The human microbiome is an extensive collection of microorganisms that lives in a symbiotic association with us. Under normal circumstances, they mostly protect by inhibiting colonisation by pathogenic invaders. It is estimated that there are as many or more human microbiota as the number of human cells in the body. So, we can consider these microorganisms as our extended appendages for defence.
With millions of bacterial genes, the microbiome is a rich source of modifiable targets of therapeutic effects and allows us to intervene. The flora keeps on changing based on various external and internal factors, including environmental changes, usage of medicine, antibiotics, food, water, immune status of the host, etc. Most importantly, gut bacteria – the largest microbiome reservoir – can affect a person’s response to cancer immunotherapy. The clinical significance of the microbiome has, in recent times, triggered the interest of many a researcher globally.
Our gut harbours a large variety of microbes that are mostly helpful or benign. However, there are some that do possess oncogenic potential. In the 19th century, Virchow predicted that cancer cells were derived from human cells, and chronic triggers such as inflammation leads to the stimulation of cancer cells. During these recurrent inflammatory episodes, there is persistent and amplified immune response resulting in increased accumulation of phagocytes and secretion of pro-inflammatory cytokines.
This physiological process leads to the production of reactive oxygen species (ROS) and reactive nitrogen oxide species (RNOS) to kill potential pathogens. These free radicals and secondary metabolites may damage DNA, protein, and cell membranes, resulting in point mutations. Examples include the contribution of Hepatitis B and C viruses in the development of hepatocellular carcinoma, Helicobacter pylori in gastro adenocarcinoma, Salmonella paratyphi and Salmonella typhimurium in biliary cancer, Chlamydia trachomatis and Human papillomavirus (HPV) in cervical cancer.
It raises a very pertinent question: With trillions of microorganisms in the gut, how do people evade inflammatory episodes? If this flora does intend to cause inflammation, it can result in havoc. But fortunately, it coevolves with us and plays a crucial role in maintaining immune and metabolic homeostasis and protects against pathogen colonisation. It is proven that any change in flora pattern – called dysbiosis – often leads to many inflammatory diseases and infections, and also aids in the progression of specific cancer types.
Dejea et al. discovered biofilms of E. coli and Bacteroides fragilis which can produce oncotoxins like colibactin and B fragilis toxin in the guts of patients who are genetically predisposed to cancer. Studies have also shown that over-representation of Fusobacterium nucleatum sequences, a rare constituent of faecal microbiota, is seen in tumours as compared to control specimens. Microbial metabolites like butyrate inhibits the proliferation of tumour cells. Also, it exhibits chemoprotective effect by increased expression of GSTM2 (Glutathione S-transferase Mu 2) genes in colonocytes, which helps in protecting against DNA damages and H2O2 (Hydrogen peroxide)-induced oxidative stress. Significant reduction of butyrate-producing microbes such as Faecalibacterium spp. and Roseburia spp. impair anticancer immune surveillance. Similarly, probiotics with lactic acid-producing Lactobacillusspp. and Bifidobacterium spp, have shown a direct anti-proliferative effect on tumour cells.
The gut microbiome can influence the therapeutic efficacy of anticancer immunotherapy employing immune checkpoint inhibitors. A study (Vétizou et al., 2015) on the experimental mouse model has shown that the anti-tumour effect of antibodies targeting CTLA-4 was compromised in germ-free mice as well as antibiotic-treated mice. Faecal transplant of humans to mice confirmed that the immune response enhancement is specifically initiated by bacteria such as B. thetaiotaomicron and B. fragilis. Positive therapeutic effects are observed when anti-tumour antibodies are administrated along with non-enterotoxin-producing Bfragilis or immunisation with immunostimulatory B fragilis polysaccharides or by adoptive transfer of B fragilis-specific T-cells.
Similarly, Sivan et al., reported that Bifidobacterium could facilitate PD-L1 blockade efficacy via augmenting dendritic cell function and enhancing CD8+ cells priming and accumulation in the tumour microenvironment. Experimental studies with mice has shown that combination therapy with oral administration of Bifidobacterium along with PD-L1-specific antibody helped in preventing tumour proliferation.
Faecal microbiota transplant is considered as a promising therapy, but the safety of faecal transplant is a debatable topic, especially with the current antimicrobial resistance crisis. Author Claire Ainsworth reported in her Nature Outlook article quoting Willem de Vos, a Dutch microbiologist, that almost a decade ago, the first randomised clinical trial of faecal microbiota transplant for C. difficile infection was called off, more due to the accepted norm that it is not ethical to give antibiotics to a control group with whom it was being compared and not because such a unique approach did not work. De Vos was part of a team investigating gut infections caused by Clostridium difficile.C difficile infection leads to pseudomembranous colitis, causing severe damage to the colon and even death. The therapeutic approach of restoration of gut microbiota from healthy donor faeces helped in a marked reduction of pro-inflammatory cytokines such as TNFα (tumour necrosis factor α) and plasma level elevation of human antimicrobial peptide IL–37 (interleukin-37), thereby confirming a high cure rate.
Recent advances in human gut microbiota studies have evolved an interest in engineering and modifying the gut microbiota to design microbiome-based medicines for treating diseases, including cancer. Humanised gnotobiotic mice can be used as an experimental model for monitoring PK/PD changes in gut bacteria, thus facilitating the optimisation of doses.
Longevity with well-being is considered a challenge in medicine. The current emphasis of advances in medicine is all about specific efforts towards personalised medicine. Given the multitude of benefits that these minuscule creatures in our gut offer, the future seems to be steering towards microbiome-driven personalised therapies across disease areas.
- Dejea et al., Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria, Science 02 Feb 2018:Vol. 359, Issue 6375, pp. 592-597,doi: 10.1126/science.aah3648
- Kho ZY, Lal SK. The Human Gut Microbiome – A Potential Controller of Wellness and Disease. Front Microbiol. 2018; 9:1835. Published 2018 Aug 14. doi:10.3389/fmicb.2018.01835
- Chang AH, Parsonnet J. Role of bacteria in oncogenesis. Clin Microbiol Rev. 2010; 23(4):837‐857. doi:10.1128/CMR.00012-10
- Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079‐1084. doi:10.1126/science.aad1329
- Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084‐1089. doi:10.1126/science.aac4255
- https://www.nature.com/articles/d41586-020-00201-6, Therapeutic microbes to tackle diseases Nature577, S20-S22 (2020) doi: 10.1038/d41586-020-00201-6