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ISIS Report 26/02/14

The Gut Microbiome and Cancer

Our gut microbiota influence cancer susceptibility of our digestive tract as well as distant organs including the skin, lungs, breasts and liver
Dr Eva Sirinathsinghji

Cancer is a leading disease in industrialised nations and the incidence is rising sharply in developing nations as a result of aging demographics, “westernised” diets, exposure to chemical carcinogens and inactivity. Though there are genetic causes for certain cancers that give a significant risk to the individual carrier e.g. BRCA1 mutations and breast cancer, most cancers are linked to environmental factors. Despite this overriding environmental determinant in cancer susceptibility, we still know relatively little about the environmental factors involved. Recent research on the gut microbiota reveals a complex and important role that this ‘forgotten organ’ may play, not only in preventing or promoting carcinogenesis, but also in modifiying the efficacy of different therapies.  

Clues that the bugs in our guts may influence cancer development have been around at least since the late 19th century when anti-tumour effects were observed in sarcoma patients after bacterial infections or following the injection of heat-killed bacteria (Coley’s toxin) [1, 2]. In the 1970s, studies of germ-free mice suggested tumour-promoting effects of the microbiota in spontaneous, carcinogen-induced and genetically-induced cancer models. Indeed, there is now a well known association of the gut microbiota with inflammation and metabolism, two hallmarks of cancer, with germ-free animals displaying decreased weight gain and resistance to obesity, hypoglycaemia and low insulin.  With the advent of metabolomics and deep sequencing techniques, researchers are beginning to decipher the role of specific microbes as well as specific global microbiotic profiles associated with different cancers. These discoveries are leading to new avenues of research into cancer prevention and treatment.

One bug, two bugs, all or none?

The relationship between our gut microbiota and cancer appears to be complex, involving both specific microbial species as well as dysregulation of the global microbiota, called dysbiosis. Epidemiological studies have linked a number of cancers to individual microbes, e.g. the human papillomavirus (HPV) in cervical cancer; H.pylori in gastric cancer; chronic infection in hepatitis B virus (HBV); hepatitis c virus (HCV) in hepatocellular carcinoma (HCC); chronic Salmonella enterica subsp infection in gallbladder cancer; infection with Chlamydia pneumonia in the development of lung cancer; and infection with Haemophilus influenza and Candida albicans in the development of lower respiratory tract malignancies [3-6]. The clearest example for bacterially driven carcinogenesis is H.pylori infection, with epidemiological studies suggesting it is responsible for 1-3 % of gastric cancer cases of H.pylori infected individuals. This microbe has been widely defined as a carcinogen by public health institutions including the International Agency for Research on Cancer [7].

Most of the microbiome differences seen in cancer studies involve dysbiosis of the overall microbial community. Even in those ‘one microbe –one disease’ cases, the story appears more complicated than it seems. With H. pylori infection and gastric cancer, mice colonised with this species alone develop fewer gastric tumours than those colonised with a complex mixture of species [8]. It is interesting to note that H.pylori is also linked to a lower risk of oesophageal adenocarcinoma in humans, emphasising the organ-specific effect of bacterial communities on carcinogenesis [9]. The emerging understanding of colorectal cancer is similarly complex, with metagenomic studies showing underrepresentation of two bacterial phyla, Bacteroidetes and Firmicutes as well as overrepresentation of the invasive Fusobacterium nuculeatum species (previously associated with periodontis and appendicitis) in the tumours [10, 11].  Even though there were consistent patterns of dysbiosis between the patients in these studies, the overall microbiotas between tumours and noncancerous regions of the colon of individual patients were more similar to each other than they were to tumours of other patients or colon samples from unaffected patients. This intricate association with cancer suggests that any therapy involving the gut microbiota many rely on individualised therapies for successful treatment. Furthermore, these associations to do not prove causation so further analysis is much needed.

Dysbiosis of the gut microbiota has also been linked to cancers of distant organs, exemplified by cancers of the liver and pancreas, which do not have a known microbiota of their own. The role of the gut microbiota therefore appears wide-reaching, affecting much more than the gut itself [12-14].

How do microbiota influence cancer susceptibility?

There are many mechanisms by which gut microbiota may alter susceptibility to cancers including activation of the innate immune system, modulation of inflammation, influencing gene expression as well as the genomic stability of host cells. A failure of the intestinal barrier to limit host-microbiota interactions is also thought to be important. Anatomical separation between the host and microbes is a crucial first line of defence and is maintained through an intact epithelial lining and mucosal layer, as well as a sensing system that detects and eliminates bacteria. Consistently, ulcerative colitis, a condition that disrupts the barrier, increases the risk of colon cancers. Studies that have induced barrier failure in lab animals have also shown that carcinogens are more likely to pass through a disrupted gut lining, leading to increased tumour formation in local and distant organs [15].

Inflammation is an important mechanism by which the microbiota is thought to mediate cancer risk. As is the case with Coley’s toxin treatment (as mentioned above), the innate immune system can be activated to induce an anti-tumour response and this is utilised in immunotherapy for cancer. However in most cases, a bacterial microbiota profile does not appear to activate an immune response strong enough to have anti-tumour effects. Instead, activation of the innate immune system and the accompanying low-grade chronic inflammation is initiated or maintained by the microbiota that can then promote cancer susceptibility. How the microbiota induce inflammation is not entirely understood, though recent findings indicate that the sensing of commensal microorganisms by the innate immune system maintains intestinal homeostasis and induces healing responses following injury. The microbes themselves play an important role in maintaining this homeostasis, with beneficial bacteria playing an active role in limiting the growth of potentially harmful pathogens and producing anti-inflammatory molecules [16]. This is seen in experimentally induced colitis models where polysaccharide A is secreted by Bacteroides fragili, suppressing the pro-inflammatory interleukin-17 and activating the secretion of anti-inflammtory interleukin-10 (IL-10) [17]. This cross talk between the immune system and the microbes also regulates epithelial cell turnover and maturation, therefore maintaining the integrity of the intestinal barrier.

As described above, a tight homeostasis is crucial for maintaining gut health and when it is disrupted by dysbiosis or tissue damage (as experienced with colitis for example) activation of the innate immune system can be triggered. This is highlighted by mouse models with genetic mutations in the innate immune system that alter the host–microbiota equilibrium, resulting in enhanced susceptibility to experimental colitis and carcinogenesis. For example, mice lacking the anti-inflammatory IL-10 have dysbiosis of the gut, with 100-fold overrepresentation of members of the Enterobacteriaceae family, and 2 members of the family (Escherichia coli and Enterococcus faecalis) sufficient to induce colitis when introduced to germ-free mice [18]. E. coli alone is also sufficient to drive colorectal cancer after treatment with a carcinogen in these IL-10 deficient mice, suggesting that this microbe is necessary but not sufficient for carcinogenesis in this model. Mice lacking other important mediators of the innate immune response such as pathogen recognition receptors (PRR’s) show comparable associations with cancer. The role of PRRs is to indentify foreign organisms or pathogens through the recognition of microorganism associated molecular patterns (MAMPs) - molecules associated with groups ofpathogens recognized by cells of the innate immune system e.g. liposaccharides, nucleic acids and flagellin. Mice lacking the PPR called toll-like receptor (TLR) - 4 which recognises lipopolysaccharide (LPS), show reduced susceptibility to colon, liver, skin and pancreatic cancers [5]. Activated TLRs have been recently shown to increase reactive oxygen species (ROS), which may be one of the mechanisms by which the immune system combats invasive pathogens but is also associated with inflammation, DNA damage and cancer [19]. ROS activation is also increased in tumour cells and may promote cell malignancy [20]. These mechanisms do not just apply to local organs, but distant ones too, with bacterial metabolites and release of MAMPs thought to reach the liver via the portal vein [5].

Similarly, TLR-2 which recognises bacterial cell wall components is thought to drive gastric cancer. TLRs activate nuclear factor κ B (NF- κB), a so-called master regulator of the inflammatory response and signal transducer and activator 3 (STAT3), which can also reduce apoptosis and increase cell-cycle progression [12, 21].  Deficiency of another PPR called NOD2 increases risk of colorectal cancer, increases bacterial infections while reducing ability to kill gut bacteria [22]. NLRP6 deficiency induces dysbiosis which can be transferred to other mice, leading to increased colitis and colorectal cancer [23]. The transferability of the symptoms supports the idea that the bacteria are at least partly responsible for the symptoms. Emphasising the importance of a tightly regulated homeostasis between the immune system and the microbiota are TLR deficient mice, which reportedly have increased risk of colitis and colorectal cancers. Sensing of the gut microbiota is crucial for maintaining tissue repair, with TLR-2 and TLR-4 deficient mice showing problems with the intestinal mucosa, increased cell proliferation as well as increased susceptibility to colitis and colorectal cancer following exposure to carcinogens. 

The microbiota may also promote cancer development through the release of toxins that can cause genetic instability. Bacterial toxins such as cytolethal distending toxin (CDT) and colibactin are genotoxins, producing double-stranded breaks and inducing DNA repair activity in mice [25, 26].

Microbial metabolites can also be toxic and may promote cancers. Diet is an obvious determinant of microbial metabolism, with fats, red meat and alcohol being examples of foods that produce toxins when metabolised by the gut flora. The gut microbiota as a whole expresses more genes related to nutrient, bile acid and xenobiotic metabolism as well as for synthesis of vitamins and may well promote obesity and its related metabolic problems, activate or inactivate phytochemicals, affect the metabolism of hormones and the generation of tumour--promoting secondary bile acids [27, 28].

Gut microbes modulate cancer therapies

As the gut microbiota influence susceptibility to cancer through all the above described mechanisms, it makes sense that they also modulate cancer therapies. This appears to be the case for different therapies that employ both inflammation-dependent and/or independent mechanisms of action. A recent Science study shows that mice pre-treated with an antibiotic cocktail three weeks before tumour inoculation responded poorly to tumour immunotherapy and the same was observed with germ-free mice [29]. Immunotherapy works by inducing necrosis (cell death) of tumour cells through the production of the pro-inflammarory tumour necrosis factor (TNF) from myeloid cells followed by CD8 T cell response to eradicate the tumour. Mice on antibiotics also showed a diminished expression of TNF and other pro-inflammatory cytokines. The researchers were able to restore the immunotherapy effectiveness by giving the mice bacterial lipopolysaccharides.  Analysis of the faecal bacterial content showed that bacterial abundance but not diversity was fully restored after 4 weeks without antibiotics. Most interestingly, cancer treatments that do not work via the activation of the body’s immune response such as chemotherapy agents (oxaliplatin and cisplatin) also relied on the gut microbiota for successful eradication of the tumours, with germ-free mice being untreatable with these agents. At just day 2 of chemotherapy treatment, microbiota-free mice showed suppression of cytotoxicity for tumours, altering gene expression with inhibition of genes related to monocyte differentiation, activation and function while increasing expression of genes related cellular function such as metabolism, transcription, translation  and DNA replication.  Production of reactive oxygen species was also dependent on microbiota. Oxaliplatin does increase expression pro-inflammatory genes as well activation of dentritic cells, suggesting a partial inflammatory mechanism of oxaliplatin.

To conclude, this rapidly-developing field of research is bringing crucial understanding of the environmental causes of cancer, opening the door to new strategies for prevention as well as treatment. This work exposes the importance of a healthy diet not only in preventing disease but even possibly in its eradication. Microbial treatments such as faecal transplantation may also be worth exploring further.

References

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There are 6 comments on this article so far. Add your comment
Todd Millions Comment left 2nd March 2014 07:07:45
In I -The Body Electric-R O Becker mentioned work from the 1870's on incurable tumours-Patients were given a cocktail of the most pathegenic bacteria one doctor could culture.If the infections didn't kill them,70% were reported too have tumour remissions.Food for thought.
Dr Anupam Paul Comment left 26th February 2014 18:06:44
Very interesting article. I wonder whether our corporate science lobby would thwart its research or not. After all it is for alleviating the incidence of cancer.
Dr. Lein Izzo Comment left 26th February 2014 21:09:12
Very effective article in bringing greater awareness to the "core issues" in the tissues. I have been an energy-functional medicine practitioner for 35 years and presently utilize a bio resonance device in my practice. I see every one of the "bugs" mentioned above layered energetically in the person's field as well as layered in the tissue. Today 1 out of 2 people especially women carry HPV in multiple organs. Men in prostate and women in ovaries and uterus. Any of these bugs can migrate out of the gut into whatever system will attract them according to the immune systems vulnerability, which begins in the gut. Over 80% of all people are carrying some form of viral burden today as well as a host of environmental toxins. We have created an environment that we no longer can live in and now the environment is living inside us, and literally this is the foundation of disease.
David Llewellyn Foster Comment left 4th March 2014 06:06:01
Dr Izzo: "We have created an environment that we no longer can live in and now the environment is living inside us, and literally this is the foundation of disease." I think that is very aptly phrased. The work of Bruce Lipton is extremely interesting. I also recommend the particularly lucid approach of Dr Natasha Campbell-McBride. http://www.youtube.com/watch?v=cONYR7vAD-A http://www.youtube.com/watch?v=Z_0NvcJZwa8
Joseph Walter Motacek Comment left 1st February 2016 07:07:05
Already, microbiome transplants are reversing symptoms in a number of different disease states. (Dr. Thomas Borody, and Microbiologist Glen Taylor). When will we see this intervention used in conjunction with cancer treatment ? Specifically, after the chemotherapy to restore the microbiome to optimal health. We cannot continue to ignore the human microbiome, especially if the intestines are in a state of dysbosis, before or after chemotherapy. Dr. Borody, and Glen Taylor are perfecting the procedure of microbiome transplants for optimal results.
Joseph W. Motacek Comment left 1st February 2016 07:07:52
I want to amend an earlier post; we need to examine microbiome replacement therapy, both before and after chemotherapy, following the expert experience and advice from Dr. Thomas Borody and Glen Taylor.

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