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The Human Microbiome and Cancer Part 1

Updated: May 16, 2023

The human microbiome is the collection of all microorganisms that reside in or on the human body. It includes bacteria, fungi, protozoa and viruses. The collection of organisms that reside in our gastrointestinal tract is called the gut microbiome. It contains about 100 trillion microbes, bacteria being the predominant type. This complex system of microorganisms is known to have a profound impact on human health and well-being as it helps us digest food, produce important vitamins (especially vitamin K and B vitamins), protect us from disease-causing pathogens, help modulate weight and metabolism, and train our immune system.[1]

The exact make-up and abundance of species in each individual’s microbiome will vary from person to person. These differences arise from a variety of factors including whether or not a person was breastfed, birthing method, their diet, and geographical location. Our medical history can also play a role in shaping the abundance and kinds of species that live inside us - past infections or use of medications may cause this unique landscape to fluctuate over time.

A healthy gut microbiome is characterized by four main qualities: high diversity, stability, resistance to competition and stress, and resilience. An unhealthy gut microbiota generally has a considerably lower abundance and variety of organisms. Microbiota imbalance can significantly impact the health of an individual in numerous ways.

The microbiome is an area of huge interest in the scientific community with many studies being published in a wide range of settings such as metabolic and autoimmune diseases as well as mental health. In recent years, the role of the microbiome in cancer has come under increasing scrutiny. An increasing body of evidence has suggested that alterations in the gut microbiome can also be linked to the development and progression of many cancers including breast, bladder, lung, gastrointestinal and hepatobiliary malignancies such as oesophageal, liver, pancreatic and colorectal cancer.[2][3][4][5][6]

While certain types of bacteria are associated with an increased risk of cancer, research has also found that others seem to protect against it. One of the ways the microbiome influences risk is through inflammation and immune function. The microbiome can also affect how the body responds to cancer treatment. The aim of this blog post is to provide an overview of the current state of knowledge regarding the role of the microbiome in cancer.

The Microbiome and Cancer Risk Factors

The microbiome regulates inflammation and immune function which impact cancer risk by influencing cell growth, DNA damage and repair, and tumorigenesis.[7] Additionally, some microbes may themselves produce harmful substances that can damage DNA or disrupt normal cell growth.

Fortunately, healthy microbes in the gut may play a role in protecting against cancer through:

  1. competing with harmful bacteria for space and nutrients,

  2. training the immune system to recognise and destroy cancerous cells, and

  3. regulating inflammation through the production of short-chain fatty acids (SCFAs).[8]

However, in a state of dysbiosis, imbalance of gut flora can promote opportunistic pathogenic bacteria. Numerous scientific investigations have now corroborated the association between carcinogenicity and alterations in microbial balance. For example, recent research in newly diagnosed bladder cancer patients has found a reduced abundance of Clostridium cluster XI and Prevotella alongside a decrease in the faecal levels of the short-chain fatty acid butyrate.[9]

Several studies show that both the lung and gut microbiome promote lung cancer initiation and development by inhibiting immune function and producing inflammation.[10] In gastrointestinal cancers, microbial metabolites can play a key role in carcinogenesis by triggering a cascade of proinflammatory responses. For example, secondary bile acids can activate receptors which lead to increased intestinal cell proliferation, DNA damage, and cellular aging eventually promoting an environment conducive to malignancy.2

The prevalence of unhealthy dietary patterns is recognized as one of the leading contributors to non-communicable diseases including obesity, type 2 diabetes, cardiovascular diseases and several types of cancer. There is growing evidence that this association may be in part caused or accompanied by alterations in gut microbiota.[11] Studies suggest that the development of colorectal cancer for example, may be heralded by significant microbial and metabolic modifications. These are often the result of consuming diets that are rich in processed foods, animal fats and red meat, together with a low intake of fibre and fruits.[12]

Consuming a typical Western diet is characterized by a significant decrease in the number and variety of beneficial bacterial species and an increase in the proportion of harmful bacteria. The ubiquitous presence of sugar, salt, and fat in the standard Western diet has been linked to gut microbial dysbiosis, and leads to a cascade of deleterious effects on the intestinal barrier eventually leading to leaky gut. This can result in the presence of large bacterial toxins (lipopolysaccharides) in the bloodstream, causing chronic inflammation throughout the body.[13]

The Human Microbiome and Cancer Treatment

The gut microbiota is receiving increasing attention for its role in modulating chemotherapy and immunotherapy treatment effectiveness in cancer treatment. Recent studies demonstrate that the microbiota can contribute to the tumour microenvironment by creating a milieu that favours the toxic effect of chemotherapy drugs on cancer cells.[14] The metabolism of chemotherapy drugs by gut bacteria before they reach their target tissues can influence the effectiveness of chemotherapy drugs. Some gut bacteria have been shown to increase resistance to chemotherapy drugs while others may increase sensitivity.[15] [16] [17]

The potential use of microbiota in immunotherapeutic responses is an area of growing interest and research. Recent studies have shown a correlation between the diversity of gut microbiota and the effectiveness of anti-PD-1 immunotherapy in patients with metastatic melanoma. Patients with a higher diversity of gut microbes may have a longer time without their cancer progressing. Whereas, using antibiotics within 30 days of taking immune checkpoint inhibitors may shorten the time before progression and reduce survival times in patients with advanced renal cell carcinoma and non-small cell lung cancer. These findings are promising and suggest that understanding the role of microbiota in immunotherapy can lead to more effective treatments for cancer patients.[18]

There is also evidence to suggest that manipulation of the gut microbiome could potentially be used as a strategy for enhancing radiotherapy treatment response. Studies have shown that certain types of gut bacteria are able to convert radiation therapy into reactive oxygen species (ROS). ROS are highly toxic molecules that can kill cancer cells without harming healthy tissue. Therefore, manipulation of the gut microbiome could potentially be used to enhance radiotherapy efficacy while minimizing side effects. [19]

As more studies are conducted on the gut microbiome it is becoming clearer that a healthy microbiome can support optimal health, and an unhealthy microbiome may contribute to diseases such as cancer. Manipulation of the gut microbiome represents a promising new frontier in cancer prevention and therapy. This research opens up exciting new possibilities for treatments that include restoring the balance of the microbiome or even manipulating the microbiome to limit harmful inflammation involved in cancers or other conditions. It’s exciting to consider how much progress could be made with further understanding of this complex ecosystem!

References [1] Dzutsev A, Badger JH, Perez-Chanona E, et al. Microbes and Cancer. Annu Rev Immunol. 2017;35:199-228. doi:10.1146/annurev-immunol-051116-052133 [2] Long Y, Tang L, Zhou Y, Zhao S, Zhu H. Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study. BMC Med. 2023 Feb 21;21(1):66. doi: 10.1186/s12916-023-02761-6. PMID: 36810112; PMCID: PMC9945666. [3] Baba Y, Iwatsuki M, Yoshida N, Watanabe M, Baba H. Review of the gut microbiome and esophageal cancer: Pathogenesis and potential clinical implications. Ann Gastroenterol Surg. 2017;1(2):99-104. Published 2017 Jun 7. doi:10.1002/ags3.12014 [4] Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol. 2017;14(9):527-539. doi:10.1038/nrgastro.2017.72 [5] Wei MY, Shi S, Liang C, et al. The microbiota and microbiome in pancreatic cancer: more influential than expected. Mol Cancer. 2019;18(1):97. Published 2019 May 20. doi:10.1186/s12943-019-1008-0 [6] Castellarin, M., Warren, R. L., Freeman, J. D., Dreolini, L., Krzywinski, M., Strauss, J., ... & Holt, R. A. (2012). Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome research, 22(2), 299-306. [7] Meng C, Bai C, Brown TD, Hood LE, Tian Q. Human Gut Microbiota and Gastrointestinal Cancer. Genomics Proteomics Bioinformatics. 2018 Feb;16(1):33-49. doi: 10.1016/j.gpb.2017.06.002. Epub 2018 Feb 21. PMID: 29474889; PMCID: PMC6000254. [8] Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013 Dec 19;504(7480):451-5. doi: 10.1038/nature12726. Epub 2013 Nov 13. PMID: 24226773; PMCID: PMC3869884. [9] He, C., Li, B., Huang, L., Teng, C., Bao, Y., Ren, M., & Shan, Y. (2020). Gut microbial composition changes in bladder cancer patients: A case-control study in Harbin, China. Asia Pacific journal of clinical nutrition, 29(2), 395-403. [10] Zhao Y, Liu Y, Li S, Peng Z, Liu X, Chen J, Zheng X. Role of lung and gut microbiota on lung cancer pathogenesis. J Cancer Res Clin Oncol. 2021 Aug;147(8):2177-2186. doi: 10.1007/s00432-021-03644-0. Epub 2021 May 20. PMID: 34018055; PMCID: PMC8236441. [11] García-Montero C, Fraile-Martínez O, Gómez-Lahoz AM, Pekarek L, Castellanos AJ, Noguerales-Fraguas F, Coca S, Guijarro LG, García-Honduvilla N, Asúnsolo A, Sanchez-Trujillo L, Lahera G, Bujan J, Monserrat J, Álvarez-Mon M, Álvarez-Mon MA, Ortega MA. Nutritional Components in Western Diet Versus Mediterranean Diet at the Gut Microbiota-Immune System Interplay. Implications for Health and Disease. Nutrients. 2021 Feb 22;13(2):699. doi: 10.3390/nu13020699. PMID: 33671569; PMCID: PMC7927055. [12] Gonzalez CA, Riboli E. Diet and cancer prevention: Contributions from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Eur J Cancer. 2010;46(14):2555-2562. doi:10.1016/j.ejca.2010.07.025 [13] Beam A, Clinger E, Hao L. Effect of Diet and Dietary Components on the Composition of the Gut Microbiota. Nutrients. 2021 Aug 15;13(8):2795. doi: 10.3390/nu13082795. PMID: 34444955; PMCID: PMC8398149. [14] Fernandes MR, Aggarwal P, Costa RGF, Cole AM, Trinchieri G. Targeting the gut microbiota for cancer therapy. Nat Rev Cancer. 2022 Dec;22(12):703-722. doi: 10.1038/s41568-022-00513-x. Epub 2022 Oct 17. PMID: 36253536. [15] Elinav E, Garrett WS, Trinchieri G, Wargo J. The cancer microbiome. Nat Rev Cancer. 2019 Jul;19(7):371-376. doi: 10.1038/s41568-019-0155-3. Epub 2019 Jun 11. PMID: 31186547; PMCID: PMC6700740. [16] Roy S, Trinchieri G. Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer. 2017 May;17(5):271-285. doi: 10.1038/nrc.2017.13. Epub 2017 Mar 17. PMID: 28303904. [17] Kumar M, Singh P, Murugesan S, Vetizou M, McCulloch J, Badger JH, Trinchieri G, Al Khodor S. Microbiome as an Immunological Modifier. Methods Mol Biol. 2020;2055:595-638. doi: 10.1007/978-1-4939-9773-2_27. PMID: 31502171. [18] Zhao M, Jiang G, Zhou H, Li J, Xiang W, Li S, Wang H, Zhou J. Gut microbiota: a potential target for improved cancer therapy. J Cancer Res Clin Oncol. 2023 Jan;149(1):541-552. doi: 10.1007/s00432-022-04546-5. Epub 2022 Dec 23. PMID: 36550389. [19] Eaton, S.E., Kaczmarek, J., Mahmood, D. et al. Exploiting dietary fibre and the gut microbiota in pelvic radiotherapy patients. Br J Cancer 127, 2087–2098 (2022).

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