Bladder cancer's relationship with the urinary and gut microbiomes

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Published: 21 Sep 2017
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Dr Jeremy Burton - Lawson Health Research Institute, London, Canada

Dr Jeremy Burton talks to ecancer at the Microbiome in Cancer and Beyond 2017 meeting about his talk concerning the relationship between bladder cancer and the urinary and gut microbiomes. He discusses the risks that could arise during polymerase chain reaction (PCR) and sequencing due to a high potential for contamination and artefacts.

Dr Burton's research field is relatively understudied, and he believes there is still more to be found concerning this complex relationship. He also wants to delve further into the impact of certain cancer drugs on these microbiomes as they could have negative associations with other systems. Recent data surrounding the regulation of testosterone also goes some way to provide an explanation for the resistant characteristics of some drugs.

He ends by underlining the technical difficulty surrounding the future of his research, particularly without a large number of resources. The youth of this particular field also means there are many avenues that could be pursued. Without much further research prevention will be limited to relatively crude methods such as transplantation or probiotics.

The title of my talk was relating to what potential role the urinary microbiome and the gut microbiome have in relation to urology. So the urinary microbiome is a relatively new entity and people don’t often think that the microbiome plays much of a role in urology. But that’s not actually true and it goes beyond urinary tract infections. So people think of bacteria and urology and think of urinary tract infection and I’m sure that that’s important and we’re learning more about it and we’ve got a lot more to learn, but actually the bladder itself has its own microbiome. It doesn’t have a lot of microbes; we know that it has bacteria, no-one has really looked at other micro-organisms. Our work has actually also looked at above the bladder, so the kidneys, and also I didn’t talk about it today but we’re interested in ureteral stents - we know that biofilms, that they pretty quickly become colonised with bacteria that shouldn’t be there. We’ve also done studies looking at kidneys that have been taken out of people; there are not many bacteria that get up there but we can detect bacteria there. So you have to be very careful when you’re analysing microbiomes, especially in places where there isn’t many bacteria expected and there’s a lot of risk from the contamination by environmental samples and the inherent risks of the technology that we use. So we use PCR-based amplification and then sequencing of those PCR products so under certain circumstances you can amplify the wrong thing or the contaminants and that will give you a false result. So we had to put a lot of development into creating methodologies that ensured that we weren’t contaminating our samples and were giving us a result too.

We also went back and started using more old-fashioned techniques. Allan Wolff’s group in Chicago has re-pioneered some of the culture work for the urinary tract using extended culture. We can now actually grow some of the bacteria from those sites where clinical samples, they only look for some of the pathogens which are easy to grow and relatively straightforward.

So we’re interested in the urinary microbiome so it could potentially have a role in a number of diseases. We’ve done some preliminary work in bladder cancer; we’ve presented some bladder cancer microbiome work today. Actually the urinary microbiome doesn’t show a correlation if you have bladder cancer or not but we’re taking a sample which is urine from the whole bladder whereas the bladder cancer samples that we’re interested in are just small tumours in reality. So unless you have a field change you may not actually see a microbiome change. We all want to find the magic bullet of what’s causing bladder cancer, beyond the carcinogens or whether it’s the microbes converting things to carcinogens, we want those magic markers as well. So at present the technology doesn’t really allow for that. The early tumours are typically ablated by the urologist as soon as they see them so we don’t get that sort of material. Maybe later on the bigger tumours are not necessarily representative of the early tumour environment. I’m not a cancer specialist but that’s my perception.

What else is heavily linked to your research?

A lot of what ends up being produced from the gut, and you’ve probably talked to other people today about it’s a major metabolic organ, that a lot of that will come in to the host and out through the urinary system. So we’re interested in that and we’re interested in a number of different things. We’re interested in drugs that are involved in reducing androgen in prostate cancer. We know that some of those drugs are really insoluble. You take them orally, they spend a long time in your digestive tract. They’re in the presence of bacteria for a significant amount of time and that allows them the opportunity to interact with them. So sometimes they will utilise those as carbon sources; in other cases they’ll be antimicrobial. So when you start taking these agents you change a lot of things; you start to modify the microbiome, you’re depleting testosterone, you’re changing a lot of the major important physiological things that are going in your body. We have testosterone for a reason.

So we’re interested in that and we’re interested in that there are some recent studies which show that the microbiome can influence the regulation of testosterone and that’s very important in prostate cancer because prostate cancer is driven by testosterone. So the drugs are being modified by the bugs so that might have an influence on efficacy but, on the other hand, if they’re also potentially regulating testosterone levels that might provide an opportunity to reduce testosterone in men by a female faecal transplant. We’ve got preliminary data that suggests that certain androgens are being produced by bacteria. So it’s like the microbiome is starting to compensate for the deprivation of androgens in the host system and that it kicks into action and may potentially play a role in why some of those drugs become resistant.

How will you collect more data?

We’d like to do more things, there are a few technical issues to overcome. So how do we get access to those small tumours? We are not Imperial College and we’re not the NIH so the methodology that I’d probably employ would be something like single cell sequencing and then do the microbiome of each cell. I know that I collaborate with some bladder cancer diagnostic companies and they can get very good signatures off very low numbers of cells. So we’d like to maybe eventually correlate some of the diagnostic read-outs of single cells in relation to the microbiome that’s on the surface. Now that’s a technically challenging thing to do and we’re going to have to learn some skills to do that.

So could the urinary and intestinal microbiomes have a role in urologic cancers?

I think absolutely it has a role but we need to learn a lot more. This is a very new field; the urinary microbiome has only been described since 2011. The interaction of these drugs has never been described, this xenobiotic metabolism side is a very new area. Essentially any ingested oral drug could be modified or changed by the microbiome yet there are no studies on really just about any drugs. We know that metformin now there are a couple of papers in Nature which show that some of the benefit of metformin comes from the microbial xenobiotic metabolism and producing some of the short-chain fatty acids.

What does this mean for disease prevention and management?

It could mean a whole lot of things. Maybe it could give us markers to start off with so we’d know that you’ve got the right bugs, that sort of thing. The Japanese in the 1980s, ‘90s and early 2000s did studies with probiotics. Some of the human studies that they did showed a lot of promise but they had their weaknesses. We have a lot more technology now, we should go back and revisit those. Because bladder cancer is very recurrent they can show that reduced recurrence. So simply a dietary change, introducing a probiotic, may have some effect in that population at the very simplest of manipulations. In time we might be able to do other sorts of manipulations, so people have done faecal transplants, what about urine transplant? Or maybe that’s too crude, maybe we can derive very specific drugs that target certain pathways that lead to whether it be protection or disease. There’s a whole lot more to be done.