The Effect of Probiotics on Colorectal Cancer

Colorectal cancer (CRC), includes rectum and colon cancer1, is the third most prevalent cancer and the second origin of cancer-related2 fatality among various cancer types in the world3. The incidence of CRC has been increasing steadily because of the causative role of diet and eating habits in developing countries despite technological improvements and health awareness campaigns4. Unfortunately, its incidence and mortality rate is expected to increase by 60% to over 2.2 million new cases and 1.1 million deaths in the next decade5.

Recent searches indicated that the gut microbiota composition may affect the emergence of CRC and other gut dysbioses4. The gastrointestinal tract (GI) is already populated with microbes at birth3,4, and throughout the host’s lifespan. The normal gut microbiota is composed of bacterial species, such as probiotics, that have morphological, physiological, and genetic characteristics that enable them to colonize and multiply in specific environments at specific sites, coexist with other colonizing microorganisms, and inhibit the growth of pathogenic bacteria through competitive exclusion3. In the recent past, this area of research has acquired considerable attention and has transformed the perspective on resident microbes and their functions3.

Figure 1: Colorectal Cancer (CRC)1.

Probiotics and CRC

Probiotics have been in existence for more than a century in practice4. According to the definition by the International Scientific Association for Probiotics and Prebiotics (ISAPP), “Probiotics are live microorganisms that when administered in adequate amounts confer a health benefit on the host.”2,3. They commonly fall under the lactic acid bacteria category and include Lactobacillus spp. and Bifidobacterium spp.3. Probiotics have been shown to enhance human health in many aspects, such as acting as an antibacterial agent against intestinal pathogens, managing blood cholesterol levels, decreasing the incidence of colitis and inflammation, regulating the immune system, and preventing cancer4,6,7. Especially, probiotics can play an anti-mutagen role in preventing the emergence of CRC4.

Preventive Mechanisms of Probiotics versus CRC

The specific mechanisms of probiotics remain not entirely elucidated. However, probiotics are supposed to have an antimutagen effect, according to recent experiments. Some of the proposed mechanisms by which probiotics exert anti-tumor effect:

  • The alteration metabolism of gut microbiota,
  • Inactivation of carcinogenic compounds,
  • Competition with putrefactive and pathogenic microbiota,
  • Enhancement of the host’s immune response,
  • Apoptosis and cell differentiation modulation for anti-proliferative effects,
  • Inhibition of tyrosine kinase signaling pathways3,4,6.

The Alternation Metabolism of Gut Microbiota

A particular type of bacteria in the gut may produce toxic metabolites, which could be a risk factor for CRC. Microbes in the gut that produces enzymes such as NAD(P)H dehydrogenase (azoreductase), nitroreductase, β-glucuronidase, β-glucosidase, and 7-α-dehydroxylase may be a trigger for the growth of cancer. Probiotics and commensal gut microbiota can affect the gut microbiota to inhibit CRC. Synthesizing a colonic fermentation product, short-chain fatty acids (SCFA), and antimicrobial peptides may have antimicrobial activity against bacteria that promote CRC. Probiotic bacteria contribute to transforming carcinogens into less hazardous compounds by detoxification, hence inhibiting CRC3,4,6.

Inactivation of Carcinogenic Compounds

Food carcinogens such as polycyclic aromatic hydrocarbons (PAH), heterocyclic amines (HCA), N-nitroso compounds (NOC), mycotoxins (aflatoxins), and acrylamide are formed when food is cooked at high temperatures. These components are possible risk factors for CRC and other cancer types. It has been discovered that HCA and N-nitroso compounds as well as other carcinogens can be bound or metabolized by lactic acid bacteria and other commensal bacteria. After exposing HCA to the bacterial strains, a decrease in mutagenicity was identified, and this is highly correlated with binding or degradation. Probiotics may be one of the major mechanisms for eliminating carcinogens from the human body through the binding or degradation of HCA3,4,6.

Competition with Pathogenic Microbiota

Research has shown that secondary bile salts are cytotoxic and carcinogenic. It is well known that a diet high in animal fat increases the growth of bacteria that produce them. The pathogenesis of CRC has been linked to the putrefactive gut microbiota, including Bacteroides spp. and Clostridium spp. Many lactic acid bacteria have been demonstrated to have cancer-preventing properties by competitive exclusion6,7. The adhesion to enterocytes and decrease in pH may mediate these effects. Probiotics may therefore inhibit the growth of CRC by competing with the pathogenic gut microbiota3,4,6.

Enhancement of the Host’s İmmune Response

The immune system is crucial in the regulation of tumor growth and process.  The development of a potent anti-tumor immune response depends on the interaction of multiple immune system components, including antigen-presenting cells (APCs), diverse T cells, B cells, and natural killer cells. Cytotoxic T-cells and natural killer (NK) cell activation are enhanced by probiotics’ promotion of macrophage and dendritic cell differentiation8. According to research, probiotics strengthen gut barrier activity by secreting anti-oxidative and anti-carcinogenic components and extend the immunostimulatory activity by generating anti-inflammatory cytokines3,4,6.

Figure 2: Immunomodulator effects of microbiota and probiotics on CRC2

Regulation of Apoptosis and Cell Differantation

Apoptosis is a genetically determined cell death mode crucial for regulating cell proliferation. Reduced ability to initiate apoptosis, associated with altered cell proliferation control systems, is significant in cancer. Probiotics may regulate cell proliferation and apoptosis, several potentially important processes in the prevention of CRC.  By interfering with the various phases of signaling pathways, they may induce apoptosis3,4,6.

Inhibition of Tyrosine Kinase Signaling Pathways

A cell communicates with the extracellular environment through a sequence of metabolic events known as signaling pathways. The tyrosine kinase signaling pathway plays a crucial role in carcinogenesis by regulating cell proliferation and differentiation.

Several different human gastrointestinal diseases can be prevented or treated using Saccharomyces boulardii (Sb), a safe probiotic agent. It has been claimed that Sb exerts its effects by altering the host signaling pathways that control the inflammatory response of the gut mucosa. Sb inhibits the mitogen-activated protein kinases (MAPK) signaling pathways, which are present in several growth-factor receptors, including the epidermal growth factor receptor (EGFR). Sb enhanced apoptosis, decreased EGF-mediated cell proliferation, and prevented the growth of cancer.  Probiotics may suppress the EGFR and other tyrosine kinase signaling pathways, and they can lead to a potential therapeutic benefit3,4.

Figure 3.1: Preventive Mechanisms of Probiotics on CRC3.
Figure 3.2: Preventive Mechanisms of Probiotics on CRC3.

Conclusion

When administered in adequate amounts, probiotics are proven to have significant adjuvant effects on the host’s health. The effects and mechanisms of probiotics on colorectal cancer, which is quite prevalent cancer worldwide, were evaluated in this review. Future-looking probiotics may pave the way for the onset of colorectal cancer and treatments.

References:

  1. Hossain, M. S., Karuniawati, H., Jairoun, A. A., Urbi, Z., Ooi, D. J., John, A., Lim, Y. C., Kibria, K. M. K., Mohiuddin, A. K. M., Ming, L. C., Goh, K. W., & Hadi, M. A. (2022, March 29). Colorectal cancer: A review of carcinogenesis, global epidemiology, current challenges, risk factors, preventive and treatment strategies. MDPI. Retrieved March 10, 2023, from https://www.mdpi.com/2072-6694/14/7/1732
  2. Shang, F., Jiang, X., Wang, H., Chen, S., Wang, X., Liu, Y., Guo, S., Li, D., Yu, W., Zhao, Z., & Wang, G. (2020, December). The inhibitory effects of probiotics on colon cancer cells: in vitro and in vivo studies. Journal of gastrointestinal oncology. Retrieved March 10, 2023, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807261/
  3. Uccello, M., Malaguarnera, G., Basile, F., D’agata, V., Malaguarnera, M., Bertino, G., Vacante, M., Drago, F., & Biondi, A. (2012, November 15). Potential role of probiotics on colorectal cancer prevention – BMC surgery. BioMed Central. Retrieved March 9, 2023, from https://bmcsurg.biomedcentral.com/articles/10.1186/1471-2482-12-S1-S35#Abs1
  4. Ambalam, P., Raman, M., Purama, R. K., & Doble, M. (2016, February 19). Probiotics, prebiotics and colorectal cancer prevention. Best Practice & Research Clinical Gastroenterology. Retrieved March 10, 2023, from https://www.sciencedirect.com/science/article/pii/S1521691816000135#sec7
  5. Mahdavi, M., Laforest-Lapointe, I., & Massé, E. (2021, June 18). Preventing colorectal cancer through prebiotics. MDPI. Retrieved March 10, 2023, from https://www.mdpi.com/2076-2607/9/6/1325
  6. Chong, E. S. L. (2013, September 26). A potential role of probiotics in colorectal cancer prevention: Review of possible mechanisms of action – world journal of microbiology and biotechnology. SpringerLink. Retrieved March 9, 2023, from https://link.springer.com/article/10.1007/s11274-013-1499-6
  7. Pandey, K. R., Naik, S. R., & Vakil, B. V. (2015, July 22). Probiotics, Prebiotics and synbiotics- A Review – Journal of Food Science and Technology. SpringerLink. Retrieved March 9, 2023, from https://link.springer.com/article/10.1007/s13197-015-1921-1
  8. Torres-Maravilla, E., Boucard, A.-S., Mohseni, A. H., Taghinezhad-S, S., Cortes-Perez, N. G., & Bermúdez-Humarán, L. G. (2021, May 10). Role of gut microbiota and probiotics in colorectal cancer: Onset and progression. MDPI. Retrieved March 12, 2023, from https://www.mdpi.com/2076-2607/9/5/1021

Figure References:

  1. Colon cancer: Q&A with a gastroenterologist. Colon Cancer: Q&A with a Gastroenterologist | Johns Hopkins Medicine. (2023, January 31). Retrieved March 27, 2023, from https://www.hopkinsmedicine.org/health/conditions-and-diseases/colon-cancer/colon-cancer-qanda-with-a-gastroenterologist
  2. Torres-Maravilla, E., Boucard, A.-S., Mohseni, A. H., Taghinezhad-S, S., Cortes-Perez, N. G., & Bermúdez-Humarán, L. G. (2021, May 10). Role of gut microbiota and probiotics in colorectal cancer: Onset and progression. MDPI. Retrieved March 12, 2023, from https://www.mdpi.com/2076-2607/9/5/1021
  3. Chong, E. S. L. (2013, September 26). A potential role of probiotics in colorectal cancerprevention: Review of possible mechanisms of action – world journal of microbiology and biotechnology. SpringerLink. Retrieved March 9, 2023, from https://link.springer.com/article/10.1007/s11274-013-1499-6

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