Cancer, the exposome, and the microbiome

This is the First Prize Winner of the 2024 Molecular Oncology Writing Competition: Impact of the exposome on cancer risk.
Cancer, the exposome, and the microbiome
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As part of World Cancer Day (4th Feb), the journal of Molecular Oncology invited researchers to take part in a writing competition aimed at highlighting the impact of the exposome on cancer risk. This entry, by Hayley Brownless (University of Edinburgh, UK), received the first prize.

As humans we are constantly exposed to factors with the potential to cause cancer, perhaps most obviously are carcinogens within cigarettes and UV radiation. However, there are several dietary factors which may cause or increase cancer risk. Consumption of the western diet (defined by high intake of energy-dense, processed foods which are poor in nutrients) is particularly interesting as this is associated with gut dysbiosis (Clemente-Suárez et al., 2023), an emerging risk factor for multiple cancer types. By exploring evidence within the current literature, I hope to explain the impact of gut dysbiosis on cancer risk and indicate how dietary modifications may reduce this risk.

Each human body is home to a unique assortment of commensal microorganisms which carry out essential functions within our bodies, known as the microbiome, however dysbiosis can occur when growth of these microorganisms becomes abnormal or imbalanced (Vimal et al., 2020). There are multiple causes of dysbiosis, for example, antibiotic use has been shown to significantly change the composition of the gut microbiome, particularly through reducing the diversity of microorganisms (Luchen et al., 2023). Western diets are also considered drivers of gut dysbiosis, for example, Agus et al. (2016) demonstrated the western diet induces inflammation within the gut and significantly alters the microbiome of the colon in murine models. 

There are several mechanisms by which gut dysbiosis has the potential to increase cancer risk, many of which have been studied in colorectal cancer, however, gut dysbiosis has also been linked to several cancer types, including lung, prostate, and breast cancer which, alongside colorectal cancer, comprise the most common cancer types. In some cases, microorganisms directly impact cancer risk whilst more generally, dysbiosis can promote oxidative stress and inflammation which may increase an individual's risk of cancer (Clemente-Suárez et al., 2023).

Enterotoxigenic Bacteroides fragilis (ETBF) asymptotically colonises between 20 and 35% of adults and was demonstrated to increase colorectal cancer risk in murine models (Wu et al., 2009). This is mediated by activation of STAT3 within the colon, which then activates a subset of helper T cells which produce IL-17 (Wu et al. 2009). Since IL-17 inhibition prevented carcinogenesis, Wu et al. (2009) demonstrated ETBF induces carcinogenesis in a pathway dependent upon IL-17. Zhong et al. (2022) also implicated STAT3 in carcinogenesis by transplanting prostate tumours into mice, following induction of gut dysbiosis using oral antibiotics. When comparing healthy mice and antibiotic treated mice, the latter had greater tumour volume and tumour weight (Zhong et al., 2022). The tumours in the antibiotic treated group also contained significantly higher lipopolysaccharide, which is produced by gram negative bacteria, this promotes inflammation and cancer progression by activating IL-6 and STAT3 (Zhong et al., 2022).

In patients with lung cancer, analysis of microbial DNA in faecal samples found composition of the microbiome is distinct compared to the gut microbiome of healthy controls, and exhibits depletion of Firmicutes bacteria (Liu et al., 2019). Similarly, colorectal cancer patients also exhibit significant depletions in bacteria from the Firmicutes phylum (Wang et al., 2012). Firmicutes bacteria produce Butyrate which is known to be involved in several processes which reduce carcinogenesis, including anti-inflammatory pathways, oxidative stress response, induction of apoptosis and reducing co-carcinogenic enzyme activity, when depleted, the ability to perform these functions is reduced, thereby promoting carcinogenesis (Liu et al., 2019; Wang et al., 2012).

Altogether, this paints a rather bleak picture for those of us who require antibiotic treatment or consume a western diet, but hope is not lost, as individuals and as researchers we may be able to manipulate the exposome to reduce gut dysbiosis and the risk of cancer. The impact of antibiotics on gut dysbiosis may be alleviated through fibre supplementation prior to antibiotic treatment, as this leads to a smaller reduction in gut microbiome diversity and a more complete microbiome recovery (Penumutchu et al., 2023). Dietary modifications can also reduce cancer risk; consumption of the mediterranean diet, which is high in fruit, vegetables, whole-grains, fish, olive oil, and red wine is known to reduce gut dysbiosis (Grosso et al., 2013; Mitsou et al., 2017).

Ongoing studies may also provide more insight into the association between gut dysbiosis and cancer. Currently, the relationship between gut microbiome composition and various stages of breast cancer is being investigated by Plaza-Díaz et al. (2019), with the hope of better understanding changes to the gut and mammary microbiota and the environmental contaminants which may cause these alterations.

References

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  • Clemente-Suárez, V. J., Beltrán-Velasco, A. I., Redondo-Flórez, L., Martín-Rodríguez, A., & Tornero-Aguilera, J. F. (2023). Global Impacts of Western Diet and Its Effects on Metabolism and Health: A Narrative Review. Nutrients, 15(12). https://doi.org/10.3390/nu15122749
  • Grosso, G., Buscemi, S., Galvano, F., Mistretta, A., Marventano, S., Vela, V. La, Drago, F., Gangi, S., Basile, F., & Biondi, A. (2013). Mediterranean diet and cancer: epidemiological evidence and mechanism of selected aspects. BMC Surgery, 13(S2), S14. https://doi.org/10.1186/1471-2482-13-S2-S14
  • Liu, F., Li, J., Guan, Y., Lou, Y., Chen, H., Xu, M., Deng, D., Chen, J., Ni, B., Zhao, L., Li, H., Sang, H., & Cai, X. (2019). Dysbiosis of the Gut Microbiome is associated with Tumor Biomarkers in Lung Cancer. International Journal of Biological Sciences, 15(11), 2381–2392. https://doi.org/10.7150/ijbs.35980
  • Luchen, C. C., Chibuye, M., Spijker, R., Simuyandi, M., Chisenga, C., Bosomprah, S., Chilengi, R., Schultsz, C., Mende, D. R., & Harris, V. C. (2023). Impact of antibiotics on gut microbiome composition and resistome in the first years of life in low- to middle-income countries: A systematic review. PLOS Medicine, 20(6), e1004235. https://doi.org/10.1371/journal.pmed.1004235
  • Mitsou, E. K., Kakali, A., Antonopoulou, S., Mountzouris, K. C., Yannakoulia, M., Panagiotakos, D. B., & Kyriacou, A. (2017). Adherence to the Mediterranean diet is associated with the gut microbiota pattern and gastrointestinal characteristics in an adult population. British Journal of Nutrition, 117(12), 1645–1655. https://doi.org/10.1017/S0007114517001593
  • Penumutchu, S., Korry, B. J., Hewlett, K., & Belenky, P. (2023). Fiber supplementation protects from antibiotic-induced gut microbiome dysbiosis by modulating gut redox potential. Nature Communications, 14(1), 5161. https://doi.org/10.1038/s41467-023-40553-x
  • Plaza-Díaz, J., Álvarez-Mercado, A. I., Ruiz-Marín, C. M., Reina-Pérez, I., Pérez-Alonso, A. J., Sánchez-Andujar, M. B., Torné, P., Gallart-Aragón, T., Sánchez-Barrón, M. T., Reyes Lartategui, S., García, F., Chueca, N., Moreno-Delgado, A., Torres-Martínez, K., Sáez-Lara, M. J., Robles-Sánchez, C., Fernández, M. F., & Fontana, L. (2019). Association of breast and gut microbiota dysbiosis and the risk of breast cancer: a case-control clinical study. BMC Cancer, 19(1), 495. https://doi.org/10.1186/s12885-019-5660-y
  • Vimal, J., Himal, I., & Kannan, S. (2020). Role of microbial dysbiosis in carcinogenesis & cancer therapies. The Indian Journal of Medical Research, 152(6), 553–561. https://doi.org/10.4103/ijmr.IJMR_1026_18
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  • Wu, S., Rhee, K.-J., Albesiano, E., Rabizadeh, S., Wu, X., Yen, H.-R., Huso, D. L., Brancati, F. L., Wick, E., McAllister, F., Housseau, F., Pardoll, D. M., & Sears, C. L. (2009). A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nature Medicine, 15(9), 1016–1022. https://doi.org/10.1038/nm.2015
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