By T. Chakraborty, Ph.D.
While it may come across as a surprising fact, the human gut comprises millions of bacteria that harbor a symbiotic relationship with the body. The microbiota is comprised of various microbes including bacteria such as Bacteroides, Clostridium among others . The gut microbiome plays an important role in regulating the body’s normal physiological and homeostatic functions. A healthy gut microbiota contributes to a good immune system by providing protection against external pathogens while regulating the endocrine and enteric nervous system . By producing a variety of bioactive and signaling metabolites, it regulates key metabolic processes including drug metabolism, further impacting the host immune system. Any imbalance in the gut microbiome (gut dysbiosis) may lead to various illnesses including neurological disorders (Parkinson’s, Alzheimer’s), cancer and inflammatory bowel disease (IBD).
Role of Gut Microbiome in Cancer Etiology
Previously unnoticed, the gut microbiome has been a key piece of the puzzle in studying tumor development in cancer. Gut dysbiosis has been shown to negatively regulate the host metabolism and immune responses which has been linked to both local and distant tumor development. Though cancer is a multifactorial disease and there are more than 200 types of cancer in different organs and cell types, around 20% of the tumorigenesis has been linked to the gut microbiome imbalance further suggesting the importance of these bacterial populations residing in our gut.
One of the major causes of tumor development and cancer is damage in host DNA leading to mutation or activation of certain genes. During gut imbalance, certain bacterial population like E. coli produces toxic compounds which can directly alter the host DNA through mutations. The gut microbiome can also alter the host DNA replication and repair machinery leading to further mutations, tumor development, and cancer.
The effect on the host genome could be both direct and indirect. Certain bacteria like Helicobacter pylori and Salmonella enterica can induce host survival pathways which leads to tumorigenesis. Furthermore, the gut microbiome has been shown to modulate host hormone metabolism leading to cancer development and tumor formation. Bacterial species like Clostridium, for instance, have been found to affect estrogen receptors. Estrogen receptor activation has been linked to an increased risk of breast cancer development .
Role of Gut Microbiome in Cancer Treatment
Our immune system plays a crucial role in fighting cancer. Although the initiation of cancer is defined by changes in genetic components, its longevity is dependent on its ability to avoid host immunity. Evolving pieces of evidence suggest that the “gut microbiota” of cancer patients govern their response to a variety of targeted cancer therapies. This critical breakthrough has led to the emergence of immune checkpoint inhibition (ICI), a Nobel Prize-winning discovery (2018). Cancer cells evade immunity via direct inhibition of T-cells by engaging specific immune checkpoint pathways, such as programmed cell death –1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) . Blocking these pathways has shown promising activity in multiple cancers prompting the approval of PD-1 and CLTA-4 inhibitors . These inhibitors now find routine use in treating patients with advanced melanoma, renal cell cancer, bladder cancer, hepatocellular carcinoma among others. While ICI helps in improving the quality and prolonging lives of cancer patients, it works selectively on certain cancer types, thus prompting more research on its applicability to a broader spectrum.
Recent Advancements in Cancer Immunotherapy and Gut Microbiome
Pre-clinical and clinical studies have highlighted the critical role of the microbiome in cancer immunotherapy. Cyclophosphamide (CYC), one of the most commonly used chemotherapeutic agents for solid tumors and hematologic malignancies has been found to alter the composition of the gut microbiome which made the tumors susceptible to CYC . Furthermore, research indicates that microbial diversity could be an important predictor of mortality rates in patients who undergo stem cell transplantation .
The discovery of ICI in 2018 paved the way for more positive and reproducible pre-clinical results. Studies on germ-free mice that lack intestinal microbiota have suggested that different bacteria phyla contribute to immune actions. Research on humans has also demonstrated that the diversity and composition of the gut microbiome helped in improving survival rates in cancer patients. For instance, a study conducted on melanoma patients receiving PD-1 inhibitors showed that abundant presence of certain phyla of bacteria (e.g. Ruminococcaceae and Faecalibacterium of the Firmicutes phylum) are associated with a higher survival rate. Alternatively, lower diversity of the gut microbiome and the increased presence of bacteria belonging to certain phyla (e.g. Bacteroidetes phylum) are associated with an inferior survival rate .
On the other hand, clinical studies in patients receiving antibiotics with immune-based cancer treatments, have shown mixed results. Some have found that the presence of antibiotics during PD-1 inhibition is associated with higher mortality rates, while others have dismissed this notion by stating that clinical outcomes were not impacted by previous antibiotic usage. Further evidence is required to make a concrete statement in terms of antibiotic-related impact on gut taxa in cancer patients.
Precision Medicine and Microbiome
Keeping in mind the diverse nature of cancer manifestation and with the era of big data and genomics coming to the forefront, precision medicine has been gaining importance. Personalized chemotherapy is already in clinical trials. Given the unique signature of the gut microbiome in different individuals, the potential of manipulating the gut microbiome to treat cancer is an interesting and growing idea that needs to be pursued further. Multiple studies have shown that alteration in gut microbiome in combination with immunotherapy is beneficial to patients. Fecal microbiota transplant (FMT) that has been used in other diseases, can be utilized as a supplementary cancer treatment in the future .
With each passing day, the field of “onco-microbiome” is advancing. Driven by the era of personalized medicines, it is highly likely that this field is going to draw greater interest and funding. Companies like Bristol-Myers Squibb in collaboration with Paris-based Enterome Biosciences aims to develop novel immunotherapies and biomarkers by utilizing the latter’s in-house proprietary metagenomic platform. The impact of the gut microbiome on immune-based cancer therapeutics will be a breakthrough in terms of improving patients’ outcomes and the field is evolving rapidly to live up to its hype.
Editor: Rajaneesh K. Gopinath, Ph.D.
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