The European Prospective Investigation into Cancer and Nutrition

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Published: 22 Sep 2017
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Dr David Hughes - Conway Institute, University College Dublin, Ireland

Dr David Hughes talks to ecancer at the Microbiome in Cancer and Beyond 2017 meeting about EPIC (European Prospective Investigation into Cancer and Nutrition) which studies a large number of Europeans from a healthy status through to the development of cancer. This allows for the comparison between cancer patients and healthy individuals who do not contract the disease.

The primary focus was to study the nutrition of these individuals, with the study being further developed into many new areas. Important metabolites were highlighted such as short chain fatty acids which protect against cancer. Dr Hughes explains that a Western diet with high levels of red meat causes a dysbiosis in the gut microbiome and production of carcinogens.

New data from EPIC concerns Streptococcus gallolyticus, with high presence in cancer patients, supported by its previous involvement in cancer using animal models. Furthermore, the antigens for this bacterium are present in healthy individuals.

Dr Hughes encourages the discussion of prevention of dysbiosis in the microbiome, rather than treatment. This will focus on diet and probiotics. 

He finally touches upon the current debate concerning Fusobacterium nucleatum which is has increased tissue presence in colorectal cancer. His impression is that it is more involved with the progression of colorectal cancer as opposed to intiation, and thus the functionality of microbes is more improtant than presence or abundance.

Mainly I’m working on cancer epidemiology, especially in nutritional factors, in genetic factors that contribute to carcinogenesis. I work with a large European cohort called EPIC, the European Prospective Investigation of Cancer and Nutrition, which has sampled half a million Europeans at baseline, so when everyone was healthy. Then we follow these people up over the intervening years to find out what kind of cancers they develop. That gives us the chance to closely match them with other people in the cohort who didn’t develop these cancers and so, very important, we can have this very close case-controlled matching. Because the samples were taken before diagnosis this helps to minimise issues to do with reverse causality, the fact that things go awry when you have a disease, so it’s very difficult to say whether these factors are implicated in the disease or they’re just because you have a disease. So this is the power of this kind of study design, prospective cohort.

What are the results so far?

We’ve done a lot of studies; mainly the cohort was set up to look at nutrients, that and nutrition. Its scope has widened in the intervening years to look at a lot of other factors. In regards to the microbiome and microbes we’re very interested in the metabolites produced by bacterial metabolism. We need bacteria, it’s critical that we have our gut bacteria or else we couldn’t break down a lot of the foods, especially carbohydrate fermentation. We need these bacteria to do that job for us and they produce some critical metabolites that help us, we wouldn’t be able to survive without them. So some of these bacterial metabolites are very, very important, such as short-chain fatty acids; these help protect us against cancer. Now we have a situation sometimes when the balance of our bacteria in our gut, what’s called eubiosis, this symbiotic relationship with our gut bacteria, becomes disturbed. This process is called dysbiosis. This can be caused by many different things that go wrong. One of the things we think is, for example, a Western diet – red meat, high protein, especially overcooked red meat. This often alters the composition of our gut bacteria; it alters their metabolic products so often we get these nitrosyl compounds from bacterial digestion of red meats and these compounds are carcinogenic or have the potential to be carcinogenic. This is one of the ways we feel that an altered gut bacterial composition can lead to cancers, specifically of the gastrointestinal tract, like colorectal cancer would be one of the major ones, but there’s also increasing evidence that this can lead to cancers at various organ sites in the body.

So one of the things we’re doing in the EPIC cohort is that we’re measuring many of the products of bacterial metabolism, such as these nitrosyl compounds, short-chain fatty acids and others. Another thing is we want to measure directly the immune system response to these bacteria to see if there’s an immune response to the bacteria before cancer onset. So this will give us some evidence as to which microbes may have been involved in the actual process of cancer development. So some very interesting new data that we’ve just submitted recently is on the bulk Streptococcus gallolyticus. This has been shown to be increased in cancer patients, in the tumour tissue of cancer patients, and other mouse models of this Streptococcus bacterium have shown that it may be involved in cancer. So there’s some very good evidence looking at case controlled animal models but we haven’t had the evidence previously in a large epidemiologic cohort to say this is there before disease onset. So we see that antigens to this bacterium are more frequently present in people who went on to develop colorectal cancer than in the control people who didn’t develop the same cancer.

Will this further develop into bacteria pills for prevention or even treatments?

It’s a huge area for development, there’s huge scope in this area. We see also very interesting work has shown that bacterial metabolism affects chemotherapeutic drugs. This is a fascinating new area that you actually can modify your bacterial profile to help the efficacy of chemotherapeutic drugs. So this is huge. That’s in treatment, however much more would be in the area of prevention and this can be simple dietary advice but also the scope for probiotics and prebiotics to help maintain a healthy gut microbiome has huge scope. But we need lots of evidence to really back this up. So there’s been a lot of research in probiotics before but it hasn’t been very well controlled as to exactly what’s been given, what’s the dosage, what’s it affecting, measuring the pathways, measuring the effect. So this will need a lot of study but the scope for healthy lifestyles, prevention of cancer, prevention of other chronic diseases that the microbiome is involved in, is really, really huge and very exciting.

Can you tell me about the debate you’re a part of?

Again the debate comes back to the age-old problem we have in aetiology – is something causing the disease or is it just there because you have a disease? So in the debate today we’re going to have that question which will be speaking for and against the motion that the microbiome is a driver of carcinogenesis. Because when we look, for example if we look at the profile of there are so many different bacteria in our gut; there’s just millions, billions of bacteria, they’re all in different proportions. When we look at people with a disease such as colorectal cancer against people who don’t have the disease we see all these kinds of differences. We see, for example, there’s a lot of debate on Fusobacterium nucleatum; this is seen to be increased a lot in the tissue of people with a colorectal cancer. Now is this just because in a cancer tissue it’s getting increasingly inflamed, this is a very good neighbourhood for Fusobacterium to hang out, to grow, is this what’s happening? Are they just there because you have a diseased tissue or are they actually driving that progression of the disease tissue? So I’ve done some work, along with others that have done similar work, and we’ve come up with very similar validatory findings which show an increase in this Fusobacterium during increasingly dysplastic transitions from normal tissue to adenomas to cancers and Fusobacterium increases at each stage. Then another level which is very fascinating is that it also associates with survival from cancer, so people with higher levels of this bacterium have a worse survival. The reason this seems to happen is because it seems to affect the potency of treatments for colorectal cancer. So from different evidence sources we see that this bacterium does seem to play a role in cancer progression, whether it is also there for cancer initiation is another question and it’s one of the things we’ll address today. There may be some other microbial changes or maybe some other processes and this is what we have to study more.

If you were to speculate?

I actually think that probably something that we see gross changes in, something like Fusobacterium, where we see a big change between normal tissue and diseased tissue, this is probably more the progression stage. It can affect how severe the cancer becomes or your response to treatment. I don’t think it’s right there at the beginning with the initiation process, I feel this would be more low copy number bacteria, so Streptococcus, that might be involved in bacterial products, this is colibactin which directly damages your DNA. E. coli is another one that produces a product called colibactin which is shown to directly damage your DNA, induces epithelial cell damage through DNA damage. This is a core hallmark of cancer. So these are more likely to initiate the process and the reason the differences can be the strain, the type, of this bacteria is critical. You can have the same number as someone with a cancer, as someone who doesn’t develop the cancer, but it’s the type of bacteria, what products they’re able to produce that may make the key differences.

You won’t see this on just a simple numbers of bacteria, whether they’re increased or decreased, but it’s what the function of those bacteria is, that’s what’s critical. This is probably the initiators, then how this neoplastic transformation, how it progresses, because most of the time these things won’t progress to cancers. So how this progresses may involve other changes such as the large increase in levels of bacteria such as Fusobacterium and others like Parvimonas and other ones that we have seen in tissue of people with cancers.