The gut microbiome may well hold the largest unexploited treasure trove of new discoveries for human health—and the first steps toward unlocking the microbiome’s secrets have proven to be immensely promising. In recent years, a flurry of new research has shed light on the possibility that the gut microbiome holds the key to effective treatment of a broad range of health conditions due to its multidimensional role in key physiological processes. Indeed, supporting the microbiome is increasingly considered a critical part of managing everything from neurological diseases to gastrointestinal disorders. Now, some researchers believe that the gut microbiome may hold the key to enhancing cancer treatment.
The gut microbiome is composed of billions of bacteria that live in harmony—or conflict—with the cells of the human gastrointestinal tract. The bacteria of the microbiome consume material that the human body can’t use and provide nutrients or chemical energy sources that the body can use in return. In healthy microbiomes, the microbiota that provide highly efficient chemical energy are widespread, helping to control inflammation and ward off pathogenic bacteria. In unhealthy microbiomes, the opposite is true, leading to production of inefficient chemical energy sources and subsequent subpar gut cell health. However, recent research suggests that the gut microbiome is responsible for far more than nutrient absorption, controlling inflammation, and preventing harmful bacteria from taking root.
“The gut microbiome is the strong foundation upon which people can build their health,” says Al Czap, founder of Tesseract Medical Research and pioneer in microbiome-focused therapies. While Czap is referring in part to broad support for optimizing overall well-being, he is also talking about the potential of employing the microbiome in the treatment of specific diseases. One of the most exciting areas of study has focused on the possibility of manipulating the gut microbiome to improve cancer treatment outcomes due to its ability to participate in drug metabolism. While this upends decades of scientific canon in pharmacology and oncology, effective microbiome support, such as butyric acid supplementation, that can help patients overcome the most threatening diseases and the harshest therapies may now be within reach thanks to intensive research efforts.
New Research Suggests That the Microbiome Metabolizes Many Therapeutics Directlya recent review published in Drug Metabolism Reviews, there is evidence that the microbiome directly metabolizes many chemicals on its own via separate chemical processes than those in the liver rather than merely enabling the activities of the liver by altering absorption or by providing useful chemical precursors. This finding, while not contested, is a major upset in terms of the canon of traditional pharmacology, where liver-based metabolism is nearly universal.
Canonically, orally consumed drugs are first digested in the stomach, then diffuse through the intestinal wall into the bloodstream via small capillaries. Once in the bloodstream, the drugs circulate until they reach the liver. The majority of drugs are active in the body until they reach the liver. The enzymes of the liver metabolically break down the drug molecules into smaller molecules which are easier to excrete. These metabolites are subsequently excreted. However, as the authors of the review point out, an increasing number of drugs and supplements have been found to be metabolized by the intestinal microbiota with the liver playing a secondary role or no part whatsoever.
Microbiota-driven metabolism relies on the enzymes of the bacteria in the gut rather than enzymes in liver cells to process drug molecules. After microbiota metabolize the therapeutic, a metabolite of the therapeutic is secreted, making its way into the bloodstream. Once in the bloodstream, the metabolite then goes on to affect human tissues and provide the desired therapeutic effect. Drug metabolites may be subsequently metabolized and further removed from the bloodstream by the liver, leading to excretion from the body via incorporation into fecal matter with the help of the microbiome as would occur with most liver-metabolized therapeutics.
While researchers widely accept that there are instances where the liver does not play a major role in drug metabolism, the majority of extant pharmaceutical science assumes that these instances are rare. Given recent discoveries about the microbiome, however, it is likely that this traditional model of pharmacology is incorrect; the abundance of new research suggests that the microbiome is often a substantial partner to the liver’s processing of incoming substances rather than a negligible minority and, in some cases, may be the principal actor. New research thus seeks to identify the bacteria which are active participants in drug metabolism rather than mere accomplices in drug excretion after the liver has performed the majority of the metabolic work. By exploring the microbiome’s role, new models of pharmacology will be able to deliver safer and more effective drugs—and possibly open up new frontiers of therapy in the process.
The Microbiome Can Make or Break Cancer Therapies
Quantifying the role of the microbiome in the efficacy of therapeutics is a process of determining which bacterial species impacts the metabolism of which therapeutic chemical. Researchers formerly struggled with a similar yet distinct challenge: quantifying the beneficial secretions of gut microbiota on the basis of the material the bacteria consumed for energy. However, in instances where more than one species of bacteria in the microbiome consume the same material for energy, trouble can result. “Each microorganism is only ‘trained’ to produce one thing,” explains Czap. If one species of bacteria produces a critical product but its energy source is being consumed by a more abundant species of bacteria, the body won’t get what it needs. Given that each bacterial species in the microbiome has a plethora of potential energy sources, a diet which favors certain kinds of bacteria could easily lead to the deficiency of others. As Czap says, “The microbes are trying to produce the product that the body wants, but they are in the wrong ratio relative to what the body may need.”
This could lead to situations where divergent microbiomes lead to poor drug efficacy and poorer patient outcomes, a possibility supported extensively in the scientific literature. Given that in healthy people the composition of the microbiome is dominated by factors like diet, the link between diet and drug efficacy may be even deeper as a result of the microbiome. However, some health conditions, such as autism spectrum disorder, gastrointestinal disorders, and neurodegenerative disorders, are associated with microbiome imbalances that are unexplained by diet, which means patients with these disorders may be particularly vulnerable to poor therapeutic response from some medications. When it comes to cancer treatment, researchers have found that gut microbiota can dramatically impact chemotherapies like oxaliplatin or cyclophosphamide by modifying their efficacy and altering their toxicity. More specifically, patients with favorable microbiome characteristics might experience superior efficacy and lower toxicity than patients with less favorable microbiomes.
While this phenomenon remains poorly researched in traditional chemotherapies, promising data has emerged from studies on newer cancer treatments, like immunotherapy. For example, according to a landmark paper on 112 melanoma patients undergoing immunotherapy, having the right gut bacteria can boost the efficacy of immunotherapy and increase survivorship. In the study, researchers found that patients with healthy microbiomes exhibited superior anti-tumor effects compared to patients with a less healthy microbiome. Significantly, they also determined that the most important measure of microbiome health is the diversity of the bacterial populations of the microbiome, which has also been identified as instrumental in the function of other therapies, including stem cell transplantation. In the immunotherapy study, patients who responded to treatment were more than twice as likely to have more than 10 different major bacterial species in their microbiomes than those who did not respond. Furthermore, patients with microbiotal diversity classified as “high” —those whose microbiomes exhibited more than an average of 11.63 different species of bacteria—did not see their cancer progress, whereas those with medium or low microbiotal diversity experienced cancer progression after a median of 232 days and 188 days respectively. In other words, patients with highly diverse microbiomes were able to drive their cancer into remission with the help of immunotherapy, whereas the patients with less robust microbiomes became sicker and may have eventually died. Due to the extraordinary association between diversity and survivorship, researchers drilled down further into bacterial populations to identify which subpopulations, if any, made therapeutic contributions.
The subsets of bacterial diversity measured in the study were the bacterial genuses Clostridiales and Bacteroidales. While both genuses contain bacteria which are normal components of a healthy microbiome, the researchers found that immunotherapy responders were more likely to have more species represented within the Clostridiales genus, whereas non-responders were more likely to have more species of the Bacteroidales genus. Due to the high variability of patient’s microbiomes, researchers couldn’t draw firm conclusions about whether these genuses were contributing to more effective metabolism of the therapeutic chemical or whether they were merely crowding out other bacteria which were exhibiting a detrimental effect. Additionally, the location of the beneficial bacteria within the microbiome was also hypothesized to be a factor, but researchers at present do not have the technology to detect any relevant differences between the regions the gut microbiome.
The Limitations and Future of Microbiome Science
Basic questions are still unanswered regarding the gut microbiome, and researchers have a long way to go before providing a convincing explanation of the link between different microbial populations and drug efficacy. As the immunotherapy study demonstrates, one major area of confusion is about the subdivisions within the gut microbiome and how they relate to the bacteria which live there. Indeed, basic difficulties of measuring the microbiome have stymied many efforts to provide a clearer explanation regarding the way that the microbiome participates in the metabolism of therapeutics. “The problem we have is that there’s no great measurement that says ‘in the upper third of the large intestine, this is at this level and that is at that level,’” says Czap. “We have to measure whatever comes out the rear end.” Relying solely on stool samples has thus been the standard of microbiome research despite its limitations, leaving key questions about how different regions of the gut might exhibit different microbiotal populations largely unanswered. New techniques may address this gap in the scientific knowledge, but until then, researchers are forced to think of the microbiome as an abstraction in the gut rather than thinking about the regions of the gut as niches for different microbiota.
Despite these gaps of knowledge, microbiome interventions stand to become more and more commonplace within clinical practice, and many researchers envision that the microbiome’s role in the metabolism of therapeutics can be harnessed as an element of personalized medicine. By assaying the microbiomes of patients, clinicians could correct deficiencies before initiating critical treatments, increasing the chances of success. For high-risk therapies for cancer like chemotherapy or immunotherapy, the prospect of potentially augmenting treatment response has an immense potential to benefit patients.
But how can this growing body of knowledge help patients who are undergoing cancer treatment today? Czap’s opinion on the issue is unambiguous: “What we need to do to support health is increase the level of certain microorganisms and decrease the level of other microorganisms.” This idea is decidedly uncontroversial, but researchers have yet to come to a consensus regarding the best method for correcting microbiomes which may be clashing with therapies. Using diet to encourage the regulation of bacterial populations based on energy source allocation is one potential strategy. However, while many microbiome-support diets exist, their efficacy is poorly supported in the literature at present, and many patients find them to be extremely restrictive. As such, supplementing the human cells surrounding the microbiome directly is a more favorable approach. In particular, butyric acid can be a powerful supplement-based therapy to support the gut microbiome by encouraging healthy growth of beneficial bacteria, attenuating the activity of immune cells in the gut, and preventing harmful bacteria from taking hold. Importantly, butyric acid is safe and highly tolerable, which means it can be easily integrated into treatment.
In the future, additional therapies targeting the gut microbiome may provide even better support for patients undergoing cancer treatment and many, including Czap, are particularly excited about the potential of fecal matter transplant. But despite their potential efficacy, FMTs are unlikely to become popular and at the present time, they remain only theoretical possibilities. But Czap stresses that cutting-edge supplements aimed at bolstering the health of the microbiome, however, are currently allowing patients to experience greater therapeutic benefit than ever before due to improved bioavailability and targeted action. As such, these products could serve as an important tool for patients as they seek to strengthen the efficacy of cancer treatments and improve their chances of survival.
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