Cancer and microbiome — the long-awaited holy grail?
The enormous burden of cancer continues to grow and its impact not only on the healthcare system but on the individual is undisputed. Even though survival rates are improving due to earlier detection and innovative treatments, cancer remains the second leading cause of death globally. However, recent studies have demonstrated that the microbiome, especially the bacteria of the gut, may play a key role in the success of tackling cancer and advancing precision oncology.
In the last few years, our commensal bacteria have been at the center of scientific attention, with huge contributions made to our understanding for health and disease. The idea that the trillions of bacteria outweigh our body cells in count and gene amount has unleashed a wave of microbiome research, helping to unravel the impact of our gut bacteria on our bodies.
The Nobel Prize is buried in the stool, it just needs to be revealed.
— A wise (wo)man
We live in a constant symbiosis with thousands of distinct bacterial species that have co-evolved with us. The intestine in particular is host to the largest population of microorganisms, whilst the diversity and composition of these gut bacteria define our unique microbial signature. The physiological capabilities of microorganisms are manifold and range from digestive and metabolic functions to playing a key role in training your immune system.
The good, the bad and the ugly — our microbiome
In principle, we cannot be separated from our intestinal bacteria and they are of immense value to our well-being. Without these wonderful tiny organisms we wouldn’t be able to survive. They not only influence the way we take up nutrition and help break down complex fibers, but also have an impact on mood, personality and resilience to anxiety and stress. They produce a variety of hormones and neurochemicals similar to those of anti-anxiety drugs. Even further, our bacteria are actually able to turn our appetite on and off and influence what kind of food we are craving. Gut microbes manipulate our eating behavior in ways that promote their own fitness, sometimes at the expense of ours — quite self-serving! Especially, the microbial diversity is a key indicator of a healthy gut, as many different bacteria perform different tasks, and a diverse workforce brings more skills to the table.
Fewer than 100 species of bacteria cause diseases directly e.g. Clostridium difficile derived colitis, and hardly any microbes are known to enhance the risk for cancer, such as human papillomavirus (HPV), infamously known for its potential to induce tumor formation in the genital region. The thousands of types of microbes found in our gut are mostly harmless and vital for us. However, the composition of these bacteria needs to be balanced. Numerous studies increasingly indicate that a disturbed composition of intestinal bacteria is associated with a variety of diseases. Ulcerative colitis, Crohn’s disease, Alzheimers, Multiple Sclerosis, Psoriasis, Atherosclerosis, just to name a few, have all been linked to an altered gut microbiome.
Only very few microbes cause cancer directly (e.g. HPV), but many seem complicit in its growth, often acting through our immune system. Studies have shown differences in the intestinal microbiome compositions between patients with colorectal cancer (CRC) and healthy individuals meaning that specific microbes are more abundant or depleted in these patients. The direct relation remains unclear, however, inflammation, diet and oxidative stress play a key role in cancer formation. Fusobacterium nucleatum is a well studied bacterium which is associated with poor treatment outcome of CRC patients. It is thought that F. nucleatum attaches to the mucosal surface of the gut and induces oncogenic and inflammatory responses, altering the immune response and inducing tumor growth.
On the other hand, emerging evidence suggests that interactions between some gut bacteria and our immune system can have major anti-tumor effects. For example, in a melanoma immunotherapy-cohort, differences in the microbiome were identified between responders and non-responders to treatment. Specifically, patients with a more diverse gut microbiome and high abundance of Ruminococcaceae and Faecalibacterium had an enhanced response to therapy, mediated by increased antigen presentation and improved T cell function. In comparison, non-responders were associated with lower diversity and a high abundance of the bacterial order Bacteriodales. The mechanism remains unknown, however, the relationship between the intestinal microbiome and gut mucosa, and thus our immune system, plays a key role in efficient immunotherapy. This theory is supported by the fact that antibiotics, which alter microbial diversity, seem to reduce the efficacy of immunotherapy and decrease overall patient survival. Furthermore, transforming the microbiome by performing fecal microbiota transplant (FMT) (meaning transplanting donor stool to a recipient) increases the number of patients responding to treatment.
But what exactly is immunotherapy?
The new kid on the block: immunotherapy
Our body is an ecosystem with its own police, protecting us from intruders but also if our own cells transform malignantly. It patrols everywhere, and if it finds a disturbance, it calls for back-up. What makes cancer cells so dangerous is their ability to hide from this police. One of the common methods utilized is checkpoint signaling, where cancer cells trick our police force into thinking they are normal healthy cells. The evasion of the immune system then allows for boundless growth and metastasis of the cancer cells to different parts of the body. Now, one could ask “If checkpoint signaling helps cancer cells escape the immune system’s detection and therefore is harmful, why does it exist?” Because checkpoint signaling also regulates our immune system and prevents the body from attacking healthy cells, as it occurs in autoimmune disorders.
Immune checkpoint inhibitors are a novel biological therapy that have revolutionized cancer treatment. Basically, they are monoclonal antibodies (thus ending with -mab e.g. Ipilimumab) that stimulate the immune system by inhibiting the immune checkpoints and thus allow the immune system to identify and destroy cancer cells. Common targeted checkpoints are the PD-1/PD-L1 and CTLA-4 pathways. As checkpoints for healthy cells can also be blocked, immunotherapy can sometimes result in the immune system attacking normal body cells too causing serious side effects like autoimmune diseases.
What makes immunotherapy so interesting is that it uses the power of our own immune system to kill cancer cells. In particular, T cells which are our special forces, take on most of the fighting and even memorize the defeated opponent. Similar to the mechanism of vaccines that help our immune system fight reoccurring infections, these “memory” T cells can remember the cancer cell and quickly attack again at encounter, even if it occurs at a distant body location.
Microbiome as a game changer for precision oncology
The terms “personalized”, “individualized” or “precision medicine” are used interchangeably to describe the ability to tailor treatment to the most appropriate group of patients. Personalized medicine is the older and misleading term as it implies that treatments are developed uniquely for each individual whereas precision medicine correctly describes the tailoring of medicine to specific patient groups based on their variable genetics, age, lifestyle and environment. Compared to our current one-size-fits-all approach, the aim of precision medicine is to identify common characteristics across patients that would allow a more efficient therapy.
Precision medicine is already applied in a few medical fields, e.g. blood transfusions are given based on specific genetic characteristics that lead to your specific blood type. Instead of randomly administering the transfusion, a donor’s blood type is first matched to the recipient to avoid complications.
A major part of precision medicine is the inclusion of genomics data into the decision-making process of physicians.
Pharmacogenomics is part of precision medicine and includes the analysis of one’s genes to better understand how drugs affect the body. Especially in cancer care, pharmacogenomics is particularly important as the therapeutic margin of the drugs is normally quite narrow and the consequences of adverse effects can be severe or even life-threatening. As most anti-tumor drugs are not specific to cancer cells, they are also able to damage healthy cells, thereby limiting the usage of high doses to eradicate tumor cells. The variability in therapeutic response can be explained by the individual human genome, but also by its microbiome.
Until recently, the microbiome has been mostly neglected concerning therapeutic decisions. Our body has around 25,000 genes in each cell, but the human microbiome is thought to hold over 200 times more. Its impact and relevance in our body is indisputable. The term Pharmacomicrobiomics is however hardly known.
At BiomeDx, we believe the gut bacteria might be an excellent biomarker in predicting the response of immunotherapy. Therefore we are currently conducting a large European study with multiple clinics to assess the application of such a marker in patients with melanoma, lung cancer and renal cell cancer. It would not only be possible to identify patients with a high risk of severe adverse effect beforehand but also allow further therapeutic applications to improve the drug efficacy. Related to the blood transfusion example, FMTs might become more useful, as stools of previously identified responders could be transplanted to improve the microbiome and thus the patient’s sensitivity to immunotherapy.
The microbiome would not only advance precision medicine regarding therapeutic measures, but would also benefit tumor prevention. As mentioned above, alterations of the intestinal bacteria such as F. nucleatum and other species could be used as screening biomarkers for early CRC detection. This would allow accurate and non-invasive tests to predict the occurrence of such malignancies and treat them earlier on. Our company BiomeDx is currently conducting such a study with over 1000 patients in Austria.
🌿 We believe the microbiome may be the holy grail to finally advance precision medicine and establish more effective prevention and treatment methods in clinical cancer routine. The bacteria within us matter. We have ignored, feared and killed them off with antibiotics. It is now time to appreciate them and use them to the advantage of our health — only so both our body and the bacteria can flourish.
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