Possible colon cancer vaccine target uncovered in bacteria

(Press-News.org) Higher rates of certain cancers in countries, such as the UK, may be linked to two particular strains of bacteria. Targeting these with treatments or vaccines could help reduce the risk of colorectal, bladder, and prostate cancers.

Researchers from the Wellcome Sanger Institute, the University of Helsinki, and collaborators investigated the differences in cancer incidence for colorectal, bladder and prostate cancers, and compared these to global data tracking Escherichia coli (E.coli) strains. Specifically, they looked at the dominant two E.coli strains that produce a substance that has been previously identified as a risk factor for colorectal cancer.

Their paper, published today (4 December) in the Lancet Microbe, notes that these two E.coli strains are found more commonly in industrialised countries where they cause high rates of urinary tract infections (UTIs) and bloodstream infections. These strains do not cause food poisoning.

The researchers suggest that the higher rate of certain cancers in these countries could be linked, at least in part, to these two E.coli strains that produce a substance known as colibactin, but stress that further investigation is needed.

The ability to produce colibactin is a rare feature of some E.coli and is mainly only found in two strains that have been estimated to be at least 300 hundred years old. Therefore, interventions that tackle these two strains, such as a vaccine or a probiotic, could prevent these bacterial strains from circulating and, in turn, reduce cancer risk.

As these E.coli strains are also the leading causes of UTIs and bloodstream infections across industrialised countries, an intervention to eliminate them would also reduce the infection burden and antibiotic use.

The bacterium, E. coli, is commonly found in the human gut. Most strains of E. coli are harmless; however, if the bacterium gets into the bloodstream due to a weakened immune system it can cause infections, ranging from mild to life-threatening.

Researchers, including those from this team, have been using genomic surveillance to track the different strains of E.coli across different countries, including the UK, Norway, Pakistan and Bangladesh. This has allowed them to identify factors that cause certain strains to spread and highlight new possible ways to stop strains that cause disease.1

In 2020, research found that colibactin, a substance produced by certain bacteria including two strains of E.coli, causes DNA breaks in human cells. The team also found evidence of damage from colibactin in tumour samples from colorectal cancer patients.2

Preliminary evidence suggests that colibactin-producing E.coli strains also play a role in the development of cancers of the urinary tract, such as bladder and prostate cancers, as this is a common site of E.coli infection.3,4

In this study, researchers compared cancer incidence rates with genomic surveillance data of E.coli. They found that the two strains of E.coli that produce colibactin are seen in industrialised countries which also have higher levels of bowel, bladder, and prostate cancers.

Comparatively, in under-resourced countries, such as Bangladesh and Pakistan, the two colibactin-producing strains are much rarer, and incidences of bowel, bladder, and prostate cancers are also lower.

The team hypothesise that the geographical variation in cancer incidence is affected by varying levels of population exposure to these two strains of E. coli. Nonetheless, further large-scale investigation is needed, including wide-spread tumour sampling, to clarify the role of colibactin in cancer.

Producing colibactin is energetically expensive for E.coli and requires a genetic adaptation that ensures the process is not too costly for the bacteria. This adaptation is difficult to acquire by horizontal gene transfer, which is the way bacteria share traits. Due to this, only two successful E. coli strains, out of the hundreds of E. coli strains circulating globally, have managed to establish a stable maintenance of the colibactin producing genes during the last centuries.

Therefore, interventions that focus on eradicating these two strains, such as a vaccine, could be hugely effective. Another avenue could be developing therapeutic probiotic products that help displace these two E.coli strains from the human gut, aiming to remove them from the population.

Dr Tommi Mäklin, first author of the study, from the University of Helsinki and the Wellcome Sanger Institute, said: “E. coli can be found around the world, in many different forms, and understanding how strains of this bacteria impact humans differently can give us a more complete picture of health and disease. Having access to global genomic data on which strains are found in an area can uncover new trends and possibilities, such as strains in industrialised countries potentially being linked to the risk of certain cancers. We also need to keep ensuring that countries and regions around the world are included in genomic surveillance research so that everyone benefits from new discoveries.”

Dr Trevor Lawley, senior author from the Wellcome Sanger Institute, said: “Our guts contain many different types of bacteria, most of which are harmless, including some strains of E.coli. As not all bacterial strains can live in your gut at the same time, they have to compete for space and resources. In the future, it could be possible to develop therapeutic probiotics that help to displace unwanted bacterial strains, such as the ones that release colibactin. Understanding more about the interactions between E.coli and cancer risk highlights the impact our microbiome has on our health and is a crucial avenue to explore if we want to work with our bodies to help combat certain conditions.”

Professor Jukka Corander, senior author from the Wellcome Sanger Institute, University of Oslo and the University of Helsinki, said: “We have been using large-scale genomics to track E. coli strains across multiple countries for the last 5 years, using data that goes back to the early 2000s. This has allowed us to start to see the possible connections between two E.coli strains and cancer incidence rates. Science is not a stand-alone endeavour and by working together with cancer and microbiome experts, we are hopeful that in the future this work might lead to new ways to eradicate colibactin-producing E. coli strains. Vaccines or other interventions that target these E.coli strains could offer huge public health benefits. Such as reducing the burden of infections and lessening the need for antibiotics to treat these, as well as reducing the risk of cancers that could be linked to the effects of colibactin exposure.”

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Rachael Smith

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Notes to Editors:

In 2024, a team from the Wellcome Sanger Institute, the University of Helsinki, and collaborators highlighted ‘remarkable and unexpected differences’ in the distribution of Escherichia coli (E. coli) between the Punjab in Pakistan, Europe, and the USA. They showed that the E. coli strains responsible for many urinary tract infections, and common in countries including the UK, are not found in the Punjab region. Full story can be found: https://www.sanger.ac.uk/news_item/western-superbugs-do-not-dominate-in-pakistan/ Pleguezuelos-Manzano, C. et al. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature 580, 269–273 (2020). Shrestha, E. et al. Oncogenic gene fusions in nonneoplastic precursors as evidence that bacterial infection can initiate prostate cancer. Proc. Natl. Acad. Sci. U. S. A. 118, (2021). Chagneau, C. V. et al. Uropathogenic E. coli induces DNA damage in the bladder. PLoS Pathog. 17, e1009310 (2021). Author interests:

Dr Trevor Lawley is also a co-founder and Chief Scientific Officer of Microbiotica, a clinic-ready biopharmaceutical company specialising in the development of adult precision live biotherapeutic products with lead products in immuno-oncology and inflammatory bowel disease.

Publication:

T. Mäklin, A. Taira, S. Arredondo-Alonso, et al. (2024) Geographical variation in colorectal and urinary tract linked cancer incidence is associated with population exposure to colibactin-producing Escherichia coli. Lancet Microbe. DOI: 10.1016/j.lanmic.2024.101015

Funding:

This research was funded in part by the Research Council of Norway, the Academy of Finland, and Wellcome. A full acknowledgement list can be found in the publication.

Selected websites:

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