Microbiome Insights is proud to be the sponsor of season 2 of Ruairi Robertson's Biomes Podcast. 

In this episode Ruairi talks to Dr. Wendy Garrett, a professor at Harvard Medical School. Here are the key takeaways from the conversation: 

• Dr. Garrett's history combining her studies in clinical medicine with the emerging field of microbial ecology
• How changing global dietary patterns have led to increased incidences of colorectal cancer in developing and emerging countries, and in previously low-risk age groups.
• Dr Garrett elaborates on the effects gut-dwelling bacteria and microbes may have in the genesis of intestinal polyps or tumors.
• Some bacteria that form stable environments in distal body parts, such as Fusobacterium nucleatum, are found in abundance in the colon and stool of cancer patients...how is this happening?
• Future avenues for this field of research, including the potential for targeted phage-based therapeutics against causative microbial elements in the gut.
  
  

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Full Transcript 

Ruairi Robertson:

Hello, and welcome back to Biomes, the place to learn about the latest, fascinating developments in human microbiome research, and to get a full dose of microbes in your ears. You actually have a lot of bacteria in your ears, would you believe? And some evidence shows that if you acquire or lack some of these microbes, this can lead to ear infections mainly in children. But that's not what we're here to talk about today. This third or fourth episode of the series is actually all about cancer, particularly cancer in the lower intestine known as bowel cancer or colorectal cancer, depending on where you are in the world.

Ruairi Robertson:

And as you might've guessed from the theme of the podcast, there are some significant links between the types of microbes in your intestine and your risk of developing colorectal cancer by either causing or preventing certain cells in the gut to change and become cancerous. In fact, tumors have their own microbiomes and the microbes that they contain may control how much that that tumor grows and spreads. And if that wasn't enough, recent evidence shows that combining therapies that target the gut microbiome with traditional therapies can improve the efficacy of certain cancer treatments.

Ruairi Robertson:

This week, I speak to one of the leading figures in this field, professor Wendy Garrett of Harvard Medical School. Professor Garrett is both a medical doctor treating cancer patients and a researcher examining the processes by which gut microbes cause and prevent colorectal cancer. Her work has shown fascinating links between microbes that originate in the mouth and how they traveled to the gut and may contribute to colorectal cancer. We discussed this exciting research and the future for targeting the gut microbiome as an approach to tackle colorectal cancer.

Ruairi Robertson:

And as always, this episode of the second season of Biomes is sponsored by Microbiome Insights. The team at Microbiome Insights have partnered with some of the world's leading cancer research institutes, helping researchers incorporate microbiome sequencing and analysis to their clinical studies. You can get free study consultation from the team at microbiome insights. So head over to microbiomeinsights.com to find out more and tell you were listening to the podcast.

Ruairi Robertson:

Thank you very much, Professor Wendy Garrett for agreeing to have a chat in these crazy COVID times, whenever it was connected by Zoom, but it's great to connect and hear about your work as a leading figure, I suppose, in the gut microbiome. Especially in your speciality, looking at how the gut microbiome is associated with colorectal cancer and also inflammation in the colon. You look at IBD as well, which is... We'll chat about all these different things. But maybe we can start off and just hear about your career and how you got to where you are today. You're an MD as well as a scientist. So, how did you get to where you are and how did you become interested in the microbiome field?

Wendy Garrett:

Sure. So as you said, I'm a physician scientist. Clinically, I'm a medical oncologist with subspecialty training and interest in gastrointestinal malignancies. And you're right, bowel cancer or colorectal cancer is my clinical passion. And you also said I'm also a scientist. I have been interested in the immune system in bacteria for a very long time since graduate school. And it was fantastic to see a field, coalesce that's been around for hundreds of years. Like many of the people in this series, I am a microbiome studies scientist or researcher advocate.

Wendy Garrett:

And as anyone that's listening knows that's the collection of organisms, not only that live within and on the human body, but on our furry pets, on our furniture, in our built environments. I'm very interested in how those exposures shape our immune development and shape our susceptibility or resistance to disease. I was growing bacteria in my basement home in middle school.

Ruairi Robertson:

No way.

Wendy Garrett:

and that might've been more microbiome or fungal elements of our world. But it's been a long time, that I've been interested in science since I was a kid or a wee one. And so, I definitely think all of us that are in science should work to promote, science and technology and interest in engineering and mathematics, from the earliest ages from pre-school on up. So youth can have and develop curiosity about the living world, which is really what microbiome studies is all about.

Ruairi Robertson:

Yeah, exactly. That's great. You're doing it from your time as a kid as well, growing microbes. And in your medical training, was there any... I know we learn from the basic science that microbes cause disease, but was there any appreciation back when you were doing medical training for the microbiome field? And this is greater appreciation of the microbiome as a whole, as a major regulator of all these things, we now know it plays a role in the body, or was it always the microbe disease model that you learned about?

Wendy Garrett:

Well, we didn't use the word microbiome when I was in med school many years ago, but we definitely had some infections that you've probably covered in your podcast. One of those being Clostridium difficile, and I did hear about stool transplants in medical school, and I thought the idea was wild and fascinating. And so we were talking in some fashion, there was an idea that even though we might study model organisms in the lab, like salmonella, that there was more complexity in the gastrointestinal tract.

Wendy Garrett:

And within mammals, the number of organisms that a particular host was serving as a home, for microbes. So yeah, I think there was some understanding and appreciation. Now it's much more explicit. So through the Harvard Chan Center and microbiome and public health, we're teaching master's in public health students and we're teaching medical students and we're teaching our graduate students in immunology and biomedical sciences about this more ecological think to the human organism and also model organisms that we study. And how the microbiome can inform so many different physiological processes, et cetera.

Ruairi Robertson:
So it's making its way into the medical curriculum and public health curriculum. That's great to hear. As you mentioned, your speciality is bowel cancer and colorectal cancers, and you've done a lot of work in, the immunology on the microbiology behind that. So maybe we'll just have a brief background as if you're giving a presentation about the epidemiology of colorectal cancer. Are rates increasing around the world? What are the big stats with colorectal cancer that make it such an important disease to study for you?

Wendy Garrett:

Well, across the globe, it's the third leading cause of cancer related mortality. And I know in the UK, you call it bowel cancer, in the US we call it colorectal cancer. And there are differences in the disease in terms of where it pops up in the right colon or the transverse colon or the left colon or the sigmoid colon, or the rectum that most distal part of the colon. The experts obsess about that geography of it. The other piece that's very concerning is that with the change in dietary patterns across the world, we're seeing an increased incidents in countries that were historically had low levels of it. So countries like the people's Republic of China, having much higher increased risk.

Wendy Garrett:

We're seeing some tickle of increased in the larger African continent, of course, many, many countries there. So that's concerning. The other place where we're seeing a very concerning epidemiological trend is with this idea of young onset colorectal cancer. And it's really inexplicable in some ways, sometimes there are genetic syndromes or there might be patterns and families, and we have names for those syndromes. The lid syndrome or hereditary nonpolyposis colorectal cancer, or adenomatous polyposis coli gene is involved in familial adenomatous polyposis.

Wendy Garrett:

But these young people, people in their 20s and 30s, people younger than 50 that are developing colon cancer often don't fit that pattern. And it isn't some clear signal like obesity. No, it's not that at all. And so, that is a very concerning trend. Seeing this disease creep up and pop up in younger and younger populations. And one big reason is why? Why are we seeing it in younger, younger populations? As someone in microbiome studies, I own my bias. We're wondering if it's some trend in the microbiome or some pattern there or something popping up there with an environmental exposure related to the microbiome.

Wendy Garrett:

So definitely young onset colorectal cancer and seeing different trends in emerging or developing nations in terms of increased rates of colorectal cancer. Bit concerning, very concerning. So that's the epidemiology, I think.

Ruairi Robertson:

There's a lot to it, I guess. I will go into detail a bit about your work specifically and views of bacteria, but give us a little insight into what were the first discoveries in terms of how the microbiome may be association with colorectal cancer. It might seem obvious now that we think about it, the intestinal environment, particularly the large intestine is full of these bacteria, viruses, everything. And so it's safe to hypothesize or assume that they may play a role in cells mutating and changing differently leading to cancer. So what was the first signs of this, or evidence that changes in the gut microbiome may be associated with and colorectal cancer?

Wendy Garrett:

It goes way back. So even when I was in med school, I was learning this pearl or this little gem or nugget of knowledge that we still teach our students, that there's some organisms that can be found in the blood and they shouldn't be there. It's an infection or a bacteremia. And sometimes their Streptococcus or Streptococcaceae. One of them is now called Streptococcus gallolyticus, it used to be called historically Streptococcus bovis. And if you saw that bacteremia, that infection in the blood, you needed to order that patient a colonoscopy because there was an association or a correlation with the presence of an adenoma, a tumor in the colon or Frank Colon cancer.

Wendy Garrett:

And so that was known for many, many, many decades before I even came to medical school. So hearing about that and learning about that in medical school and seeing those case reports and series and collections or small cohorts of patients. That definitely put that tickle early on or that psychic itch in my head, during my medical education of, what were the names? It intuitively makes sense that as you noted, the colon is the most densely populated microbial ecosystem. Why wouldn't the microbes there have play a role. But it was the clinical observations that planted the seed for me.

Ruairi Robertson:

That's great. That's seems like what happens, isn't it? It's these strange clinical observations that lead to the broader questions. I think that's exciting about your role being on that fence of being a clinician and scientist as well, it allows you to lead those observations, discoveries down a detailed route in science.

Wendy Garrett:

It's such a fortunate path, the path of the physician scientist. I think it also speaks to while it's wonderful that some people are able to invest the time and have the opportunity. It's a position and educational path of privilege. And so I own that privilege and I'm very grateful for it. But it means, doctors and scientists need to talk, because sometimes their patterns and observations that can only, if you have a particular maybe training or think might that bubble up to a thought and really make an impact in terms of uncovering biology.

Ruairi Robertson:

You're right.

Wendy Garrett:

Talk to people over Zoom or at conferences. Those sort of nascent ideas and observations that other people had made really inspired me to ask those basic research questions. And then there was this emergence of microbiome sciences. And an emergence of applying sequencing technology that came out of the human genome project and the hard work of many folks applying sequencing technology to looking at microbes.

Wendy Garrett:

And so we could begin to look at microbes at a larger scale using different technologies in human stool and look for trends with the emergence or diagnosis of polyps or cancers. We could begin to look at the tissues too. And when I see this is a field of many researchers, that's not just one lab. And begin to look at those tissues and see what were the resident microbes in those tissues. And, not surprisingly certain patterns popped up. And one of those patterns or signals or features, was sequence of an organism that you already mentioned, Fusobacterium nucleatum.

Wendy Garrett:

And these are beautiful, long ,gram negative rods that guess what? You and I probably both have. But guess what? They live here at our gingival crevices, along our buccal Mucosa the inside of our cheek on our tongue. And there's a huge literature generated by the oral microbiologists about their role and plaque and gingivitis, and a lot of us have been doing okay with them. And so when a couple labs, the Meyerson lab that I've been collaborating with for many years and the whole lab started to see those in colon tumor samples, it was puzzling. What is an oral bug, a mouth associated microbe that you and I have, doing in a colon tumor sample or a colon cancer sample.

Wendy Garrett:

These weren't just samples from one site in Canada or one site in Boston. These were samples from Germany and Spain and Vietnam. These are truly global samples. So then, you're always worried, did someone spit in the sample? Could happen. Well, you can use other technologies besides sequencing, you can use different kinds of sequencing. You can try to grow the organism. And what was born out was that some colon tumors, in terms of the microbial or bacterial sequences were there were dominated by Fusobacterium.

Wendy Garrett:

60% of the microbial or bacterial reads were mapping to this Fusobacterium nucleatum. And when you looked at larger populations, sometimes depending on the collection of patients, 11 to maybe 70% of the patients using PCR based technologies had some of this Fuso DNA. That was unbelievable. Again, that's correlation, but it generates a whole bunch of questions. How does it get there? Is it just a by stander or is it a driver of some behavior? What about a tumor enables it to be a host for a Fuso? What about Fuso enables it to leave the mouth? It's normal or a native niche in a human, and get to the tumor. And is it of consequence? Is it a bad thing? So then you get lots of folks involved, you get molecular epidemiologists involved that have access to lots of human tissues.

Wendy Garrett:

And clinician scientists can do correlations with survival and response to disease. You get microbiologists that want to look at all the genomes of all the different Fusobacterium nucleatum species and figure out what's different and how similar are Fuso in the mouth and the tumor. You get the immunologists. That like to pull apart the tumor micro environment or gut tissues and asks, where is Fuso? How does it interact with different immune cells? Does it draw more immune cells in? Does it affect anti-tumor immunity? And you explode a field because you make this observation and it's not solved yet. And guess what? Fusobacterium nucleatum isn't the only bug enriched in tumor tissues. There are Polyketide synthases or PKS pathogenicity island harboring Escherichia Coli, PKS, positive E Coli.

Wendy Garrett:

And that island can harbor several genes that result in the elaboration of a toxin that we colloquially call Colibactin, that can damage DNA. So then you get chemical biologists and classic bacteriologists involved, and stem cell biologists and immunologists trying to figure out, and cancer genomicists how that talks and bond gets out of the bacteria is process, damages the DNA. Then you get the people to think about, why did it evolve that not to cause cancer.

Wendy Garrett:

Probably to fight other bacteria and when the war of occupying a niche. So you've got PKS positive E coli. You have the super cool bug that a few labs, especially Cindy Sear's lab has studied called Enterotoxigenic Bacteroides fragilis. There are certain toxin producing Bacteroidetes that some people have, and those are enriched in some colon tumors and polyps.

Ruairi Robertson:

So maybe we can explore some of those, particularly the Fuso bacteria, because I think that's a really interesting one. Originates in the mouth, we all have it, as you say, Most people will have it somewhere. What is it? Why does it move? Or what do we know about the causality? Is it moving down and causing cancer or is something happening in environment or happening in our mouths or our bloodstream that is just allowing it to pass down and what have you and what have others found out about that? And why does it pass from the mouth to the gut if it does do that?

Wendy Garrett:

We've asked those questions and in my lab and collaborative with other labs, like the lab of Gilad Bachrach in Israel, at Hebrew University at Hadassah hospital and also with the Curtis Huttenhower's lab. So there are a couple of ways. So just sit there for a minute. You have saliva in your mouth, guess what? You're going to swallow some. How do you interrogate questions about how do mouth bacteria end up in your colon? Are they biologically active? Are the [inaudible 00:20:09]? You can ask within an individual how similar are mouth bacteria and then bacteria in the colon by looking at spit samples or tongue samples and fecal samples. And guess what, it's a minority of the organisms that are transcriptionally active both in the mouth and in the colon or colon resident bacteria that ended up active in the mouth.

Wendy Garrett:

So it's not a usual thing. There are some but not many that can do that. You can also ask generic questions about how common is Fusobacterium nucleatum in the stool of a healthy person. Guess what? Not really that common. It likes to live in the mouth. So then you can say, why is it so good at living in the mouth? And that's because it's got a lot of adhesins we think. Sticky proteins, we know it has those and it binds to other bacteria. That's really helps to construct that biofilm, that we all call plaque. So Fuso is good, we know generally a feature of Fuso is it's good at sticking to other bacteria and some things or tissues. What's another thing you do maybe at least twice a day, I hope.

Ruairi Robertson:

Brush your teeth [crosstalk 00:21:20].

Wendy Garrett:

Yes. I've talked a lot about Gilad Bachrach, about this. He's an oral microbiologist. So you brush your teeth and I'm sure you have impeccable dental hygiene, but occasionally maybe you're flossing your teeth and brushing them. And what do you notice when you spit? Your spit is a little bit red or pink tinged. That's a little blood, there's been a little damage to that oral mucosa. So what can happen and happens to people that even brush their teeth probably three or four times a day and have wonderful, beautiful teeth, is that a minority of bacteria in their mouth get into their bloodstream.

Wendy Garrett:

Guess what? You have an immune system, you have a spleen. That's a very good filter. You have a liver. Our body is ready for that in most cases. And your body will clear that, but some bacteria do get into your bloodstream. And one thought through some model system experiments that we've done with Gilad Bachrach is that maybe some fuse though gets into the bloodstream and ends up in your emerging colonic tumor. So Gilly and I debate and argue about the way, is it that you swallow some Fuso and it goes all the way down. It survives the acid of the stomach. It survives the detergents of the small bowel, and it ends up in the colon? Possible.

Wendy Garrett:

Is it possible that you have some damage in your oral mucosa with brushing and whatever else, maybe you eat something sharp and it gets into your bloodstream and ends up in the colon? It's possible. Can we ask questions like this in mice and other model systems? We can. But how does it stay in the colon? One thing is these sticky proteins. So there are sugar molecules, if you will, on the lining tissues and cells, the epithelial cells of your colon, that change as a cancer develops.

Wendy Garrett:

So the pattern of sugar molecules expressed by a colonic epithelial cell that's dysplastic or neoplastic, and cancerous is different from a healthy epithelial pattern of glycols. And Fuso has proteins that bind sugars. And guess what some of those sugars are similar between mouth bacteria that Fusobacterium nucleatum likes to bind and dysplastic and neoplastic epithelial cells. So one thought is that Fuso's adhesion proteins bind molecules on epithelial cells. And that's what allows Fuso, not only to transit through, regardless if you're a bloodstream believer or a saliva dripping down believer, but enables it to stick.

Wendy Garrett:

And once it sticks, just like we need certain things to live in a home, obviously, maybe a little heat, if you live in a cold climate, you need food. Fuso has some adaptations or metabolic features that allow it to live in the colon. It's got some metabolic specializations that enable it to find some carbon sources that it needs to grow, when it's mucosal associated. And so maybe that's why it does it and other mouth bacteria don't. But I will tell you that there is a strong mouth oral microbial signature in a lot of human colonic adenomas, and colorectal cancer. There are other mouth bugs there besides Fuso.

Ruairi Robertson:

And I know there's similar evidence for cardiovascular disease as well. People have hypothesized the same thing that there's bacteria coming from the mouth. So all of this research we do into the gut microbiome, maybe we should all become oral microbiologists instead, and start looking at those pathways.

Wendy Garrett:

They are wonderful group of people. It's a wonderful field. So I agree. More oral microbiologists.

Ruairi Robertson:

That'd be great. So once these bacteria, whether it's that this Fuso, or whether it's the strep species that you say get down. Why is it doing it in the gut and how is it interacting with the immune system or with those cells and why is it then making them become cancerous or what process is there? I know you've done a lot of immunology in this work, in this field. What is it [crosstalk 00:25:38]?

Wendy Garrett:

First of all, they're two different ways you could think about it. You could think about how it's interacting with the immune cells and the stromal cells within an evolving tumor micro environment. And you could think about what's it doing with the cell that is becoming cancerous? I love immunology. So I'll start with the immune system. So there are a whole bunch of scientists, not just me and my lab that have studied this. So Fuso is interacting with a lot of immune cells. One story or manuscript that I was involved in, again, involved some scientists in Israel, [inaudible 00:26:11] lab, and Gilad Bacharach's lab and my lab too.

Wendy Garrett:

And what we found, in the tumor microenvironment Fuso is interacting with cells that express a molecule called [tiget] that is an immune checkpoint molecule or protein. And it's normal for immune cells to have these. Immune cells, like all the cells in our body, need brakes, just like our cars need brakes or bicycles need brakes. So there's nothing bad about necessarily or biologically having an immune checkpoint or a break on an immune cell. But what Fuso does is on cells that are really important for anti-tumor immunity, like natural killer and K cells. Fuso has an adhesin protein called Fap2 that binds one of these immune checkpoint proteins on a really important antitumor immune cells.

Wendy Garrett:

Different T-cells and in K-cells express this tiget molecule and Fuso binds that immune checkpoint protein and engages it, engages signaling. So it's important not only to bind something, but if it's a protein that delivers a signal inside the cell, it does both those things. So that's not a trivial distinction. Because you can think of activating and blocking proteins when you bind. When it does that, it makes the natural killer cell a less good killer and that isn't good in the tumor micro environment. You want your immune cells killing those cancer cells and keeping that tumor in check or making a shrink away.

Wendy Garrett:

Why would a bacteria do that? Does it want to drive cancer? No, it probably wants to evade the immune system itself. It doesn't want to get killed by the immune system itself. Fuso does a lot of interesting things. It also brings in myeloid cells and molecules that Fuso induces seem to make the myeloid cells less activating of immune cells then kill tumors. So it's engaging with lots of myeloid cells like dendritic cells and macrophages and myeloid derived suppressor cells and neutrophils. And it's changing their behavior.

Wendy Garrett:

And then it also has a protein that makes certain lymphocytes, innate and adaptive, ones not kill, because it's putting the brakes on them or if they aren't directly killer cells, it's impairing their ability to productively participate in anti-tumor immunity. Not good, right?

Ruairi Robertson:

Not good.

Wendy Garrett:

Why is it doing that? Get it out of there.

Ruairi Robertson:

That was going to be the next question. What this reminds me of, I suppose what it might remind other people off who know the field is the H. pylori story, where Helicobacter pylori is found in the stomach and it was first identified by Marshall and Warren. They won the Nobel prize for it and it shows that this bacteria lead to stomach ulcers. So the standard treatment now is to give antibiotics to get rid of that. Even though H. pylori might have some advantages in certain situations. So what is the current thinking that for a Fuso bacteria, should we be getting rid of it? Is there a specific treatments for Fuso? So should it just be targeted in people who are already cancerous? Or are the thoughts around that in terms of getting rid of it or managing it?

Wendy Garrett:

Such a good question, and there's so many things to be learned from knowing about other bugs. Like Helicobacter pylori. So what is pathogenic or tumor driving or eliciting or inflammation driving or eliciting about H pylori? Well, we know about cagA, what do we know about Fuso? Not enough. So what is the bad actor in terms of us human? The other thing that you mentioned impacting is that, the presence of Helicobacter pylori might increase our risk of ulcers and gastric cancer, but guess what? Maybe having it is protective for something else, and maybe that's telling us not all Helicobacter pylori are created equally genomically or in terms of features that they have. 100% true. Won't go into that, but beautiful literature.

Wendy Garrett:

Same thing for Fuso, there's a huge world within world of different Fusobacterium species, and a genetic differences between them. So we need to better understand what Fuso was doing and what Fusos are not a problem and which Fusos are a problem for different individuals. And then what do we do? Do we just give broad spectrum antibiotics? It's actually often a cocktail for Helicobacter pylori. And Helicobacter is so wonderfully complex. So there are actual tumors, mucosal associated lymphoid tumors, gastric molds, where you can cure the patients sometimes by giving them antibiotics to target Helicobacter pylori. But that's a small minority of patients.

Wendy Garrett:

What we're learning or what we've learned, incidentally is there are antibiotics that kill Fusobacterium in the clinical lab. They clear infections with Fusobacterium nucleatum that definitely do happen clinically. But they're not necessarily specific. They're not targeted. They won't just knock down Fuso levels. They'll hit many bacteria that might be beneficial to a human or any other animal. So what we need is more targeted approaches and part of targeted approaches are, doing nice, really careful drug screens.

Wendy Garrett:

Because maybe we can find something specific. But it's also thinking about anti-violence approaches. What is virulent about Fuso? What is the problem with Fuso? So I mentioned one it's adhesin and do we somehow need to target this adhesin? Or there's out of the box thinking, Fuso has features that enables it to get to a tumor micro environment. Do we want to engineer a Fuso has the feature to get to a tumor, but then deliver something beneficial? So while there are antibiotics that exist on the shelf and our clinical armamentarium that will kill Fusobacterium nucleatum strains and strains that have been isolated from human tumors, they affect many things. Are there opportunities for the development of selective antibiotics through different screens? Most definitely.

Wendy Garrett:

Are there opportunities for more sophisticated approaches that target virulence features? Yes. Are groups working on it? 100% And of course there are lots of other interesting strategies for targeting different bacteria. I have talked to different companies that are using phage based therapeutics and there are several. And then I have a fun project with a brilliant scientist in Canada, Emma Allen-Vercoe looking at Bdellovibrio associated like organisms, which we by an acronym Bdellos. And you can grow and train them to select the bacteria they eat, other bacteria. And have these cool predator prey relationships. And you can grow and train some of these Bdellos to eat other bacteria like Fusos. And it's very specific interaction. These Bdellos develop a very specific taste for particular E Coli or particular Fuso. So there are a whole gamut of strategies.

Ruairi Robertson:

Those could be lots of strategies or treatments in the future for targeting Fuso. And I think you're right. It could be that there are different types of Fuso, which are doing different things. But the other, I suppose, hypothesis is that Fuso only becomes disease causing because of something that's happening in the environment. And I think one of my favorite environmental examples about that is this pine beetle in forests, especially up in Northern Canada.

Ruairi Robertson:

And the pine beetle is a normal part of the environment. It can live happily, but then with a change in global warming and increasing pressure, it then can expand, well not expand, but grow more and it kills a lot of these trees that it lives in. So could this be what's happening with Fuso? Is it something that's happening in the environment that makes it become disease causing and carcinogenic? Is it something dietary or is it something lifestyle that triggers it to then cause these problems in the gut?

Wendy Garrett:

I love that idea. So I'm really fortunate to collaborate with a lot of nutritional epidemiologists at the Harvard School of Public Health and also epidemiologists and clinician scientists at Dana-Farber cancer Institute. And they're asking just those kinds of questions. And so they start out by looking for patterns and big data sets and large cohort studies and asking like that, are there patterns in the diet where you're more likely to have fewer though in your tumor? And there seem to be those association. And so that identifications of those correlations or patterns is really, really, really, important. And it's the first step.

Wendy Garrett:

And ultimately we want to evolve to the gold standard of clinical care where wouldn't it be great if we could do a clinical trial and do a prospective cohort clinical trial where we could design, this is very dreamy, blue sky kind of science. An I deal dietary pattern for you or selective intervention that if goodness forbid you were at high risk, because you had had a polyp. That we could do something for you or a group of users or a group of people. Where we could then lower your risk of a second polyp or developing Frank colorectal cancer.

Wendy Garrett:

Even without thinking about the microbiome, there are beautiful associations that certain lifestyle choices about exercise or certain changes in dietary patterns, correlate with better outcomes and better survival. When you look at those data, why? Is it maybe the microbiome? So can you have an observation about a certain behavior, like biking to work? I'm just picking something out of the hat and just somehow it affects. So we don't know. There are a few papers that correlate certain features of a dietary pattern in these large cohorts and maybe having more or less Fuso on a tumor. And that's provocative, but again, that's a great observation, but then you have to push it forward, push it forward and get it mechanisms.

Ruairi Robertson:

Yeah. You have to get the mechanisms. A lot of what we know from that nutritional epidemiology would suggest that maybe there is a microbiome link because there's studies showing that people who eat more fiber for example, are less risk of colorectal cancer. And of course, fiber is the food for the microbiomes. So maybe it's these metabolites or the microbes are producing that keeps everything in check. But there's examples again from cardiovascular disease, there's this TMAO is this famous metabolite now, which is produced through the metabolism by the microbes, which then contributes to cardiovascular disease. So I guess that is what your colleagues and you might find out with some of your nutrition work in the future that, that maybe the microbiome is interacting with the diet in some way to affect colorectal cancer risk.

Wendy Garrett:

We love doing those kinds of studies in my lab. We love looking at a microbial metabolite be it TMAO or short chain fatty acids that are positively or negatively associated with a disease state in humans. And then trying to nail the biology, looking at that microbial enzyme, looking how a perturbation can change it in a more simplified host than a human, like a mouse, where we control the microbiome using nodal biotics. But that's where real free clinical systems allow you to unpack the biology. Even when we have these really beautiful associations and good preclinical studies around TMAO, there is still so much to understand about how a metabolite can contribute to vascular disease or chronic kidney disease. And how the microbiome and diet slot into that.

Ruairi Robertson:

Yeah. Because it's usually not a simple path, there's so many microbes, so many metabolites that although you can pick out one little pathway, there's probably hundreds, if not thousands of things going on. But if we're going to finish off maybe and talk about treatments, one of the biggest developments in cancer treatment in the last few years is the checkpoint inhibitor treatments, and these people won the Nobel prize for a couple of years ago. And you mentioned these checkpoint inhibitors already, where one of them is called PD1, one of these checkpoints. And if you block that, it's a very useful way of allowing the immune system to fight off cancer. And it's been shown to be very useful in certain cancers and might be useful for colorectal cancer.

Ruairi Robertson:

Some really interesting research has shown that the microbiome may be involved in that. And you've spoken a little bit about it. So maybe you can talk a little bit more, what is the future for that? Or how could the microbiome help with these treatments or how can we study them in tandem to maybe improve these really promising treatments for colorectal cancer.

Wendy Garrett:

This is an area of research really near and dear to my heart. My lab works in this field, and there have been some lovely studies from Jennifer Wargo's lab from Tom Gajewski's lab from Lauren's and Vogel's lab. And one challenge is they've all found something a little bit different and it's not because they're setting different cancers. There are really interesting signals about whether a patient is going to respond to... As you said, once the [inaudible 00:40:19] and if they're not. And it can be regardless of whether they have renal cancer or lung cancer or melanoma.

Wendy Garrett:

So within single centers, there've been shared observations about different cancers. So I think there is tremendous opportunity because really the crux of all those observations goes back to that eco evo thing that you were alluding to when you mentioned the pine beetle. That the immune system and the microbiome have co-evolved and co adapted. And if we understand how the immune system integrates and takes in all the collective signals of a particular microbiome. And how the microbiome shapes immune system development at a really basic level, how it's integrating all these signals and how that leads to the development of different cellular states, cell types, cell numbers of the immune system, maybe we can begin to tune that system to make things like immunotherapy for cancer work. But also help people with inflammatory and auto-immune disorders.

Wendy Garrett:

I'm very, very interested in that field. I'm interested in that idea from epidemiology of meta analysis, let's get all these data together across studies and let's analyze these microbiome data and see if we can see conserved signatures. And in my lab, and others are seeing features, metabolic features that are common. It might not be a taxa, a bug that I have and you have 30 other people have that help them respond (it might not be, it could be) to PD1 therapeutics. It might be a metabolic pathway. That's engaged by many bacteria that we just have to tickle or tune just the right way. Because then that gives the right series of metabolic inputs to immune cells to help immunotherapy work better.

Ruairi Robertson:

That'd be exciting. There was a fascinating small study that came out, I think a week or two ago, which showed that a fecal transplant in certain patients may improve their response to this checkpoint inhibitor therapy for cancer. So do you see that as a treatment? Is everyone who's going to be getting one of these treatments also going to get an FMT as well to try and improve their response? Or is the future targeted probiotics with your cancer therapy or something along those lines, which could help, or what do you see as the future of this field?

Wendy Garrett:

Really interesting paper about FMT and melanoma out in Israel. Very provocative. I think it tells us there's a signal there and we need to go after and refine and come up with a therapy that is perhaps more targeted. And that we can deliver and deploy to implement to more patients. Find something that's a more scalable solution, and also be mindful of how we can do it in a safe way too, and deliver it to as many people and make it effective for as many people as possible. I'll speculate many possible alternative futures.

Wendy Garrett:

Maybe it's a defined consortium bacteria. Maybe it's some small molecules, maybe it's a combination of small molecules or foods for the bacteria delivered with a consortium bacteria. And maybe it's not a one size fits all option. Maybe it's a couple different ideas that are pushed forward and by profiling someone's microbiome, we can figure out what's going to be the best fit for them in terms of their outcome, in terms of their survival, progression-free survival, overall survival and maybe even stable disease or cure.

Ruairi Robertson:

So thanks for listening to the Biomes podcast, sponsored by Microbiome Insights. My name is Dr. Ruairi Robertson. Tune in next time for some more exciting insights into latest developments in the human microbiome.