The role of the gut microbiome in cancer is a rapidly growing area of research, and its potential to enhance cancer treatments is becoming increasingly evident (1–6). From its influence on tumor progression to its ability to modulate responses to chemotherapy and immunotherapy, the microbiome plays a central role in the effectiveness of cancer treatments (1,3,5,7). As our understanding of this connection deepens, fecal microbiota transplantation (FMT) is emerging as a novel approach to improving cancer therapy outcomes.

What is the Gut Microbiome and Why Does It Matter?

The gut microbiome consists of trillions of microorganisms that reside in the gastrointestinal tract8–14. These microbes are crucial in maintaining overall health by regulating immune function, aiding digestion, and even influencing the development of diseases like cancer (8–14). Recent research shows that dysbiosis—an imbalance in the gut microbiome—can contribute to cancer progression by promoting inflammation and immune system dysfunction (1,6).

The microbiome’s role isn’t confined to just gastrointestinal cancers. Emerging evidence suggests that microbial dysbiosis is linked to a range of cancers, including melanoma, breast cancer, and liver cancer (5–7,15,16). The microbiome’s influence extends to cancer cells, immune responses, and the tumor microenvironment (TME), making it a critical area of focus for improving cancer treatments (1,5,7,17,18).

How Fecal Microbiota Transplantation (FMT) Works in Oncology

FMT is a therapeutic procedure that involves transferring fecal material from a healthy donor to a patient in order to restore a balanced gut microbiome1. By reintroducing a diverse community of beneficial microorganisms, FMT helps restore microbial diversity, enhance immune responses, and potentially reverse resistance to treatments. Here’s how FMT is making an impact in oncology (4,7,19):

1. Immune Modulation: FMT restores immune homeostasis by increasing beneficial microbes that enhance anti-tumor immunity (2,6,19–21).
2. Correction of Dysbiosis: Cancer patients often exhibit dysbiosis due to the disease or treatment side effects. FMT restores microbial diversity, potentially reversing negative effects on the host immune response, metabolism and treatment response (1,6,16,22–24).
3. Metabolic Rebalancing: Gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs), play a critical role in regulating inflammation and epithelial integrity, creating a microenvironment less conducive to tumor progression (16,20,25,26).
    

Applications of FMT in Cancer Treatment

Clinical trials are still evaluating the effectiveness and optimal protocol for FMT in cancer treatment, but early results are promising. FMT has demonstrated the ability to enhance immune responses to cancer therapies, improve clinical outcomes in immunotherapy-refractory patients, and reduce treatment-related toxicity (2,7,15,27). However, the success of FMT can be influenced by several factors, including the patient’s baseline microbiome, the quality of the donor material, and the type of cancer being treated (4,20,28). While FMT has shown positive results in small trials and preclinical studies, larger and more rigorous clinical trials are needed to fully understand its potential and limitations in oncology  (1).

1. Enhancing Immunotherapy Responses

FMT has shown great promise in improving the response to immune checkpoint inhibitors (ICIs), which are a cornerstone of modern cancer immunotherapy (1–5,7,15,20,23,29).  Studies have shown that patients who received FMT from donors who previously responded to anti-PD-1 therapies experienced improved tumor responses, even when they were initially resistant to treatment (2,5,7)​. The mechanism behind this success is thought to involve the restoration of a microbiome that enhances immune responses, particularly by increasing CD8+ T cell infiltration in tumors (7,15,27).

2. Restoring Gut Microbiome Balance 

Chemotherapy and radiation therapy often disrupt the gut microbiome, leading to side effects such as nausea, diarrhea, and mucositis. This imbalance not only affects gastrointestinal health but also impairs immune function, increasing the risk of infections and complicating treatment (7,19,19,20,28,30). By restoring microbial balance, FMT can help alleviate these adverse effects, improve immune responses, and potentially enhance the effectiveness of concurrent cancer therapies while improving patient comfort and reducing side effects, increasing treatment adherence (4,16,19,21,28). In addition, certain chemotherapy drugs require a functional microbiome for their activation or inactivation. Studies have found that FMT can overcome resistance to chemotherapy agents by reintroducing beneficial microbial populations that enhance the efficacy of these drugs, restoring the microbiome’s ability to activate these drugs (18,27,28).

3. Reducing Treatment-Related Toxicity

Chemotherapy and radiation therapy often cause gastrointestinal toxicity, which can significantly affect treatment adherence. By restoring a healthy gut microbiome, FMT helps to reduce side effects like nausea, diarrhea, and mucositis, allowing patients to tolerate aggressive treatments better (18,19). Additionally, FMT has been shown to enhance recovery from treatment-induced damage to the intestinal lining (1,7,23,31)​. By re-establishing microbial diversity, FMT may help protect against chemotherapy-induced toxicity and improve the patient’s overall quality of life (18,28).

4. Managing Graft-Versus-Host Disease (GVHD)

For cancer patients undergoing hematopoietic stem cell transplantation (HCT), graft-versus-host disease (GVHD) is a major complication. GVHD occurs when the donor’s immune cells attack the recipient’s tissues, particularly the gastrointestinal tract. FMT has shown promise in managing GVHD by restoring a healthy microbiome, which helps reduce inflammation, improve immune tolerance, and protect the gut’s epithelial barrier ​​(6,16,19).

The Future of FMT in Cancer Care

The clinical evidence surrounding FMT in cancer treatment is still in its early stages, but the potential is clear. FMT has already shown success, offering hope for those who are non-responsive to treatments or face high levels of side effects, which impact outcome and/or adherence. Early trials are encouraging, but larger, more rigorous studies are needed to fully understand the benefits and risks of FMT in oncology. Additionally, long-term safety data are still needed to assess the potential risks of FMT in cancer patients.

Conclusion

The gut microbiome plays a critical role in cancer development, progression, and treatment outcomes. Fecal microbiota transplantation is emerging as a promising novel therapy, offering a therapeutic approach to modulate the microbiome, enhance immunotherapy efficacy, and reduce treatment-related side effects. As clinical evidence continues to grow, FMT may become a key therapeutic tool in oncology, helping to optimize cancer treatment responses and improve patient quality of life, possibly becoming an integral component of personalized cancer care.

References: 1. Chen, D. et al. 2019, 2. Elkrief, A. & Routy, B. 2021, 3. Park, R., Umar, S. & Kasi, A. 2020, 4. Porcari, S. et al. 2023, 5. Zhang, J., Wu, K., Shi, C. & Li, G. 2022, 6. Zhang, X. et al. 2023, 7. Baruch, E. N. et al. 2021, 8. Belkaid, Y. & Hand, T. W. 2014, 9. Choi, H. H. & Cho, Y.-S. 2016, 10. Hooper, L. V., Littman, D. R. & Macpherson, A. J. 2012, 11. Lloyd-Price, J., Abu-Ali, G. & Huttenhower, C. 2016, 12. Perez-Muñoz, M. E. et al. 2017, 13. Sommer, F. & Bäckhed, F. 2013, 14. Wilson, B. C. et al.  2019, 15. Davar, D. et al. 2021, 16. Habibi, S. & Rashidi, A. 2023, 17. Qiu, Q. et al. 2021, 18. Woelk, C. H. & Snyder, A. 2021, 19. Wardill, H. R. et al. 2019, 20. Brusnic, O. et al. 2024, 21. Ninkov, M. et al. 2023, 22. Secombe, K. R. et l. 2019, 23. Van Dingenen, L. et al. 2023, 24. Wardill, H. R. & Tissing, W. J. E. 2017, 25. Ahmad Kendong, S. M. et al. 2021, 26. Pandey, H. et al. 2023, 27. Zhao, W. et al. 2023, 28. Ali, H. et al. 2021, 29. Peng, Z. et al. 2023, 30. Tanaka, Y. et al. 2021, 31.Ding, S. et al. 2020.