The Gut Microbiome’s Role in Cancer Therapy Effectiveness
The gut microbiome influences cancer therapy outcomes, impacting treatments like immunotherapy and chemotherapy.
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Welcome to the second installment of "Cancer and the Gut Microbiome: A Miniseries". In our first article, we explored how disruptions in the gut microbiome – known as dysbiosis – can increase cancer risk. In this next piece, we turn our attention to how the microbiome influences the effectiveness of cancer treatments, particularly immunotherapy and chemotherapy.
Emerging research reveals that the gut microbiome not only affects immune responses but can also shape how drugs are absorbed, metabolized and tolerated by the body. This growing body of evidence suggests that microbiome composition could be a key factor in determining treatment success, paving the way for more personalized cancer therapies.
The gut microbiome and immunotherapy
The development of immunotherapy has transformed cancer treatment, breathing new life into the field of tumor immunology. By harnessing the patient’s own immune system to target cancer, immunotherapy represents a major advance in precision medicine. One widely used class of cancer immunotherapies is immune checkpoint inhibitors (ICIs), which employ monoclonal antibodies to enhance T cell-mediated anti-tumor responses by blocking inhibitory receptors and ligands.
Ipilimumab, a monoclonal antibody that targets cytotoxic T-lymphocyte antigen 4 (CTLA-4), was the first ICI approved for clinical use, specifically for the treatment of advanced melanoma, marking the beginning of a new era in cancer immunotherapy.
Despite its promise, however, immunotherapy is not universally effective – while many patients experience substantial benefits, others show limited or no response. This variability underscores the need for reliable strategies to predict and improve therapeutic outcomes.
Emerging research suggests that the gut microbiome may play a pivotal role in shaping immunotherapy responses. The microbiome can modulate immune activity through multiple mechanisms, including influencing the abundance and functionality of immune cells such as T cells, which are central to tumor targeting.
“Recent research has implicated the microbiome in the metabolism, absorption and even mechanism-of-action of both chemotherapy and immunotherapy,” Dr. Peter Turnbaugh, a professor in microbiology and immunology, told Technology Networks. “While much of the data comes from cell culture or animal models, compelling associations are now emerging in human patients as well.”
Key microbial species linked to immunotherapy efficacy
The ability of gut microbiota to modulate anti-tumor immunity suggests it may play a role in determining the success of immunotherapy. Frankel and colleagues were among the first to associate gut microbiome composition with responses to ICIs in patients with metastatic melanoma, using shotgun metagenomic analysis. Notably, a higher baseline abundance of Bacteroides caccae was linked to improved responses to ICI therapy, regardless of the specific checkpoint targeted.
In addition, gut metabolomic profiling revealed that ICI responsiveness was positively correlated with levels of anacardic acid, a compound that may exert anti-tumor effects by promoting local T-cell recruitment. Similarly, an increased abundance of Bacteroides thetaiotaomicron (B. thetaiotaomicron) and Bacteroides massiliensis was associated with enhanced response to ICIs and prolonged progression-free survival, respectively, in patients with unresectable metastatic melanoma.
However, conflicting evidence exists. Some studies have reported that patients receiving anti-CTLA-4 therapy with gut microbiota enriched in Bacteroides species had lower response rates. Another study found that a high prevalence of B. thetaiotaomicron and Escherichia coli (E. coli) was associated with poorer responses to anti-PD-1 therapy.
These findings indicate that alterations in the gut microbiome can either potentiate or hinder the immune system's ability to respond to checkpoint blockade. As a result, strategies to modulate the microbiome before treatment are now being explored as a means to enhance immunotherapy outcomes.
Microbiome manipulation as a strategy
Given the mixed responses regarding how microbial species influence immunotherapy, researchers have been investigating strategies to manipulate the gut microbiome before treatment begins. Common microbiome-modifying approaches include dietary interventions, antibiotics, probiotics, prebiotics and fecal microbiota transplantation (FMT).
Among these strategies, the use of antibiotics in cancer therapy is seen as a double-edged sword. While antibiotics can significantly alter the gut microbial landscape, their use before or during immunotherapy may reduce effectiveness against solid tumors. Conversely, recent studies suggest that antibiotics do not affect the immunotherapy response of patients with microsatellite instability-high or mismatch repair-deficient tumors or those with non-small-cell lung cancer.
Transplantation of defined bacterial consortia or fecal matter from immunotherapy responders has also shown promise in overcoming resistance to ICIs. Recent clinical studies have demonstrated that FMT from complete responders enhanced the efficacy of ICIs in a subset of melanoma patients, warranting further exploration.
The potential for microbiome-based cancer therapies is exciting. By integrating preclinical findings with clinical data, researchers are working toward personalized treatment plans that account not only for a patient’s genetic profile but also for their unique microbiome composition. Personalized microbiome analysis could help clinicians predict which patients are most likely to benefit from specific immunotherapies and enable more tailored treatment strategies.
The gut microbiome and chemotherapy
Chemotherapy, one of the oldest and most widely used cancer treatments, works by targeting the DNA or cellular machinery of rapidly dividing cancer cells. While often effective, chemotherapy is also associated with significant side effects, including gastrointestinal distress, fatigue and immunosuppression. Increasing evidence suggests that the gut microbiome plays a critical role in modulating both the efficacy and toxicity of chemotherapy.
Chemotherapy can alter the composition of the gut microbiome, often leading to reduced diversity and promoting the overgrowth of pathogenic bacteria. For example, researchers have observed an abundance of Fusobacterium nucleatum (F. nucleatum) in colorectal cancer tissues from patients who experienced recurrence following chemotherapy. This bacterium was associated with specific clinicopathological features and was found to promote chemoresistance in colorectal cancer by activating the autophagy pathway through TLR4 and MYD88 innate immune signaling and modulation of specific microRNAs.
In breast cancer patients undergoing chemotherapy, Bilenduke and colleagues reported distinct differences in microbiome composition compared to healthy individuals. Notably, there was a reduced relative abundance of Akkermansia, a mucin-degrading genus, in breast cancer patients, highlighting the potential link between microbiome alterations and cancer progression or treatment response.
Microbial modulation to reduce chemotherapy toxicity
Chemotherapy-induced toxicity remains a major concern for patients, often leading to dose reductions or treatment interruptions.
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A recent study from researchers at UC San Francisco, led by Turnbaugh, has discovered that some gut bacteria can reduce the side effects of chemotherapy, with one family of cancer drugs potentially boosting the protective bacteria.
Turnbaugh’s team found that colorectal cancer patients taking a class of cancer drugs known as fluoropyrimidines had much less diverse microbiomes in their digestive system. However, the surviving bacteria did something amazing.
“They were able to gobble up the chemotherapy and chemically transform it into a harmless byproduct,” said Kai Trepka, a student in the Medical Scientist Training Program at UCSF who co-authored the study.
The team also observed that measuring the abundance of helpful bacteria could predict whether a patient would develop severe side effects, such as nausea or vomiting, that make it hard for people to complete their treatment.
When the researchers administered these drug-processing microbes to mice experiencing severe chemotherapy side effects, their symptoms greatly improved, suggesting that humans may be able to use the bacteria as probiotics.
“We were very excited by these results, which demonstrate broad and significant changes in the gut microbiomes of patients during chemotherapy,” Turnbaugh told Technology Networks. “Our results suggest that some of these microbiome shifts could be beneficial, leading to an increased ability of gut bacteria to detoxify drugs that remain in the gastrointestinal tract. These results extend our earlier work conducted in cell culture and mice, providing initial support for the translational relevance of the gut microbiome in the context of oral fluoropyrimidines.”
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Another study from Turnbaugh’s team revealed the microbiome can also protect patients from painful numbness or a tingling sensation, another common side effect of chemotherapy, by producing vitamin K2.
When the researchers examined the microbiomes of 56 colon cancer patients, they observed that the fluoropyrimidine drugs had killed off some organisms and bolstered the populations of others.
Among those that thrived during chemotherapy was a nonpathogenic strain of E. coli that produced vitamin K2. When the researchers gave vitamin K2 to mice who’d been treated with fluoropyrimidine drugs, their neuropathy resolved. Patients who reported fewer side effects of chemotherapy also had more K2 in their microbiomes.
“Numerous gut bacterial genes are altered during chemotherapy,” Turnbaugh said. “We focused on the marked expansion of bacterial genes involved in the production of vitamin K2. Our follow-up studies in cell culture and mice suggest that these compounds protect both bacterial and mammalian cells against the toxicity of fluoropyrimidine drugs.”
“These results could help to inform dietary guidelines for [cancer] patients while also raising intriguing questions about the microbial contributions to the levels of K2 and other vitamins that we are currently working to unpack.”
Wesley Kidder, MD, an associate professor of medicine who specializes in gastrointestinal cancer, added: “For a long time, the microbiome has seemed like a black box. We’re now starting to be able to shine little flashlights and find clues to how we can influence it for the better – in this case, better outcomes for cancer patients.”
Towards the future: Personalized cancer treatments
Looking ahead, a major objective in oncology is to harness the therapeutic potential of the human microbiome to improve cancer treatment outcomes. By leveraging the unique microbial composition of each patient, researchers aim to develop personalized therapies that can more accurately predict individual responses to treatment. This precision-based approach could help tailor interventions and minimize adverse effects while maximizing the efficacy of treatments such as immunotherapy, chemotherapy and targeted therapies.
A promising pathway toward this goal lies in the emerging field of "pharmacomicrobiomics" – the study of how the microbiome interacts with drugs to influence their metabolism, effectiveness and toxicity. This discipline is shedding light on the complex bidirectional relationships between microbes and medications, offering valuable insights into why certain patients respond better to specific treatments than others.
As our understanding deepens, microbiome modulation strategies – such as dietary interventions, probiotics, prebiotics and FMT – may be incorporated into standard cancer treatment regimens. These adjunctive approaches could help reshape the microbiome to enhance therapeutic responses, reduce resistance and improve patient outcomes across a broad spectrum of cancers.
