What do bacteria have to do with cancer?

Human beings are a symbiont of human and microbial cells, with more bacterial cells in our body than human cells (around 2:1). Although most of these microbes live within our gut, collections of microbes are also found in most body parts. These collections of microbes within a given region are known as a microbiota, a term originally coined in 1988, and the collection of microorganism’s (microbiota) genes is known as the microbiome. These congregations of microbes, which may include not only bacteria but also fungi, yeast, and viruses, are site-specific, with the microbiota of each body part having distinctive characteristics regarding overall numbers and diversity of microbial species. The highest diversity (widest range of types) is found within the gut microbiome (GM) and generally speaking, the greater the diversity and number of bacterial species, the better for our health. Our GM represent a virtual organ that performs essential body functions such as digestion and metabolism of nutrients, maintenance of a healthy gut wall and defending against disease-causing microbes. Also, the GM is partly responsible for the development of a healthy immune system and brain. Even our moods are constantly being influenced by these invisible creatures who evolved hundreds of millions of years before us. However, with the evolution of the first gut in some ancestral worm, these single celled organisms have since evolved in step with their multicellular symbionts.

For humans, the first major colonisation event with our microbial partners is at birth, which depending on the mode of birth, will at first closely resemble either the skin or gut microbiota of the mother. After this, our GM is shaped by external factors such as diet, lifestyle, and environmental biodiversity, and as such, our microbiome composition varies with age. On average, the adult GM is composed of approximately 300-500 species. With age there is a decline in microbial diversity and by > 65 years there is usually a significant reduction in diversity.

Dysbiosis (from Ancient Greek  (dus- “bad”) and (bíōsis- “way of living”)) refers to an imbalance in our microbiome. Dysbiosis is an imbalance in the microbial diversity of the microbiome with a reduction in the number of beneficial species and an increase in the proportions of disease causing microbes. Dysbiosis negatively affects all the functions that our GM carries out, and if not brought back into balance, will lead to disease over time. Dysbiosis has been found to promote cancer growth, mainly through its interactions with the immune system, where it has been found to suppress the regular activity of the immune system to destroy any malignant growths.

In a balanced state, the microbiome promotes positive health and prevents tumour growth by positively influencing the immune system and maintaining gut barrier integrity. Conversely, during dysbiosis, there can be a loss of gut barrier integrity, which can lead to potentially harmful bacteria making their way past the gut wall and taking up residence in other body compartments. Context is all important; a beneficial species that usually resides in the gut can have adverse effects in other areas of the body. This can result in chronic inflammation in distal sites and the production of cancer promoting bacterial by-products such as toxins which can cause DNA damage.

Chronic inflammation contributes to cancer growth at all stages, from initiation to progression and spread (metastasis). It has been found that up to 20% of all cancers are preceded by chronic inflammation at the cancer site. While in some cases bacterial species such as Helicobacter pylori, are directly responsible for some gastric cancers, most of the time bacteria are merely enablers of some aspect of cancer growth.

It was not until the advent of next-generation DNA sequencing that the influence of bacteria began to be teased out. Many of the residents of our gut cannot be grown in the laboratory, but now that we can read their DNA, they can be readily identified. This has led to the use of microbiome-wide association studies whereby all of the gut microbes can be identified from an individual. When this method is applied to populations with large sample sizes, it can be extremely powerful in allowing scientists to discriminate between beneficial and detrimental species for any disease, including cancer.

Very recently, this has been applied to the study of cancer treatments, where it has been found that the GM affects many types of treatment outcomes from chemotherapy to radiotherapy and the latest immunotherapies. Currently, many clinical trials are ongoing where faecal matter transplants (FMT) are being carried from patients who have had a good treatment outcome to patients who are missing these collections of microbes. This is equivalent to an organ transplant but is a black box approach, in that whilst we currently might not completely understand mechanistically what is going on, it can drastically improve the lives of individual patients.

Of the many beneficial molecules that bacteria produce, of which there are too many to discuss in a short blog, short chain fatty acids have been shown to have the most potent anti-cancer properties, with butyrate having been found to have the strongest effect. Members of the Firmicutes produce butyrate in the large intestine through anaerobic fermentation of indigestible dietary fibre and resistant starch. Butyrate’s protective properties, including anti-inflammatory effects, suppression of blood supply to tumours, and reversion of the silencing of tumour suppressor genes, among others. A high fibre diet promotes the maintenance of butyrate-producing bacteria, making it cancer-protective. Conversely, the opposite effect is true; depletion of butyrate-producing bacteria may promote inflammation and tumorigenesis systemically. If I have one bit of advice from my studies of the GM on avoiding cancer development, it would be to eat more fibre!

About the author: Ciarán Devoy is a PhD researcher in Prof. Mark Tangney's group in University College Cork. You can read more about Ciarán's project here .