How Gut Bacteria Can Make Chemo More Effective
We can add one more health effect of our gut bacteria to the growing list.
Researchers from the UK have just reported that the gut microbiota plays a role, both directly and indirectly, on the toxicity and efficacy of chemotherapy. Their findings are published online in the journal Nature Reviews Gastroenterology & Hepatology.
It's a complicated process, involving players from the absorption, metabolism, and immunity realms, but one that may eventually be exploited for the benefit of cancer patients receiving chemotherapy.
Everyone's gut microbiome—the bacterial community residing in our guts—is different. However, there are some bacteria known to be beneficial, and we know of many harmful disease-causing bacteria that can also set up shop there.
People who eat typical American diets have been found to have an abundance of Bacteroides bacteria in their guts. Other bacteria, Clostridium, Bifidobacterium, Eubacterium, Lactobacillus, Streptococcus, and Escherichia, were also commonly found, but in less abundance. These bacteria were present in people free of disease and felt to represent a healthy gut microbiome.
Several bacteria can be found in unhealthy guts where disease is present. Clostridium difficile, Salmonella, and some strains of Escherichia coli, like E. coli O157:H7, represent some pathogenic gut bacteria.
On top of the great personal diversity of our gut microbiome, their composition varies as we age, with each disease state, with what we eat, and with what we are exposed to in the environment.
Those variations make it tough to make general comments about how our gut bacteria affect chemotherapy, but many studies have highlighted specific changes. And having cancer itself may change the balance of good and bad bacteria, adding another layer of complication to the interaction.
The researchers in the Nature Reviews study, all who hail from the Department of Surgery & Cancer at Imperial College London, use the acronym "TIMER" to describe key mechanisms in gut bacteria. The easiest way to understand this concept is with a few examples, which will help illustrate where and how chemotherapeutic agents exert their effect on the gut microbiome community.
In translocation, both beneficial and disease-causing bacteria are moved through the gut into the blood where they can affect the whole body.
The chemo drug cyclophosphamide exhibits this action. The drug can shorten the vili—fingerlike projections on the inside of the intestine that serve to absorb materials from the gut—and damage the mucus lining of the gut. This allows bacteria to cross from the gut into the blood where they can cause infections.
Several good gut bacteria help the immune system work better in response to tumors. Lactobacillus, for example, can help signal the accumulation of immune cells that fight tumors.
Some cancer patients are treated with a biologic agent called anti-PD-L-1 that increases the natural immune response to cancer cells. In patients treated with anti-PD-L-1, Bifidobacteria causes specific white cells, called T lymphocytes, to increase their numbers at the site of the tumor.
Studies have shown that antibiotic treatment that killed gut bacteria significantly reduced the ability of mice to kill tumors and decreased their survival.
Modulation of the immune system by gut bacteria is one of ways they assist chemotherapy agents to more effectively treat cancer.
Drug metabolism is another complicated subject, so for now we will stick to drug processing by enzymes in the body. In general, the drugs we take in are either in a useable, active form or a form called a prodrug—a form that must chemically react with the body to become active before it can do its job.
Both drugs and prodrugs are eventually metabolized and removed from the body, and the length of time the drug stays at an active concentration in the body helps to determine dosing regimens.
Sorivudine, an antiviral drug, is sometimes given with chemotherapy drug 5-fluorouracil. After the death of 16 patients in Japan, it was discovered that these two drugs can cause a fatal drug-to-drug interaction—and it's due to bacterial enzymes.
Certain types of Bacteroides bacteria in the gut have an enzyme that metabolizes sorivudine to another chemical. That chemical, in turn, inactivates another enzyme that usually prevents the toxicity of 5-fluorouracil. Without the action of the enzyme that keeps the toxicity of 5-fluorouracil in check, the end result was a fatally high 5-fluorouracil concentration.
In this case, the Bacteroides is still a good gut bacteria, but its action caused an adverse event due to the presence of both the antiviral drug given and the chemotherapy drug.
On the flip side of this is a bacteria called Mycoplasma hyorhinis, a bacteria associated with several cancers, including stomach cancer. This bacteria has several different affects, depending on the drug present. The chemo drug capecitabine is more effective in the presence of this bacteria because the bacteria secretes enzymes that convert the prodrug to the active form. However, M. hyorhinis makes the chemo drug gemcitabine less effective.
Some chemotherapy drugs, especially methotrexatec, can reduce beneficial bacterial like Firmicutes, Actinobacteria, Proteobacteria, Streptococci, and Bacteroides. When present in the gut, these bacteria serve to limit inflammation, and patients with this shift in good bacteria experience diarrhea and colitis (inflammation of the colon).
We know that our gut bacteria can change the toxicity and efficacy of chemotherapeutic agents—that themselves may complicate the scene because they may change the types and numbers of beneficial and deleterious gut bacteria.
Treatment with good gut bacteria can reduce some of the side effects of chemotherapy, too. Probiotics, including a mixture of types of Streptococcus, Bifidobacteria, Lactobacillus, and Bulgaricus bacteria, have been shown to help decrease diarrhea and weight loss in cancer patients receiving chemotherapy.
"The implication is that the gut microbiome represents a notable target for making chemotherapy safer and for further improving rates of cancer survival," wrote the Nature Review study authors.
These contributions from bacteria may be as simple as increasing or decreasing certain bacterial populations, or it may be a much more sophisticated manipulation of the actions of the bacteria. But one thing is for certain—gut bacteria are important and under-appreciated players in cancer treatment protocols.