A Gut Feeling: The Association Between Cancer and the Microbiome
Article by Elizabeth Donald, MSC; Medical Writer at EPG Health
Over the last decade, ground-breaking advances in the field of microbiome research have highlighted the complex relationship between the gastrointestinal (GI) microbiome and cancer. This insight provides immense real-world implications for predicting, identifying, and treating cancer. Among these breakthroughs is the understanding of how GI microbes directly and indirectly affect carcinogenesis through their influence on common immune pathways and gene expression1-3.
In the emerging field of pharmacomicrobiomics – the impact of the human microbiome on systems pharmacology, the microbiome can even determine the effectiveness of anti-cancer therapies4-7.
For this reason, the latest research has begun experimenting with harnessing and modulating the microbiome to improve the lives and clinical outcomes of people with cancer.
Microbiome homeostasis is a perpetual balancing act, favouring either a pro- or anti-oncogenic state
The gut microbiome has been colloquially referred to as “the last undiscovered human organ” due to its central and complex role interacting with the immune system8. Commensal microorganisms modulate local and systemic innate and adaptive immunity and are essential for facilitating the cytotoxic effect of anti-cancer therapies.
Dysbiosis – a disruption to commensal microbiome homeostasis and colonisation of pathogenic bacteria – impairs the normal immune function of commensal microbes and causes breakdown of the mucosal barrier9. This allows gut bacteria to ‘leak’ into intestinal lymph nodes, triggering a cascade of local and systemic inflammatory mediators. In this inflammatory state, immune checkpoints become inhibited whilst oncogenic signalling pathways are promoted, creating the ideal environment for carcinogenesis10-12.
Dysbiosis is characterised by an imbalance of pathogenic microbes, resulting in a pro-inflammatory state favouring carcinogenesis
The role of inflammation in cancer pathogenesis is well established and evidenced by the high proportion of cancer in people with chronic inflammatory conditions such as irritable bowel disease and ulcerative colitis13. The predisposing role of dysbiosis to inflammation is not as widely explored, however, it is becoming a topic of intense investigation. For example, in a recent large-cohort study of people with colorectal cancer, an over-abundance of Fusobacterium nucleatum, was associated with shorter survival14. Interestingly, the authors noted that this was not only due to its role in instigating inflammation, but also because it was found to promote chemoresistance by bolstering cancer cells’ regenerative capabilities15. Evidence has also implicated an imbalance of several other bacterial species in colorectal cancer pathogenesis, including Parvimonas micra, Akkermansia muciniphila, Streptococcus gallolyticus, Bacteroides fragilis, Escheria coli, Escheria Faecalis and Peptostreptococcus stomatis and anaerobius16-22.
Bacteria, however, are not the only pathobionts of the human microbiome, with fungi and viruses deserving their time in the microbial spotlight too. Commensal fungome and virome populations are typical components of the normal human gut microbiome2,11. In instances of dysbiosis however, they too can have pro-oncogenic implications. For example, an enrichment of fungi from the phylum Chytridiomycota and Glomeromycota have been found in colorectal adenomas23 and there is evidence linking numerous viruses such as the human polyomavirus 2, hepatitis B, human papillomavirus and Epstein-Barr to colorectal cancer pathogenesis24,25.
Dysbiosis, inflammation and cancer are directly inter-related, with numerous pathobionts being linked to carcinogenesis
While there is overwhelming evidence supporting the oncogenic role of microbiome dysbiosis, intriguing accounts of anti-cancer activity have also been reported. For example, Proteobacteria and Actinobacteria, organisms usually considered pathogenic and disruptive to microbiome homeostasis, improved survival rates of people with pancreatic ductal carcinoma26. Similarly, microbial ‘defenders’ such as Lachnospiraceae, Bifidobacterium animalis and Streptococcus thermophilus have been found to protect against cancer, and are commonly depleted in people with colorectal cancer27,28. In fact, numerous reports of microbes acting as indirect anti-cancer agents through improving drug bioavailability and reducing dose-limiting side effects of immune- and chemo-therapies have been documented29,30. This raises the question; can we use this knowledge to modulate a patient’s microbiome and improve their clinical outcome? And if so, how effective would it be?
Not all ‘pathogenic’ microbes are oncogenic, some have been linked with improved survival and drug efficacy
With the expanding knowledge of how the microbiome contributes to cancer outcomes, aiming to modulate the microbial balance has become a potential strategy for prevention and treatment. Approaches including probiotics, prebiotics, postbiotics, antibiotics and fecal microbiota transplantation (FMT) have all been performed in clinical settings with great success31-33.
One such extraordinary example involves irinotecan, a potent anti-cancer drug used in colorectal cancer. Despite this drug’s efficacy, it can cause such chronic intestinal inflammation that doses often need to be limited or ceased all together – a phenomenon labelled dose-limiting toxicity. Researchers were able to link this toxicity to a family of microbes called Enterobacteriaceae which secrete β-glucuronidase, an enzyme they discovered re-activated the drug after it has already undergone metabolism and neutralisation in the liver34. Once irinotecan was re-activated in the gut, it wrought havoc, causing significant intestinal damage and the associated toxicity and side-effects. By modulating the microbiome and ‘disabling’ these bacteria, investigators were able to prevent re-activation of irinotecan, allowing it to pass harmlessly through the gut with no side-effects. This significant discovery has vast implications for optimising chemotherapy and improving quality of life in people undergoing treatment with irinotecan.
In another groundbreaking study, patients with melanoma who were unresponsive to PD-1 immunotherapy, received an FMT from a patient who was responsive. After receiving treatment, almost half of the participants who had not originally responded to immunotherapy showed tumour reduction and long-term disease stabilisation35. In a similar study, microbiome samples taken from people with melanoma were orally administered to mice genetically altered to develop epithelial tumours. Results showed that human samples with the most diverse microbiome were associated with reduced tumour growth and improved responsiveness to immunotherapy36. The same study also showed that antibiotic use before treatment was associated with worse outcomes and decreased responsiveness to immunotherapy due to a loss of diversity in commensal microbes. FMT has yet to be extensively studied in human models of colorectal cancer37, but has shown promising results in studies using mice38-40.
Romina Goldszmid of the National Cancer Institute in Bethesda, Maryland, who has done research on the topic, says the goal of future research is to identify the underlying mechanisms of microbiome influence on carcinogenesis. “What’s really missing in the field, rather than knowing who is there and who isn’t there, is knowing what the bugs are doing,” she says. “We need more information about that.”
Modulating the microbiome to improve clinical outcomes for people with cancer, can and has been done, but more clinical research is necessary before it becomes a mainstream approach
Microbiome modulation is considered one of the most prospective modern strategies in medicine to improve the efficacy of anti-cancer treatment and clinical outcomes. It opens the door to novel strategies and treatment options never previously considered. Relatively unexplored, this field is ushering in a new era of drug development where the possibilities are only just being discovered.
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- Privitera G, Rana N, Scaldaferri F, Armuzzi A, Pizarro TT. Novel Insights Into the Interactions Between the Gut Microbiome, Inflammasomes, and Gasdermins During Colorectal Cancer. Front Cell Infect Microbiol. 2021;11:806680.
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