Intestinal Microflora and the treatment of cancer- Some bugs are good for us

We have microbes all over us. They outnumber normal cells by a ratio of 10:1.

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The microbes of the gut can be compared to the ecosystem of the Amazon rain forest. They live as one big family within the gut and besides many other functions, they play a special role in maintaining balance within the individual’s immunity just like how plants and animals maintain balance within the ecosystem.

As we go down the intestine towards the colon, the number of microflora increases, reaching upto 1012 microbes per ml, within the colon.

We know that in normal cases the immune system does not attack the non pathogenic tissues and cells of the body. This is called immune tolerance. Whereas if the immune system comes across any foreign antigen it mounts an immune response to destroy such cells or antigen.

The gut flora has a crucial role to play in maintaining tolerance and immune response.

The gut microbes and humans have co-evolved over thousands of years to attain a mutual benefit.

How do gut bacteria modulate our immune system?

The way our gut flora modulates the immune system is quiet amazing and beautiful at the same time.

Colonisation of the gut by microbes takes place at birth. This process is integral in the maturity of the gut, and is also crucial in the development of innate as well as acquired immunity of an individual.

Our gut has tiny dome like structures, within the mucosa called ‘peyer’s patches’. The mucosa overlying these patches are very thin.

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The pink dome like structure- ‘peyer’s patches’ have thinner mucosa. The mucosa that lines these patches have a specialized cell called the ‘M cell’ (bold arrow).

The peyer’s patches contain B cells, T cells and macrophages.

The microbial and food antigens are transported across the intestinal mucosa across specialised phagocytic cell called M cells. The dendritic and macrophage cells within the peyers patches extend processes around these antigens, engulf them, digest them and then present them to T cells, which in turn produce Interleukin-10. This interleukin has a suppressive action on the immune cells of the gut.

Compare this to when a foreign antigen or pathogenic bacteria enter the gut- The T cells instead of secreting anti-inflammatory substances, secrete pro-inflammatory substances (IL-6, IL-23, TNF-a) that lead to an inflammatory response. Neutrophils are also recruited to annihilate the foreign antigens that enter the gut.

Not surprisingly, our bodies are quite partial too.
And for good reasons.

Although there is a vast spectrum of bacteria present in the gut, the bacteroides and firmicutes dominate the intestine.

It has been found that patients with breast cancer have a different gut microbe profile than controls. Patients with colorectal cancer have been found to have presence of biofilms within the gut and an increased number of fusobacterium and porphyromonas compard to controls.

Currently researchers are trying to figure out more about cancers and the impact they have on our gut ecosystem. This will help in establishing certain microbial patterns associated with different cancers.

Some studies claim the association of breast cancer with increasing use of antibiotics. Gut bacteria are responsible for estrogen metabolism, so disrupting gut metabolism with the use of antibiotics will increase the level of estrogen exposure.

Yes, but how do they actually help against cancers?

Role of gut microbes in Radiotherapy

During radiation to pelvis, radiation induced diarrhea may occur. One of the reasons for this is the alteration of the gut microbes due to radiation. Studies have shown that administration of oral lactobacillus has greatly reduced radiation induced diarrhea.

It is a known fact that bacterial cell walls contain lipopolysaccharides that are antigenic. Release of these substances from the gut wall during radiation causes activation of T cells through antigen presenting cells. Activation of T cells increases immune response against the tumor.

Role of Gut microbes in Chemotherapy

Chemotherapy is also responsible for changes in the gut flora. One commonly known drug responsible for this is cyclophosphamide. Besides acting as a DNA alkylating agent, this drug also acts as an immuno-modulating agent.

Cyclophosphamide disrupts the gut barrier, this leads to a ‘seepage’ of gut flora into the intestinal mucosa, where CD4+ T cells get sensitized and activated. These activated T lymphocytes have shown to control the tumor growth in mice.

Mice who have been treated with vancomycin showed a decrease in immune response and a decrease in the activity of cyclophosphamide.

A gram positive bacteria E. hirae have been shown to be particularly responsible in inducing this immune response. It stimulates CD4+ and CD8+ cells as well as suppresses immunosupressor cells.

Immunotherapy and gut microbes

We now know that T cell activation and secretion of factors such as TNF alpha improves immune response towards malignancies.

Alistipes shahii is a gram negative rod found mostly in the appendix.

Treating sterilized mice with A. shahii improved the response of colonic malignancies towards immunotherapeutic agents. This improved response is due to increased TNF alpha secreted by the activated myeloid cells within the tumor.

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The brothers of ‘mass’ destruction

One of the key areas of interest in oncology today are immune checkpoint pathways. These pathways are responsible for ‘curbing’ immune response and thus reducing the immunogenecity towards tumors.

Some cancers can protect themselves, from an immune attack by stimulating these pathways. Certain immunotherapeutic agents have been developed that can keep a check on these pathways thus improving immune response. A certain drug named Ipilumab has been designed to block these inhibitors. The antitumor effect of these agents was reduced in sterilized mice.

A Brief History

Besides the production of cheese and yoghurt, Bacteria find it’s use even in cancer therapy.

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He is back, to protect us from the malignant One.

Many years ago, American surgeon as well as cancer researcher, William Coley tried to come up with newer methods in treating malignancies after the death of one of his 17 year old sarcoma patient.

One of his other patients Fred Stein, who was diagnosed with small round cell tumor underwent a seemingly complete response after being diagnosed with erysipelas, a streptococcal infection.

Coley, after further investigations found 47 patients who showed tumor regression linked to certain infections.

Coley then went on to treat patients with strep pyogenes infection, but unfortunately two of his patients succumbed to the infection. Later then Coley changed his dose from live streptococcal infection to two dead bacteria- Serratia marcescens and dead Strep. pyogenes strains.

Coley’s new form of treatment (Coley’s toxins) became an area of controversy in the medical world and later faded with the development of chemo and radiotherapy.

Many years after the death of William Coley in 1936, investigators realised that Coleys concept of bacterial therapy was actually effective, paving a way for a new avenue in cancer therapy now called immunotherapy, William Coley beimg recognized as the ‘Father of Cancer Immunotherapy.’

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William Coley thinking ‘I was right, dimwits’

Later, BCG vaccine which is used to increase immunity to Tuberculosis, was tried intravesically (injected within the bladder) in bladder cancers. This technique mounted an immune response towards cancer cells.

Investigators have shown that administration of lactobacillus, improves immune response, improves natural killer cell activity and dendritic cell response.

Clinical trials have shown the efficacy of microbes in malignancies:

  1. Strep pyogenes and serratia have shown tumor regression in sarcoma patients.
  1. Heat killed Mycobacterium Obtuense (IMM-101)- have shown increased survival of metastatic adenocarcinoma pancreas and melanoma patients.
  1. Tf-CRM107 is a conjugate of transferrin and a point mutation in diphteria toxin. This agent showed a tumor regression in 9/15 patients treated.
  1. Certain strains of Listeria have shown increased overall survival in patients with pancreatic carcinoma.

SImilarly, numerous other trials that have been completed or are still in process and have shown the efficacy of microbes in cancer patients.

Many Bacterial products have also been developed which play a role against malignancies.

Bacterial products may be either toxins, ligands of pattern reognition receptors (LPRRs) and metabolites. For example Monophosphoryl lipid, a derivative of Salmonella Minnesota is used in vaccines against HPV.

Short chain fatty acids (SCFAs) are produced from dietary fibres by the action of certain strains of clostridia and firmicutes (clostridial clusters IV and firmicutes XIVa). These are mainly acetates, butyrates and propionates. The acetates are responsible for tumor growth, while butyrates and propionates have antitumor activity.

Butyrates and propionates stimulate regulatory T cells and help in the repair of intestinal mucosa and has been found to show apoptosis in colorectal cancer cells.

It has been proposed that diets low in acetate and high in propionates and butyrates is a possible way to treat and prevent cancer.

To conclude, the level of immunity (immune setpoint) within an individual is determined, besides many factors, by the gut microbiome.

As of now we are still far from knowing the intricacies and mysteries of our gut microbiome.
As we gather enough information about our microbes we can develop certain
i) probiotics,
ii) vaccines,
iii) dietary products and
iv) drugs
which can help in blocking toxins that can be carcinogenic.

These products can be used alone or in combination with conventional agents to treat and prevent cancer, and we may even be able to tailor the treatment as per the patients ‘microbial fingerprint’ i.e the microbial ecosystem present within an individual.

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A happy gut leads to a healthy life. The above article now justifies how a good microbiome can actually help in fighting cancer. And one of the key measures we can take to keep our microbiome happy is to eat healthy.

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