In the last decade, the microbiome has attracted attention in all areas of research, including cancer research, and the microbiome plays an important role here as well. Our microbiome and dysbiosis have an impact on cancer development. In addition, microbes can either support or inhibit cancer therapy or make it more or less toxic to the host. Last but not least, cancer therapy also influences our microbiome.
A disturbed microbiome can be a trigger for cancer
Chronic inflammation and the damage it causes is a very important factor in the development of cancer. Therefore, bacteria play a critical role in the development of cancer.
For example, inflammatory bowel disease is a high risk factor in the development of colorectal cancer (the third most common cancer worldwide). Fusobacterium nucleatum has been shown to be enriched in colorectal carcinomas.
The bacterium H. pylori is associated with gastric cancer, although the bacterium is only one of many triggers of gastric cancer. Environmental factors such as smoking and genetic predisposition also play a role. Stomach cancer is the second leading cause of cancer-related deaths worldwide.
Breast and prostate cancers are the leading causes of cancer deaths for women and men, respectively. Decreased levels of Methylobacterium have been associated with more aggressive breast cancer development. Prostate cancer in men is also often associated with inflammation, which may stem from a disrupted urinary tract microbiome.
The microbiome influences the success of cancer therapies
Microbes can interfere with both chemotherapy and immunotherapy in three different ways: 1) promote drug efficacy, 2) interfere with and compromise anticancer activity, and 3) mediate toxicity.
An example of anticancer drug inhibition is the presence of Mycoplasma hyorhinisin tumor tissues, which compromises the efficacy of the drug gemcitabine. Gammaproteobacteria (gram-negative bacteria such as E. coli, Serratia, Klebsiella and others) also showed favoring the development of resistance to gemcitabine therapy. These bacteria produce an enzyme that alters the drug, thereby inactivating it. In the case of gemcitabine therapy, a combination with antibiotics was shown to improve the effectiveness of the therapy.
One type of therapy that relies on the presence of certain bacteria is platinum-based chemotherapy. Concurrent treatment with a cocktail of antibiotics reduced cancer regression and survival in mice (oxaliplatin treatment), while another study showed that combining the drug cisplatin with Lactobacillus bacteria enhanced the response to therapy. In this case, the drug’s effectiveness depends on the production of reactive oxygen species (ROS) by bacteria.
Cancer therapy has a significant impact on the microbiome
Intestinal tract
Cyclophosphamide (CTX) therapy is a mixture of chemotherapy and immunotherapy. The drug is based on stimulating anticancer immunity. The immune system needs the support of bacteria for its tasks and indeed mouse models showed that CTX therapy was only effective in the presence of an intact microbiome. Treatment with CTX caused relocalization of a number of Gram-positive bacteria (Lactobacillus johnsonii, Lactobacillus murinus, and Enterococcus hirae) to lymph nodes and the spleen, where they stimulated the immune response (in mice). Germ-free mice and antibiotic-treated mice were resistant to CTX. Oral administration of E. hirae restored the response to CTX.
Bacteria can also mediate the toxicity of anticancer drugs. One example is the drug irinotecan. The drug is inactivated in the liver, but once it enters the intestine, bacterial enzymes convert it back to the active form, which can then damage the intestine or cause diarrhea. This toxicity was associated with decreased bacterial diversity and an increase in Fusobacteria and Proteobacteria in the intestines of rats.
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Immunocancer therapy in particular relies on the presence of the right bacteria, which again confirms how much our immune system depends on our microbiome. Ipilimumab therapy is highly dependent on the presence of Bacteroides thetaiotaomicron and Bacteroides fragilis. When the Bacteroides strain was strongly present, ipilimumab-mediated colitis, a side effect, was actually reduced.
The T-cell response depends strongly on the presence of Bifidobacteria. Antibody therapy against “programmed cell death protein ligand” (PD-L1), combined with a cocktail of Bifidobacterium species, almost completely stopped melanoma growth in mice.
How we can protect the microbiome during and after cancer therapy It is undisputed that cancer therapy leads to dysbiosis and dysbiosis can affect therapy efficacy. As in all fields, various strategies such as probiotics, prebiotics, synbiotics (combination of prebiotics and probiotics) and postbiotics have been explored in cancer therapy to restore the microbiome and/or prevent negative side effects of cancer therapy.
Probiotics
Most probiotics used today are Lactobacilli or Bifidobacteria because these are the best-studied genera and therefore safe to use.
In some small studies with Enterococcus faecium in humans and in further studies with different Lactobacilli and Bifidobacteria strains in rats, probiotics did not show any positive effect on the microbiome. However, the right dose, duration of administration and selection of the right strains play a crucial role in efficacy.
In several other cases, efficacy was shown in humans as well as in rats and mice. Administration of L. rhamnosus GG was able to reduce diarrhea in colon cancer patients treated with 5-fluorouracil (5-FU). The strain Bifidobacterium breve-Yakult was shown to protect and improve intestinal flora in patients with various pediatric tumors caused by infections by maintaining pH below 7.
In addition to alleviating side effects of chemotherapy, probiotics also showed improvement in the efficacy of cancer treatment. L. acidophilus reduced tumor growth in mice with lung cancer and cisplatin treatment. Akkermansia muciniphila increased anti-PD-1 efficiency in mice, and Bifidobacterium improved the response to anti-PD-L1 therapy in mice with melanoma, nearly abolishing tumor growth.
Bottom line – take care of your microbiome!
As with almost any disease, it is not only the host’s genetic makeup and environmental factors such as diet and lifestyle that play a role, but also the microbiome. This interplay between the host, a drug, and the microbiome is enormously complex. However, scientists have already done a very good job of identifying relationships within this complex interplay. We must remember, however, that most scientific studies have been conducted in animal models that are not 100% translatable to the human species.
A healthy lifestyle, a varied diet with fresh, unprocessed foods as much as possible, and the intake of (tested) probiotics and prebiotics can prevent the development of cancer, improve the effectiveness of cancer therapies, and alleviate the side effects of drugs.
