by ecancer Medical Reporter Will Davies

Unfortunate news for any readers going through an identity crisis: You are mostly not human.

Sorry.

Within you, across just about every tissue type that makes up your body, you play host to an empire of microbes who have long since colonised and conquered your skin, teeth, intestines, and everything else they can reach.

This is your microbiome, a term coined by Joshua Lederberg in 2001 to describe “the ecological community of commensal, symbiotic, and pathogenic microorganisms that literally share our body space”¹ .

On a cellular level, your microbiome outnumbers human tissue easily, with the gut microbiota alone comprising of 100 trillion cells, from up to 1000 different species², which vary further from person to person³ with 100 times as many genes as the human genome⁴.

This is to say nothing of the varied oral, nasal and skin flora.

Many of these colonists are gifted to us during birth.

Some researchers are concerned that caesarean delivery limits a child’s inner biodiversity⁵, and medical models of mice denied microbiota during conception and birth have also shown unresponsiveness to autoimmune conditions such as MS and arthritis⁶.

These populations perform symbiotic roles with their new host, aiding digestion, tissue development and shuttering out more harmful pathogens.

While it may be discomfiting to think of birth as conferring bacteria to a vulnerable infant, those same microbes are essential to the healthy development, with some describing a ‘critical window’⁷ in early life during which microbiota fluctuate⁸, and may favour the development of diseases and conditions ranging from asthma and irritable bowel syndrome to depression, autism, and cancer⁹.

Under normal conditions, there exists a quiet stalemate of microbiota and immune response, with commensal bacteria carefully directing inflammatory response and tissue damage away from their niche and towards foreign pathogens or uncontrolled growth of the commensal cohort.

This truce is mediated by secretions and cell surface signalling, often via toll-like receptors which deactivate local immune recruitment¹⁰.

TLRs account for a significant portion of immune pattern recognition receptors (PRRs), which activate dendritic cells to attract the appropriate immune response.

Different sites rely on different messenger molecules; short-chain fatty acids (SCFAs) binding to GPCRs to regulate interleukin expression and suppress inflammation in the gut, for example¹¹, or Leishmania major-associated IL-1 production in the skin directs regulatory T Cells¹².

While this regulation is key to homeostasis between the microbiome and host immunity, any imbalance in the system, or dysbiosis, provides opportunistic infections a chance to capitalise on a preoccupied immune response and a diminished microbiome, lending additional risk to the use of broad-spectrum antibiotics¹³.

Often this manifests in the gut, site of a significant portion of one's microbiota, as Crohns, colitis, and other inflammatory bowel diseases¹⁴.

Inflammation, being the hallmark of infection, is a body’s way of creating the least-favourable environment in which a foreign microbe might propagate¹⁵.

It is also, unfortunately, the environment in which tumour cells thrive.

Here is where the tangled web of immunity, microbiota, and tumourigenesis surfaces; how can one be challenged without exploitation by another?

A whole interleukin-mediated inflammasome exists for the purpose of denying a pathogenic foothold¹⁶, with knockout mice being especially at risk of colorectal cancers.

A fascinating extension of this knockout susceptibility is that it can be conferred to healthy mice using faecal transfer, rather than their full complement of microbiota giving any resistance^17,18, yet germ-free mice lacking in IL-10 expression were found unaffected by known carcinogen azoxymethane¹⁹ .

There are numerous infections known to result in cancer, and even displacement of naturally occurring microbes between organs is enough to facilitate precancerous lesions²⁰. 

Famous among tumourigenic pathogens are human papillomavirus, Helicobacter pylori, and Epstein-Barr virus, though countless others may promote dysbioses resulting in cancer.

This may be through either viral corruption of host cell cycles, direct bacterial damage to host organs, or disruption to host microbiota.

Acid production by invasive Clostridium and Bacteroides species in the gut results in DNA damage and stimulates cell proliferation to heal perceived wounding, strengthening the tumour microenvironment²¹.

Certain strains of E. coli are also associated with colorectal cancer, and dysbioses resulting from patient obesity has been causally linked to hepatocarcinoma²².

A straight line can be drawn from a diet rich in red meat to Fusobacterium nucleatum, to inflammation, DNA damage and immune evasion²³.

Disease states due to dysbioses aren’t limited to their surrounding tissues, and some effects can be distal, with gut dysbiosis reported to influence development of neuropathy²⁴.

Beyond the direct causal link to cancer, one’s microbiological population also influences response to treatment, with higher Lactobacillus presence negatively affecting CpG-ODN efficacy, and platinum compounds becoming suddenly ineffective in germ-free mice²⁵.

Dysbioses that prevent proper immune direction hamper immunotherapy, naturally, and cyclophosphamide chemotherapy is similarly neutered²⁶.

As the removal of microflora affects the efficacy of anti-tumoural drugs, the timing of radiotherapy must be considered.

While whole-body radiation does improve patient response to T cell transfer in adoptive cell therapy²⁷, tumour shrinkage by radiation was reduced following antibiotic treatment, as was oxaliplatin response in mouse models²⁵.

So far, the primary dysbioses discussed have been short term, an antibiotic course or radiotherapy fraction.

However, changes in microbiota can be charted across generations and continents, with the increased prevalence of western diets in China resulting in an increasing trend of colorectal cancer²⁸, and though limiting H. pylori infection has reduced gastric cancers, its absence may also be associated with an increase in oesophageal cancer²⁹ .

Just as balance is essential in maintaining one’s microbiome, it is important to recognise that your microflora are not merely carcinogens in waiting.

Many are capable, if not essential, to promote recovery and efficacy of cancer therapies.

After all, whilst it is a new development for clinicians, your microbiome has been manipulating immune responses for quite some time, and seems to be essential in managing these upstart human interventions³⁰.

Amongst the multitude microbiota, your gut is home to butyrate-producing bacteria, which feast upon dietary fiber.

Butyrate itself is a histone deacetylase inhibitor, assuring DNA goes undamaged, and activates genes which promote apoptosis and slow cell cycle progression, making it a potent tumour suppressor²³.

Butyrate enemas also relieve inflammation for sufferers of colitis, Crohns, and IBD, who are at significant risk of inflammation-associated colorectal cancer³¹.

Equol, a bacterial metabolite of daidzein from soy products, has been linked to reduced risk of breast cancer and prostate cancer in Asian men and women³².

Probiotics and prebiotic supplements aid in restoring internal equilibrium following microbial suppression.

As a patient's microbiome recovers, so cancer growth slows³³ and can even begin to regress³⁴.

The anti-oxidant activity associated with many prebiotics prevents inflammatory pathways from activating unduly, and can prevent damage to DNA that may later result in cancer³⁵.

Specifically engineered strains of bacteria can further limit inflammation and increase anti-oxidant expression to reduce tissue damage³⁶, even in mice lacking in IL-10.

Faecal transplant of healthy microbiota is proving effective in restoring patient responses³⁷, and can even be combined with PD-1 checkpoint therapy³⁸ with the potential to reshape patient-centric therapy in cancer and beyond.

This is all, of course, only the briefest of introductions to a field in its infancy; microbiota are changing our understanding of infectious disease, autoimmunity, and mental health³⁹.

A major struggle in cancer therapy is how to separate healthy from cancerous cells when they are so very nearly self⁴⁰.

In treating our human self we may yet reach a better appreciation of our non-human selves too.

--

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