A microbiome in dysbiosis can trigger cancer
Chronic inflammation and the damage it gives rise to, is one important trigger for the development of cancer. Microbes, therefore, play a critical role in the development of cancer.
IBD is a significant risk factor for the development of colorectal cancer (CRC; third most common malignancy worldwide). Fusobacterium nucleatumhas shown to be enriched in colorectal carcinoma tissues.
H. pyloriis associated with gastric cancer, although it is only one of many triggers which may lead to gastric cancer. Environmental influences such as smoking and host genetic predisposition also play a role. Gastric cancer is the second leading cause of cancer-related deaths worldwide.
Breast and prostate cancers are the leading cause of cancer-deaths for women and men, respectively. A reduced abundance of Methylobacteriumhas been correlated with more aggressive breast-cancer development. Prostate cancer in men often is also correlated with inflammation, which may arise from a disturbed microbiome of the urinary tract.
The microbiome influences cancer therapy
Microbes can interfere with both chemotherapy and immunotherapy with three main clinical outcomes: 1) facilitate drug efficacy, 2) inhibit and compromise anticancer effects, and 3) mediate toxicity.
One example for the inhibition of cancer drugs is the presence of Mycoplasma hyorhinisin tumor tissues, which impairs the efficiency of the drug gemcitabine. Gemcitabine resistance was also shown to be conferred by Gammaproteobacteria (gram-negative bacteria such as E. coli, Serratia, Klebsiella and others). These bacteria express an enzyme which modulates the drug, thereby inactivating it. In cases of gemcitabine therapy, a combination with antibiotics was shown to enhance the therapy’s efficiency.
One type of therapy which relies on the presence of certain bacteria is platinum compound chemotherapy. Simultaneous treatment with a cocktail of antibiotics reduced cancer regression and survival in mice (oxaliplatin treatment), while another study showed that a combination of the drug cisplatin with Lactobacillus bacteria improved the response to therapy. In this case, the efficacy of the drug is dependent of reactive-oxygen-species (ROS) production by bacteria.
Cyclophosphamide (CTX) therapy is a crossroad between chemotherapy and immunotherapy. The drug relies on the stimulation of anticancer immunity. The immune system needs the assistance of bacteria for its tasks and indeed mouse models showed that CTX therapy was only efficient in the presence of an intact microbiome. Treatment with CTX caused a relocation of a set of gram positive bacteria (Lactobacillus johnsonii, Lactobacillus murinus, and Enterococcus hirae) into the 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 cancer drugs. One example is the pro-drug irinotecan. The drug becomes inactivated in the liver, however once it enters the intestines, it is reconverted to the active form by bacterial enzymes, which can then cause damage to the intestines or instigate diarrhea. This toxicity correlated to a decreased bacterial diversity and an increase in Fusobacteria and Proteobacteria in the gut of rats.
Immunotherapy for cancer in particular strongly relies on the presence of the right bacteria, which again confirms how much our immune system is dependent on our microbiome. Ipilimumab therapy heavily relies on specifically Bacteroides thetaiotaomicron and Bacteroides fragilis. Even ipilimumab- mediated colitis was reduced when the Bacteroidetes phylum was present in high amounts.
Bifidobacterium is strongly associated with T-cell response. Antibody-therapy against the ‘programmed cell-death protein-ligand’ (PD-L1) combined with a cocktail of Bifidobacterium species nearly abolished melanoma growth in mice.
Cancer therapy influences the microbiome
Chemotherapy greatly influences the human microbiome. It has been shown that chemotherapy in Leukemia patients reduced the overall number of bacteria 100-fold (in fecal samples). The microbial diversity decreased and the predominant gut microbiome species Bacteroides species, Clostridiumcluster XIVa, Faecalibacterium prausnitzii, and Bifidobacterium species decreased 3,000–6,000-fold! While the healthy bacteria decreased, the number of pathogenic enterococci significantly increased.
Cyclophosphamide (CTX, an alkylating drug) therapy in mice led to an increased Firmicutes/Bacteroidetes ratio, with strong decrease of Bacteroidetes and an increase of Actinobacteria.
Another example of the influence of chemotherapy on the microbiome is gemcitabine therapy in mice. A significant drop in the main dominating phyla Firmicutes and Bacteroidetes has been observed. This drop of the main gut bacterial groups favoured a growth of residents which are usually minor residents: Proteobacteria (mainly E. coli) and Verrucomicrobia (mainly Akkermansia muciniphila). Overall, the changes observed suggested a pro-inflammatory bacterial selection.
In contrast to chemotherapy, much less evidence points towards a modulating effect of immunotherapy on the microbiome. However, the ipilimumab therapy led to a decrease of Bacteroidales and Burkholderiales, with an increase of Clostridia in human and mice.
How to improve the microbiome during and after cancer therapy
It is clear that cancer therapy leads to dysbiosis and dysbiosis may influence therapy efficiency. As in all areas, also in cancer therapy, different strategies such as probiotics, prebiotics, synbiotics (combination of pre- and probiotics) and postbiotics have been researched in order to restore the microbiome and/or prevent negative side effects of cancer therapy.
Most probiotics used today are Lactobacilli or Bifidobacteria because these are the most investigated genera and thus safe to use.
In some small studies with Enterococcus faecium in human, and other studies with different Lactobacilli and Bifidobacteria strains in rats, the probiotics did not show any shielding effect. However, the right dose, duration of administration, and the selection of the right strain(s) played a pivotal role in the efficacy.
Several other cases reported efficacy in both human and rats/mice. Diarrhea in patients with colon cancer and who were treated with 5-fluorouracil (5-FU) was able to be reduced with L. rhamnosus GG. Bifidobacterium breve strain Yakult has shown to protect patients with different pediatric tumors caused by infections, and to improve the intestinal environment by keeping the pH below 7.
Besides alleviating chemotherapy side effects, probiotics also showed to enhance the efficacy of cancer treatment. L. acidophilus reduced tumor growth in mice with lung cancer and cisplatin treatment. Akkermansia muciniphila boosted anti-PD-1 efficiency in mice and Bifidobacterium improved response to anti-PD-L1 therapy in mice with melanoma, nearly abolishing the tumor outgrowth.
Prebiotics are mainly fibers: non-digestible carbohydrates which are fermented by commensal bacteria in the large intestine. The products of this fermentation process are short-chain-fatty-acids (SCFA) which lower the intestinal pH, favoured by the gut-friendly bacteria Lactobacillus and Bifidobacterium. One well-known prebiotic is resistant starch (RS), which promotes the production of butyrate, which in turn is a well-known postbiotic with anti-cancer and anti-inflammatory functions.
In addition to the cancer-preventing action of prebiotics, prebiotics have been shown to even support the efficacy of chemotherapy. Inulin and oligofructose enhanced the efficacy of six different drugs (5-FU, doxorubicin, vincristine, CTX, MTX, cytarabine) in mice with liver cancer, expressed by a prolonged lifespan.
Synbiotics is a combination of pro- and prebiotics which act synergistically. In a synbiotic formulation the prebiotic should promote the growth of the combined probiotic. So far, little is known about the effects of synbiotics on cancer therapy in comparison pro- or prebiotics. Logic suggests that a boost in an effective probiotic should enhance the positive effect observed in cancer studies so far. We´ll have to wait for more studies on this topic to make any definitive statement on this.
Postbiotics are the bacterial fermentation products of prebiotics. The most famous postbiotic is the SCFA butyrate, which is produced through carbohydrate fermentation and has already been mentioned above. Postbiotics may bring about the same effects as the live bacteria producing them, making them a safer alternative to live probiotics.
One example I would like to mention is an in vitro study, which showed that the supernatant from Lactobacillus plantarum enhanced the 5-FU toxicity, increased the apoptosis (programmed cell death) and reduced the survival of cancer cells. This outcome suggests a potential use of postbiotics to increase the efficacy of cancer therapy and, at the same time, alleviate adverse side effects.
Although antibiotics deeply affect our microbiome, in some cases of cancer therapy it makes sense to apply them. Optimally, one would use very specific antibiotics, only attacking targeted adverse bacteria which inhibit cancer drug efficacy. One example for the inhibition of cancer drugs is the presence of Mycoplasma hyorhinis in tumor tissues, which impairs the efficiency of the drug gemcitabine. In this specific case, the use of an antibiotic against M. hyorhinis could enhance therapy efficiency. This has indeed been shown in mice with colon cancer, which were treated with gemcitabine and the antibiotic ciprofloxacin.
Besides this one case, in the majority of cancer treatment, antibiotic treatment has a negative impact on immuno- and chemotherapy efficacy: not only on the efficacy of anti-cancer drugs, but also on the side effects, which are often worsened by antibiotics. This has been shown in various mouse, rat and human studies with cisplatin, oxaliplatin, anti-CTLA-4, PD-1/PD-L1 -based immunotherapy, CpG oligodeoxynucleotide immunotherapy and CTX.
Conclusion – Take care of your microbiome!
As with almost every disease, not only do host genetic predisposition and environmental factors such as nutrition and lifestyle play a role, the microbiome contributes significantly as well.
This interplay between the host, a drug and the microbiome is tremendously complex. However, scientists have already done a great job at identifying relationships within this complex interplay. Notwithstanding, we must keep in mind that most scientific studies have been conducted on animal models, which is not 100% transferable to the human species.
A healthy lifestyle, a diverse unprocessed, nutrition and taking (safe) probiotics and prebiotics may prevent cancer development, enhance cancer therapy efficacy and alleviate drug side effects.
Take care of your microbiome – as it also takes care of you!
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