Radiotherapy and the Microbiome

More than half of patients with new cancer diagnoses will undergo radiation therapy, but acute radiotoxicities, such as dermatitis and mucositis, can disrupt or curtail treatment.^6,7 Half of patients undergoing cancer radiotherapy will experience gastrointestinal mucositis.⁶

Pretreatment microbiomes are believed to affect how tumors respond to irradiation and to modulate patients’ radiation toxicities. In laboratory studies, several gut bacteria, including Enterococcus, Clostridium, and Bacteroides, affect colorectal cancer cells’ production of angiopoietin-like 4 (ANGPTL4) protein, which promotes cellular resistance to radiation.⁷

Radiotoxicities and their severity vary markedly from patient to patient, depending on fraction dose, tumor location, other treatment modalities, patient comorbidities, age, smoking history, and genotypes.⁷ Although the scope of interplay between radiation oncology and microbiomes is currently uncertain terrain, radiotherapy culls radiosensitive species from the microbiome and allows radioresistant strains to thrive.

Ionizing radiation can change the composition of the microbiome and damage the human tissues on and in which microbial communities live, causing dysbiosis.⁷ Animal and clinical human studies show that irradiation of gut tissues change the diversity of microbiome species, and populations of remaining species, in ways that appear to contribute to mucositis.^6,7,17,18 For example, radiotherapy is associated with declines in gut populations of Bifidobacterium, Faecalibacterium, Enterobacteriaceae,and Bacteroides, and these changes are associated with mucositis and diarrhea.^6,7,15

Related Content

Radiation-associated dysbiosis involves reductions in beneficial populations of gut microbes that can lead to proliferation of other, pathogenic species such as Clostridium difficile and Alistipes bacteria, which is associated with and might promote the growth of colon cancer.^6-8 Pelvic radiotherapy is associated with increases in Fusobacterium in humans, some species of which appear to be tumor-promoting; in mice, Fusobacterium impairs radiotherapy against colorectal tumors.^2,19

Probiotics — swallowed living nonpathogenic microbes — might prove helpful in reversing this invasive process and restore healthy oral and gut microbiome ecosystems, but more clinical research is needed.²⁰

Radiation-induced changes in gut microbiomes, epithelium, and mucosa can also lead to the movement of bacteria through damaged barriers in the gut lining, resulting in local immune system responses and inflammation that can cause severe radiation-associated diarrhea.²

The Future of Microbiome Oncology

Microbiome and metagenomic analyses might in the future serve as prognostic and treatment response-predictive biomarkers that can inform treatment planning.⁷

Some researchers believe clinical microbiome modifications will be developed and approved to improve cancer radiotherapy’s efficacy and to reduce the incidence and severity of radiation toxicities.^2,5,7,15 Authors of a study of Fusobacterium and colorectal tumor radioresistance proposed that metronidazole, an antibiotic that kills this harmful bacteria, might be a neoadjuvant radiosensitizer for pretreatment of tumors ahead of radiotherapy.¹⁹ Genetically edited bacteria might one day be used to attack dangerous invasive strains and reengineer microbiomes.¹⁶

Priobiotics are being developed as adjuvant treatments to reduce radiotherapy toxicities. In laboratory animal studies, probiotics reduced radiation damage to intestinal tissue and reduced weight loss and mortality rates among mice.²⁰ Clinical trials in human patients show probiotics are associated with reduced rates of oral mucositis in patients undergoing chemoradiation for head and neck cancers, and reduced gastrointestinal mucositis symptoms in patients undergoing pelvic radiotherapy.^20-21 The Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for the management of mucositis suggests Lactobacillus-containing probiotics might help prevent pelvic radiation and chemoradiation-induced diarrhea.²²

Another, more controversial, field of clinical inquiry is fecal transplantation between patients.^2,5,7,12 But such experiments are not without risk. The US government halted several clinical trials of fecal transplantation in 2019 after patients were infected with antibiotic-resistant extended-spectrum beta-lactamase [ESBL] E. coli.²³

The roles of the microbiome in carcinogenesis, tumor progression, clinical oncology, and radiotherapy are just beginning to be deeply explored. One day, evidence-based, microbiome-targeted therapies might become routine. But we’re not there yet, and clinical research has been slow to materialize, perhaps in part because this research is not a promising avenue to lucrative, blockbuster cancer treatment patents. An April 2023 search of the ClinicalTrials.gov study registration database identified more than 400 registered projects investigating cancer patients’ microbiomes but only 9 phase 3 clinical trials, none of which are actively recruiting study participants.

References

1. Jansz N, Faulkner GJ. Endogenous retroviruses in the origins and treatment of cancer. Genome Biol. 2021;22(1):147. doi:10.1186/s13059-021-02357-4

2. Cullin N, Antunes CA, Straussman R, Stein-Thoeringer CK, Elinav E. Microbiome and cancer. Cancer Cell. 2021;39(10):1317-1341. doi:10.1016/j.ccell.2021.08.006

3. Jaye K, Li CG, Bhuyan DJ. The complex interplay of gut microbiota with the five most common cancer types: from carcinogenesis to therapeutics to prognoses. Crit Rev Oncol Hematol. 2021;165:103429. doi:10.1016/j.critrevonc.2021.103429

4. Bahig H, Fuller CD, Mitra A, et al. Longitudinal characterization of the tumoral microbiome during radiotherapy in HPV-associated oropharynx cancer. Clin Transl Radiat Oncol. 2020;26:98-103. doi:10.1016/j.ctro.2020.11.007

5. McQuade JL, Daniel CR, Helmink BA, Wargo JA. Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol. 2019;20(2):e77-e91. doi:10.1016/S1470-2045(18)30952-5

6. Touchefeu Y, Montassier E, Nieman K, et al. Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis — current evidence and potential clinical applications. Aliment Pharmacol Ther. 2014;40(5):409-421. doi:10.1111/apt.12878

7. Liu J, Liu C, Yue J. Radiotherapy and the gut microbiome: facts and fiction. Radiat Oncol. 2021;16(1):9. doi:10.1186/s13014-020-01735-9

8. Parker BJ, Wearsch PA, Veloo ACM, Rodriguez-Palacios A. The genus Alistipes: gut bacteria with emerging implications to inflammation, cancer, and mental health. Front Immunol. 2020;11:906. doi:10.3389/fimmu.2020.00906

9. Han H, Yi B, Zhong R, et al. From gut microbiota to host appetite: gut microbiota-derived metabolites as key regulators. Microbiome. 2021;9(1):162. doi:10.1186/s40168-021-01093-y

10. Furlow B. Gut microbe composition and metabolic syndrome. Lancet Diabetes Endocrinol. 2013;1(Suppl 1):s4-s5. doi:10.1016/S2213-8587(13)70128-1

11. Li X, Zhang S, Guo G, Han J, Yu J. Gut microbiome in modulating immune checkpoint inhibitors. EBioMedicine. 2022;82:104163. doi:10.1016/j.ebiom.2022.104163

12. Araujo DV, Watson GA, Olivia M, et al. Bugs as drugs: the role of microbiome in cancer focusing on immunotherapeutics. Cancer Treat Rev. 2021;92:102125. doi:10.1016/j.ctrv.2020.102125

13. Chen J, Li T, Liang J, et al. Current status of intratumour microbiome in cancer and engineered exogenous microbiota as a promising therapeutic strategy. Biomed Pharmacother. 2022;145:112443. doi:10.1016/j.biopha.2021.112443

14. Perrone F, Belluomini L, Mazzotta M, et al. Exploring the role of respiratory microbiome in lung cancer: a systematic review. Crit Rev Oncol Hematol. 2021;164:103404. doi:10.1016/j.critrevonc.2021.103404

15. Badgeley A, Anwar H, Modi K, Murphy P, Lakshmitkuttyamma A. Effect of probiotics and gut microbiota on anti-cancer drugs: mechanistic perspectives. Biochim Biophys Acta Rev Cancer. 2021;1875(1):188494. doi:10.1016/j.bbcan.2020.188494

16. Le Page M. CRISPR-based ‘antibiotic’ eliminates dangerous bacterium from the gut. Published November 5, 2021. Accessed April 20, 2023. New Scientist. https://www.newscientist.com/article/2296362-crispr-based-antibiotic-eliminates-dangerous-bacterium-from-the-gut/

17. Kim YS, Kim J, Park SJ. High-throughput 16S rRNA gene sequencing reveals alterations of mouse intestinal microbiota after radiotherapy. Anaerobe. 2015;33:1-7. doi:10.1016/j.anaerobe.2015.01.004

18. Jang BS, Chang JH, Cie EK, et al. Gut microbiome composition is associated with pathologic response after preoperative chemoradiation in patients with rectal cancer. Int J Radiat Oncol Biol Phys. 2020;107(4):736-746. doi:10.1016/j.ijrobp.2020.04.015

19. Dong J, Li Y, Xiao H, et al. Oral microbiota affects the efficacy and prognosis of radiotherapy for colorectal cancer in mouse models. Cell Rep. 2021;37:109886. doi:10.1016/j.celrep.2021.109886

20. Tonneau M, Elkrief A, Pasquier D, et al. The role of the gut microbiome on radiation therapy efficacy and gastrointestinal complications: a systematic review. Radiother Oncol. 2021;156:1-9. doi:10.1016/j.radonc.2020.10.033

21. Sharma A, Rath G, Chaudhary S, Thakar A, Mohanti BK, Bahadur S. Lactobacillus brevis CD2 lozenges reduce radiation- and chemotherapy-induced mucositis in patients with head and neck cancer: a randomized, double-blind placebo-controlled study. Eur J Cancer. 2012;48(6):875-881. doi:10.1016/j.ejca.2011.06.010

22. Elad S, Chen KKF, Lalla RV, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2020;126(19):4423-4431. doi:10.1002/cncr.33100

23. Furlow B. US halts faecal transplantation clinical trials. Lancet Gastro Hepatol. 2019;4(8):585-586. doi:10.1016/S2468-1253(19)30204-3

Will the Human Microbiome Yield Improvements to Cancer Radiotherapy?

Want to read more?

Want to read more?