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Bacteria

The bacteria that inhabit our gut – the gut microbiome - could have profound impact on our health. The species that live in our guts influence the development of neurodegenerative disease (Alzheimer disease, Parkinson’s disease), epilepsy, autoimmune disease, and cancer.4 They may also be helping shape whether our treatments work.

Hundreds of trillions of microbes reside in our gastrointestinal tract, primarily in the colon 1. The bacterial genomes contain 3.3 million active genes which is 150 times the size of the human genome (22,000 genes) 2. Advances in sequencing technology allows researchers to study the genetics of the microbial community quickly and cheaply. One of the most well-known examples is The Human Microbiome Project.3

In cancer research, Helicobacter pylori is the most famous and earliest defined link between bacteria and cancer 5. More recently, dysbiosis is linked to colorectal cancer.6. Atopobium parvulum and Actinomyces odontolyticus were enriched in multiple polypoid adenomas and intramucosal carcinomas, and Fusobacterium nucleatum numbers increased during progression from intramucosal carcinoma to more advanced stages of the disease.

In cancer treatment, the gut microbiome is important during treatment with immunotherapies, such as CTLA-47, PD-L1 checkpoint blockade8 and CpG-oligonucleotide treatment9.  We also know that using faecal microbiota transplantation, helped boost the immune system response in immunotherapy and in chemotherapy. 10.11

We are beginning to understand how the gut biome connects with the immune system. One Japanese group identified a collection of 11 strains of gut bacteria that have a significant and positive effect on the work of immune cells like CD8 T-cells12 and others have shown that the right gut biome can boost cytotoxic T cells.13 Like the gut-brain-axis that connects the gut microbiota with the central nervous system, immunity is the well-accepted cross talk between gut microbiota and anti-cancer treatment.

In addition, to the gut biome itself, microbial metabolites likes short chain fatty acids, phenolic acids and isothiocyanates provide other anti-carcinogenic mechanisms 14. Interestingly, short-chain fatty acid – butyrate has been shown to accumulate in cancerous cell due to the Warburg effect15 and an increased uptake of acetate has been observed in hypoxic cancer cells. These metabolites cause stress in cancer cells, which may make them more susceptible to our therapies.

There is much exciting news from studying the gut microbiota in cancer research, although there is still a long way to go in studying the role of the gut microbiota to cancer/anti-cancer treatment. The role of HPV in cervical cancer is well known. Who knows what other virome16, yeast, fungus and archaea 17 besides gut bacteria may help us fight cancer. It may be that your gut is more important than you thought! 

 

  1. Ley, R. E., Peterson, D. A. & Gordon, J. I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837-848, doi:10.1016/j.cell.2006.02.017 (2006).
  2. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59-65, doi:10.1038/nature08821 (2010).
  3. Turnbaugh, P. J. et al. The human microbiome project. Nature 449, 804-810, doi:10.1038/nature06244 (2007).
  4. Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635-1638, doi:10.1126/science.1110591 (2005).
  5. Wroblewski, L. E., Peek, R. M., Jr. & Wilson, K. T. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev 23, 713-739, doi:10.1128/CMR.00011-10 (2010).
  6. Yachida, S. et al. Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer. Nat Med 25, 968-976, doi:10.1038/s41591-019-0458-7 (2019).
  7. Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079-1084, doi:10.1126/science.aad1329 (2015).
  8. Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084-1089, doi:10.1126/science.aac4255 (2015).
  9. Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967-970, doi:10.1126/science.1240527 (2013).
  10. Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97-103, doi:10.1126/science.aan4236 (2018).
  11. Alexander, J. L. et al. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol 14, 356-365, doi:10.1038/nrgastro.2017.20 (2017).
  12. Gopalakrishnan, V., Helmink, B. A., Spencer, C. N., Reuben, A. & Wargo, J. A. The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy. Cancer Cell 33, 570-580, doi:10.1016/j.ccell.2018.03.015 (2018).
  13. Tanoue, T. et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 565, 600-605, doi:10.1038/s41586-019-0878-z (2019).
  14. Louis, P., Hold, G. L. & Flint, H. J. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 12, 661-672, doi:10.1038/nrmicro3344 (2014).
  15. Donohoe, D. R. et al. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol Cell 48, 612-626, doi:10.1016/j.molcel.2012.08.033 (2012).
  16. Scarpellini, E. et al. The human gut microbiota and virome: Potential therapeutic implications. Dig Liver Dis 47, 1007-1012, doi:10.1016/j.dld.2015.07.008 (2015).
  17. Kennedy, E. A., King, K. Y. & Baldridge, M. T. Mouse Microbiota Models: Comparing Germ-Free Mice and Antibiotics Treatment as Tools for Modifying Gut Bacteria. Front Physiol 9, 1534, doi:10.3389/fphys.2018.01534 (2018).

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