by ecancer Medical Reporter Will Davies
Unfortunate news for any readers going through an identity crisis: You are mostly not human.
Within you, across just about every tissue type that makes up your body, you play host to an empire of microbes who have long since colonised and conquered your skin, teeth, intestines, and everything else they can reach.
This is your microbiome, a term coined by Joshua Lederberg in 2001 to describe “the ecological community of commensal, symbiotic, and pathogenic microorganisms that literally share our body space”1 .
On a cellular level, your microbiome outnumbers human tissue easily, with the gut microbiota alone comprising of 100 trillion cells, from up to 1000 different species2, which vary further from person to person3 with 100 times as many genes as the human genome4.
This is to say nothing of the varied oral, nasal and skin flora.
Many of these colonists are gifted to us during birth.
Some researchers are concerned that caesarean delivery limits a child’s inner biodiversity5, and medical models of mice denied microbiota during conception and birth have also shown unresponsiveness to autoimmune conditions such as MS and arthritis6.
These populations perform symbiotic roles with their new host, aiding digestion, tissue development and shuttering out more harmful pathogens.
While it may be discomfiting to think of birth as conferring bacteria to a vulnerable infant, those same microbes are essential to the healthy development, with some describing a ‘critical window’7 in early life during which microbiota fluctuate8, and may favour the development of diseases and conditions ranging from asthma and irritable bowel syndrome to depression, autism, and cancer9.
Under normal conditions, there exists a quiet stalemate of microbiota and immune response, with commensal bacteria carefully directing inflammatory response and tissue damage away from their niche and towards foreign pathogens or uncontrolled growth of the commensal cohort.
This truce is mediated by secretions and cell surface signalling, often via toll-like receptors which deactivate local immune recruitment10.
TLRs account for a significant portion of immune pattern recognition receptors (PRRs), which activate dendritic cells to attract the appropriate immune response.
Different sites rely on different messenger molecules; short-chain fatty acids (SCFAs) binding to GPCRs to regulate interleukin expression and suppress inflammation in the gut, for example11, or Leishmania major-associated IL-1 production in the skin directs regulatory T Cells12.
While this regulation is key to homeostasis between the microbiome and host immunity, any imbalance in the system, or dysbiosis, provides opportunistic infections a chance to capitalise on a preoccupied immune response and a diminished microbiome, lending additional risk to the use of broad-spectrum antibiotics13.
Often this manifests in the gut, site of a significant portion of one's microbiota, as Crohns, colitis, and other inflammatory bowel diseases14.
Inflammation, being the hallmark of infection, is a body’s way of creating the least-favourable environment in which a foreign microbe might propagate15.
It is also, unfortunately, the environment in which tumour cells thrive.
Here is where the tangled web of immunity, microbiota, and tumourigenesis surfaces; how can one be challenged without exploitation by another?
A whole interleukin-mediated inflammasome exists for the purpose of denying a pathogenic foothold16, with knockout mice being especially at risk of colorectal cancers.
A fascinating extension of this knockout susceptibility is that it can be conferred to healthy mice using faecal transfer, rather than their full complement of microbiota giving any resistance17,18, yet germ-free mice lacking in IL-10 expression were found unaffected by known carcinogen azoxymethane19 .
There are numerous infections known to result in cancer, and even displacement of naturally occurring microbes between organs is enough to facilitate precancerous lesions20.
Famous among tumourigenic pathogens are human papillomavirus, Helicobacter pylori, and Epstein-Barr virus, though countless others may promote dysbioses resulting in cancer.
This may be through either viral corruption of host cell cycles, direct bacterial damage to host organs, or disruption to host microbiota.
Acid production by invasive Clostridium and Bacteroides species in the gut results in DNA damage and stimulates cell proliferation to heal perceived wounding, strengthening the tumour microenvironment21.
Certain strains of E. coli are also associated with colorectal cancer, and dysbioses resulting from patient obesity has been causally linked to hepatocarcinoma22.
A straight line can be drawn from a diet rich in red meat to Fusobacterium nucleatum, to inflammation, DNA damage and immune evasion23.
Disease states due to dysbioses aren’t limited to their surrounding tissues, and some effects can be distal, with gut dysbiosis reported to influence development of neuropathy24.
Beyond the direct causal link to cancer, one’s microbiological population also influences response to treatment, with higher Lactobacillus presence negatively affecting CpG-ODN efficacy, and platinum compounds becoming suddenly ineffective in germ-free mice25.
Dysbioses that prevent proper immune direction hamper immunotherapy, naturally, and cyclophosphamide chemotherapy is similarly neutered26.
As the removal of microflora affects the efficacy of anti-tumoural drugs, the timing of radiotherapy must be considered.
While whole-body radiation does improve patient response to T cell transfer in adoptive cell therapy27, tumour shrinkage by radiation was reduced following antibiotic treatment, as was oxaliplatin response in mouse models25.
So far, the primary dysbioses discussed have been short term, an antibiotic course or radiotherapy fraction.
However, changes in microbiota can be charted across generations and continents, with the increased prevalence of western diets in China resulting in an increasing trend of colorectal cancer28, and though limiting H. pylori infection has reduced gastric cancers, its absence may also be associated with an increase in oesophageal cancer29 .
Just as balance is essential in maintaining one’s microbiome, it is important to recognise that your microflora are not merely carcinogens in waiting.
Many are capable, if not essential, to promote recovery and efficacy of cancer therapies.
After all, whilst it is a new development for clinicians, your microbiome has been manipulating immune responses for quite some time, and seems to be essential in managing these upstart human interventions30.
Amongst the multitude microbiota, your gut is home to butyrate-producing bacteria, which feast upon dietary fiber.
Butyrate itself is a histone deacetylase inhibitor, assuring DNA goes undamaged, and activates genes which promote apoptosis and slow cell cycle progression, making it a potent tumour suppressor23.
Butyrate enemas also relieve inflammation for sufferers of colitis, Crohns, and IBD, who are at significant risk of inflammation-associated colorectal cancer31.
Equol, a bacterial metabolite of daidzein from soy products, has been linked to reduced risk of breast cancer and prostate cancer in Asian men and women32.
Probiotics and prebiotic supplements aid in restoring internal equilibrium following microbial suppression.
As a patient's microbiome recovers, so cancer growth slows33 and can even begin to regress34.
The anti-oxidant activity associated with many prebiotics prevents inflammatory pathways from activating unduly, and can prevent damage to DNA that may later result in cancer35.
Specifically engineered strains of bacteria can further limit inflammation and increase anti-oxidant expression to reduce tissue damage36, even in mice lacking in IL-10.
Faecal transplant of healthy microbiota is proving effective in restoring patient responses37, and can even be combined with PD-1 checkpoint therapy38 with the potential to reshape patient-centric therapy in cancer and beyond.
This is all, of course, only the briefest of introductions to a field in its infancy; microbiota are changing our understanding of infectious disease, autoimmunity, and mental health39.
A major struggle in cancer therapy is how to separate healthy from cancerous cells when they are so very nearly self40.
In treating our human self we may yet reach a better appreciation of our non-human selves too.
1 Lederberg J, McCray AT. ’Ome Sweet ’Omics—a genealogical treasury of words. Scientist. 2001;15:8.
2 Bayerdörffer E1, Neubauer A, Rudolph B, et al. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. MALT Lymphoma Study Group. Lancet. 1995;345(8965):1591-1594.
3 R. R. Jenq, C. Ubeda, Y. Taur et al., “Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation,” The Journal of Experimental Medicine, vol. 209, no. 5, pp. 903–911, 2012.
4 O'Hara AM, Shanahan F. Gut microbiota: mining for therapeutic potential. Clin Gastroenterol Hepatol. 2007;5:274–284.
5 Shilts MH, Rosas-Salazar C, Tovchigrechko A, Larkin EK, Torralba M, Akopov A, et al. Minimally Invasive Sampling Method Identifies Differences in Taxonomic Richness of Nasal Microbiomes in Young Infants Associated with Mode of Delivery. Microb Ecol. 2016;71(1):233–42. doi: 10.1007/s00248-015-0663-y. pmid:26370110
6 Chervonsky, A. V., Microbiota and autoimmunity. Cold Spring Harb. Perspect. Biol. 2013.
7 Penders J, Stobberingh EE, Van Den Brandt PA, Thijs C. The role of the intestinal microbiota in the development of atopic disorders. Allergy (2007) 62:1223–36. doi:10.1111/j.1398-9995.2007.01462.x
8 Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaugh J, Knight R, et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci U S A (2011) 108(Suppl 1):4578–85. doi:10.1073/pnas.1000081107
9 Lloyd-Price, J., Abu-Ali, G., & Huttenhower, C. (2016). The healthy human microbiome. Genome Medicine, 8, 51. http://doi.org/10.1186/s13073-016-0307-y
10 Michelle H. Nelson, Marshall A. Diven, Logan W. Huff, and Chrystal M. Paulos, “Harnessing the Microbiome to Enhance Cancer Immunotherapy,” Journal of Immunology Research, vol. 2015, Article ID 368736, 12 pages, 2015. doi:10.1155/2015/368736
11 Louis P, Hold GL, Flint HJ (2014) The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 12:661–672
12 Perez-Chanona E, Trinchieri G. "The role of microbiota in cancer therapy." Current opinion in immunology 39 (2016): 75-81.
13 Petersen C, Round JL. Defining dysbiosis and its influence on host immunity and disease. Cell Microbiol. 2014;16:1024–33
14 Frank, D. N., St Amand, A. L., Feldman, R. A., Boedeker, E. C., Harpaz, N. and Pace, N. R., Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl. Acad. Sci. USA 2007. 104: 13780–13785
15 Kamada, Nuhiko, et al. "Role of the gut microbiota in immunity and inflammatory disease." Nature Reviews Immunology 13.5 (2013): 321-335.
16 Goldszmid, R.S and Trinchieri,G. ,The price of immunity .Nat.Immunol. 2012. 13: 932–938.
17 Elinav,E.,Strowig,T.,Kau,A.L.,Henao-Mejia,J.,Thaiss,C.A.,Booth,C. J., Peaper, D. R. et al., NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 2011. 145: 745–757
18 Sears, C. L. and Garrett, W. S., Microbes, microbiota, and colon cancer. Cell Host Microbe 2014. 15: 317–328.
19 Donohoe DR, Garge N, Zhang X, Sun W, O’Connell TM, Bunger MK, Bultman SJ The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab 2011;13(5):517–26.
20 Shahanavaj K , Gil-Bazo I, Castiglia M, Bronte G, Passiglia F, Carreca A, del Pozo JL, Russo A, Peeters M, Rolfo C, Cancer and the microbiome: potential applications as new tumor biomarker, Expert Review of Anticancer Therapy Vol. 15, Iss. 3, 2015
21 Pai R, Tarnawski AS, Tran T (2004) Deoxycholic acid activates beta- catenin signaling pathway and increases colon cell cancer growth and invasiveness. Mol Biol Cell 15:2156–2163
22 Naoko Ohtani, Microbiome and cancer, Seminars in Immunopathology ,January 2015, Volume 37, Issue 1, pp 65-72
23 Bultman, SJ. "The Microbiome and Its Potential as a Cancer Preventive Intervention." Seminars in Oncology. WB Saunders, 2015.
24 Collins SM, Surette M, Bercik P (2012) The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 10:735–742
25 Iida, N., Dzutsev, A., Stewart, C. A., Smith, L., Bouladoux, N., Weingarten, R. A., Molina, D. A. et al., Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 2013. 342: 967–970.
26 Viaud, S., Saccheri, F., Mignot, G., Yamazaki, T., Daillere, R., Hannani, D., Enot, D. P. et al., The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013. 342: 971–972
27 Dudley, M. E., Yang, J. C., Sherry, R., Hughes, M. S., Royal, R., Kammula, U., Robbins, P. F. et al., Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J. Clin. Oncol. 2008. 26: 5233–5239
28 Center MM, Jemal A, & Ward E (2009) International trends in colorectal cancer incidence rates. Cancer epidemiology, biomarkers & prevention : a publication of the 25 American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 18(6):1688-1694.
29 Blaser M (2011) Antibiotic overuse: Stop the killing of beneficial bacteria. Nature 476(7361):393-394.
30 M. Vétizou et al., “Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota,” Science, 350:1079-84, 2015
31 Terzic J, Grivennikov S, Karin E, & Karin M (2010) Inflammation and colon cancer. Gastroenterology 138(6):2101-2114 e2105
32 Lampe JW (2010) Emerging research on equol and cancer. The Journal of nutrition 140(7):1369S-1372S
33 J. Li et al., “Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice,” PNAS, doi:10.1073/pnas.1518189113, 2016.
34 Khazaie K., et al. (2012). Abating colon cancer polyposis by Lactobacillus acidophilus deficient in lipoteichoic acid. Proc. Natl Acad. Sci. USA, 109, 10462–10467
35 Davis C.D., et al. (2009). Gastrointestinal microflora, food components and colon cancer prevention. J. Nutr. Biochem., 20, 743–752
36 Carroll I.M., et al. (2007). Anti-inflammatory properties of Lactobacillus gasseri expressing manganese superoxide dismutase using the interleukin 10-deficient mouse model of colitis. Am. J. Physiol. Gastrointest. Liver Physiol., 293, G729–G738
37 Ambalam, P et al. Probiotics, prebiotics and colorectal cancer prevention Best Practice & Research Clinical Gastroenterology , Volume 30 , Issue 1 , 119 - 131
38 A. Sivan et al., “Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy,” Science, 350:1084-89, 2015
39 Severance EG, Yolken RH, Eaton WW, Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res. 2014 Jul 14. pii: S0920-9964(14)00319-3. doi: 10.1016/j.schres.2014.06.027
40 Golumbek P, Levitsky H, Jaffee L, Pardoll DM. ,The antitumor immune response as a problem of self-nonself discrimination: implications for immunotherapy. Immunol Res. 1993;12(2):183-92
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