circulation.

Animal models demonstrated greater efficiency with hematogenous spread versus colonization via the gastrointestinal track. Studies have examined colonization of CRC tumors when FN was introduced by intravenous injection and by bacteria introduced orally. When introduced intravenously, FN were detected in the tumors 2 hours after injection, and bacterial proliferation was observed by 24 hours17Abed J, Maalouf N, Manson AL, Earl AM, Parhi L, Emgard JEM, et al. Colon Cancer-Associated Fusobacterium nucleatum May Originate From the Oral Cavity and Reach Colon Tumors via the Circulatory System. Front Cell Infect Microbiol. 2020;10:400.. Other studies have shown that colonization occurred at near-physiologic levels of inoculation. FN bacterial cell surface molecules can bind to chains of sugars and proteins on tumor cell surfaces. In contrast, colonization though the gastrointestinal track would be hindered by the acidic pH of the stomach, the need to pass through the gastrointestinal microflora, and the disruptive effect of food passing through the gastrointestinal track (Table 1).

Once on the surface of CRC tissue cells, FN can increase the proliferation of tumor cells, as well as make these cells more resistant to the effects of chemotherapeutic agents, primarily by reducing apoptosis (the process of programmed cell death). Other mechanisms have been shown to make tumors more resistant to host defenses, as well as promote development of cancer metastasis15Alon-Maimon T, Mandelboim O, Bachrach G. Fusobacterium nucleatum and cancer. Periodontol 2000. 2022;89(1):166-80..

Recently, a comprehensive report examined the FN-CRC relationship in greater detail, focusing on biological mechanisms. One aspect of that study examined the genetic characterization of the bacteria found in both patients with CRC and healthy individuals6Zepeda-Rivera M, Minot SS, Bouzek H, Wu H, Blanco-Miguez A, Manghi P, et al. A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche. Nature. 2024;628(8007):424-32.. In addition, this study examined FN collected from the oral cavity of persons without CRC, as well as FN collected from CRC tumor cells. The primary interest was identification of genes that facilitated FN colonization of tumor cells.

First, FN associated with tumors belonged to a particular type (subspecies) of FN organism, referred to as FNa, and that FNa could be further divided into two clades (a distinction based on the evolution of a particular organism, identified by genetic characteristics) referred to as FNaC1 and FNaC2. The FNaC2 clade was specifically associated with CRC tumors. The genetic characteristics of FNaC2 suggested adverse effects on host cell metabolism and greater colonization of tumor cells.

When FNaC2 bacteria were introduced into a mouse model that had an increased propensity to develop intestinal tumors, animals receiving these organisms had a greater number of adenomas, as well as altered cellular metabolism.

The association between FNaC2 and CRC was further supported by their finding of increased number of FNaC2 in human CRC. Analysis of stool samples from CRC patients versus healthy controls supported the relationship between FNaC2 and CRC.

This study provides a detailed and quite elegant analysis of the genetic characterization that explains the association of FN and CRC. In addition to association studies and other basic clinical and population-based studies, genetic studies strengthen the oral disease-systemic disease associations that has been the subject of great interest to dental, medical and public health providers.

Conclusions:

The identification of an association between FN and the development of CRC, and now this detailed study providing specifics of the subtype of FN (FNaC2), suggest diagnostic and therapeutic approaches. However, the story is not complete, and additional studies are needed. Analysis of levels of FN, or a biomarker for FN, as well as antibody titers in blood to FN may be part of a screening approach for CRC9Brennan CA, Garrett WS. Fusobacterium nucleatum - symbiont, opportunist and oncobacterium. Nat Rev Microbiol. 2019;17(3):156-66.. Such tests would likely be specific for the particular subspecies or clade of FN (i.e., FNaC2). Therapy could be directed to reducing or eliminating detectable levels of FN in patients. Appropriate antibiotics could be used (i.e., metronidazole, clindamycin). Projecting forward, these authors suggest that given the prevalence of CRC, development of a specific vaccine (to the FNaC2 subtype) may be warranted, especially in areas of high prevalence and poor access to oral and general health care.

As so often is the case, new discoveries lead to additional questions and the need for more research. As the FN - CRC story becomes better understood, more research is required to define the appropriate course of dental/medical treatment. However, studies such as that published by Zepeda-Rivera6Zepeda-Rivera M, Minot SS, Bouzek H, Wu H, Blanco-Miguez A, Manghi P, et al. A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche. Nature. 2024;628(8007):424-32. deepen our understanding of the oral disease-systemic disease relationship and call for greater collaboration among dental and other health care providers.

Today, given what is known, it is reasonable to suggest that for a dental patient with established periodontitis and one or more risk factors for CRC, dental professionals should inform the patient about the FN-CRC relationship. In addition to appropriate medical follow-up and care, the need for periodontal treatment should be emphasized. This interprofessional approach to health care can improve both dental and medical outcomes.

Table 1: Fusobacterium nucleatum and colorectal cancer: spread of bacteria to a remote location in the gastrointestinal track

Figure 1:
Cancer rates in the United States, top 10, all races, male and female

Source: U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; https://www.cdc.gov/cancer/dataviz, released in June 2024.

References

• 1.Simpson TC, Clarkson JE, Worthington HV, MacDonald L, Weldon JC, Needleman I, et al. Treatment of periodontitis for glycaemic control in people with diabetes mellitus. Cochrane Database Syst Rev. 2022;4(4):CD004714.
• 2.Nasseh K, Vujicic M, Glick M. The Relationship between Periodontal Interventions and Healthcare Costs and Utilization. Evidence from an Integrated Dental, Medical, and Pharmacy Commercial Claims Database. Health Econ. 2017;26(4):519-27.
• 3.Blaschke K, Hellmich M, Samel C, Listl S, Schubert I. The impact of periodontal treatment on healthcare costs in newly diagnosed diabetes patients: Evidence from a German claims database. Diabetes Res Clin Pract. 2021;172:108641.
• 4.Lamster IB MK, DiMura PM, Cheng B, Wagner VL, Matson JM, Proj A, Xi Y, Abel SN and Alfano MC (2022) Preventive dental care is associated with improved healht care outcomes and reduced costs for Medicaid members with diabetes. Front. Dent. Med 3:952182.
• 5.Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, et al. Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019;5(1):eaau3333.
• 6.Zepeda-Rivera M, Minot SS, Bouzek H, Wu H, Blanco-Miguez A, Manghi P, et al. A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche. Nature. 2024;628(8007):424-32.
• 7.U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; https://www.cdc.gov/cancer/dataviz, released in June 2024. Accessed on September 21, 2024.
• 8.cancer.org/cancer/types/colon-rectal-cancer.html. Accessed on September 15, 2024.
• 9.Brennan CA, Garrett WS. Fusobacterium nucleatum - symbiont, opportunist and oncobacterium. Nat Rev Microbiol. 2019;17(3):156-66.
• 10.Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science. 2021;371(6536).
• 11.Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006;25(27):3834-47.
• 12.Szymonowicz KA, Chen J. Biological and clinical aspects of HPV-related cancers. Cancer Biol Med. 2020;17(4):864-78.
• 13.Bakhti SZ, Latifi-Navid S. Interplay and cooperation of Helicobacter pylori and gut microbiota in gastric carcinogenesis. BMC Microbiol. 2021;21(1):258.
• 14.Cheng Y, Ling Z, Li L. The Intestinal Microbiota and Colorectal Cancer. Front Immunol. 2020;11:615056.
• 15.Alon-Maimon T, Mandelboim O, Bachrach G. Fusobacterium nucleatum and cancer. Periodontol 2000. 2022;89(1):166-80.
• 16.Komiya Y SY, Higurashi T, et al. Patients with colorectal cancer have identical strains of Fusobacterium nucleatum in their colorectal cancer and oral cavity. Gut 2019;68:1335-1337.
• 17.Abed J, Maalouf N, Manson AL, Earl AM, Parhi L, Emgard JEM, et al. Colon Cancer-Associated Fusobacterium nucleatum May Originate From the Oral Cavity and Reach Colon Tumors via the Circulatory System. Front Cell Infect Microbiol. 2020;10:400.