Carrie Daniel-MacDougall, Ph.D. (Host) Hi, I'm Dr. Carrie Daniel-MacDougall, associate professor in Epidemiology at MD Anderson Cancer Center. I'm here with Dr. Jennifer Wargo, professor of Surgical Oncology. And this is the Cancerwise Podcast. Jen, it's so good to have you here today with me. Let's talk about what the microbiome is and what, if anything, is a healthy gut microbiome.  

Jennifer Wargo, M.D. Thanks so much, Carrie. It's great to be here with you and with the audience. So, people often ask, what is the gut microbiome? And so, we know within our bodies we have trillions of microbes, right? And a lot of these actually reside in our gut. And we know that these microbes can actually help shape our immune system and actually help shape our response to cancer treatment. So people often ask, what does a healthy gut microbiome look like? And when you think about it, a healthy gut microbiome is one that's diverse, meaning that there's a large host of microbes within there. Furthermore, it means that you kind of have the right bacteria that are producing good metabolites and other factors and that you don't have the wrong microbes there, which are actually creating inflammation and may be deleteriously impacting our immune system. 

 Carrie Daniel-MacDougall, Ph.D. (Host) Well, one of the things that I've really been studying the most, of course, is how the gut microbiome is so critical to breaking down the food that we consume in terms of taking what we eat and turning it into something that the host can get the most benefit from. Of course, one of the things that we all need to make sure that we consume are the types of foods that the gut microbiome really wants us to eat. A lot of those are high fiber foods, plant-based foods that the gut microbiome can really use to build a healthy community. And of course, the whole thing behind all that that you really understand so well is how important that is for our immunity. And that's a really critical thing that we need to support in order to have that affect on our own immune system. Maybe you can comment just a little bit more on that.  

Jennifer Wargo, M.D. Yes, of course. Well, as we know, you know, several years ago, investigators here at MD Anderson, including Jim Allison, really made landmark discoveries showing that we can actually change our immune system to fight cancer, right? Namely through the use of something called immune checkpoint blockade or immunotherapy. And we know, given the critical role of gut microbes in shaping our immune system, we thought a few years ago, 'Well, gosh, what would happen if we actually look at the gut microbiome in patients with cancer who are being treated with immunotherapy?' And so we did just that. We actually studied patients with a type of skin cancer, melanoma, who were undergoing treatment with immunotherapy, actually got samples of their gut microbiome, a fecal sample from those patients and actually looked at that gut microbiome. And what we found is that patients who responded to the treatment actually had a much more diverse microbiome, and they also had different bugs in their gut with a higher abundance of specific microbes like Faecalibacteria, Clostridiales, Ruminococcaceae, whereas patients who did not respond to the treatment actually had a higher abundance of different microbes in their gut. Now, tell me what factors can actually change our gut microbiome? 

Carrie Daniel-MacDougall, Ph.D. (Host) Sure. So, there are many things that can change the day-to-day variation within an individual. So, there's kind of two things I think that are important when we talk about what is a different microbiome. There's the microbiome that you have and I have, and there's that kind of difference. However, if we're both healthy individuals, we can each have a microbiome with totally different composition that can perform a similar function. And then there's the variation within an individual. So over time, so one day I have a hamburger, a milkshake and a bottle of wine. My microbiome is going to look very different than another day, maybe where I'm having physical activity, I'm having my fruits and vegetables and I'm getting adequate sleep. And so there's that day-to-day variation within an individual. And I think we want to actually target both things and understand both things. So, we do research to characterize differences between individuals and characterize differences within individuals. And one of the things that we know is important for finding differences in both those things is antibiotic use. Different types of supplements, including probiotics, can also have an impact. Whether or not that's positive or negative, I think we might talk a little bit more about that, diet, which I mentioned, certain medications. There's actually been some interesting research that maybe even more so than the chronic condition or the medical condition itself, it's the shared medications that are used to treat those conditions. So like prescription pain meds have a profound impact on gut health in terms of maybe they cause constipation and that can also cause changes in the gut microbiome. But there's a multitude of things.  

Jennifer Wargo, M.D. So, let's get back to antibiotics because it's really interesting. There's actually been data that has shown that if patients receive treatment with broad spectrum antibiotics before they go on to treatment with immunotherapy for cancer, they actually don't respond to the treatment. So, it's really profound and I think it has a major impact. Now, sometimes patients need antibiotics, though, so I think we need to be careful about which antibiotics patients get. And we also need to be careful about not overprescribing antibiotics when patients don't need them. So, I think that's something that patients can think about on their own is, you know, whether or not, you know, if they get a

fever or, you know, in the setting of cancer treatment, you know, just making sure that their doctors know that they're, you know, they're on immunotherapy and really being their own advocates.  

Carrie Daniel-MacDougall, Ph.D. (Host) Well, let's bounce back to that a little bit. So, one thing that patients may go and do on their own after taking antibiotics is taking probiotics. And that's something we've definitely tried to study. Can you talk a little bit about the positives and negatives, particularly in the cancer patient setting for maybe probiotics, which a lot of patients are taking and interested in using as a part of their therapy?  

Jennifer Wargo, M.D. Right. And, you know, there are over-the-counter probiotics that people can buy off the shelf at Walgreens or CVS. And we asked the question of our patients, you know, are you taking probiotics? And looked at outcomes in those patients. And what we found is when we asked our patients if they were taking probiotics, at least a third of patients were actually reported taking over-the-counter probiotics. And if they did, numerically, they actually didn't do as well as patients who reported that they did not take probiotics. Now, we actually took this back to some preclinical studies and showed that if we gave over-the-counter probiotics, it actually impaired the ability to respond to treatment. And so I think it's not all probiotics that are bad necessarily. There are some probiotics that have actually been shown to enhance response to cancer treatment. But I think it's it's important to really be cautious about taking anything that might change the gut microbiome, antibiotics, probiotics and really involve your treatment team, you know, when considering changing any factor of your diet or probiotics or any lifestyle changes, I think really need to be carefully coordinated with your own treatment team.  

Carrie Daniel-MacDougall, Ph.D. (Host) And that, that really reminds me of, you know, dietary or nutritional supplements in terms of vitamins and minerals that patients are interested in taking. And, you know, the jury is really not out on whether those things have benefits. And it actually matters what the patient is in need of. And that's the case where you don't give someone vitamin D unless they're deficient in vitamin D, you can measure that in the blood. And I think one thing that would be really interesting in the future is let's measure their microbiome, figure out what they actually need versus just dropping some random thing in there and having some sort of unintended effect. I think that it's the same kind of, you know, way that we should be thinking about that. And is that something that you see maybe happening in the future that patients will get their microbiomes assessed, you know, prior to some of the treatment plans or some of the decisions that are made?  

Jennifer Wargo, M.D. Absolutely. So, at MD Anderson Cancer Center, we have a Program for Innovative Microbiome and Translational Research. We call it PRIME-TR for short. And this is a platform or a program in which we can actually look at patients' microbiome. So actually sequence a fecal sample from a patient and actually get data back. Now, I think we're starting to do this for many different patients and using that, really in the research setting, to ask important questions. Now, I'll go back to you, Carrie. You know, tell us about the work that you've done on the role of diet in response to cancer treatment.  

Carrie Daniel-MacDougall, Ph.D. (Host) Yes. Obviously, you know, this is a huge passion of mine, and I'm so thrilled that you're on board with this, and PRIME-TR is on board with this. And one thing that we have here at MD Anderson that's very special is our Bionutrition Research Core, which includes a research or metabolic kitchen where we provide meals specially made for different research protocols. And this is really a field where evidence does not exist. And there's quite a lot of crazy things on the internet that patients are finding. And I would really like that we could be the voice of evidence for patients on what should I eat to have a better treatment experience and overall outcome in terms of a durable response, but also not experiencing some of the negative side effects and toxicities? I think that patients and caregivers really understand that proper diet and nutrition are a good way to manage some of those things. And so we've been really lucky through tons and tons of work that you and I have done together, along with Dr. Jennifer McQuade and many others in the institution, to see that we can actually modulate fiber through a number of different methods in our patients through whole foods. We're doing that either through giving them all their meals and snacks and a full feeding study where we're also trying to keep their calories consistent, their percent energy from fat, protein and carbohydrates consistent, and only bring up fiber through different whole foods. We're also now testing another strategy that's a bit more flexible for patients, which is important. Obviously, a cancer patient is a marathon, not a sprint in terms of going through therapy. And there are days when they feel like eating certain things and days when they don't. And so for that, we're trying this new strategy with giving them whole food, prebiotic-based snacks. Again, no supplements all through foods. I think we're going to get a lot of really exciting answers. We're starting to see those already and I'm thrilled that we can give patients some things they can do on their own. One of the first studies that I embarked on before we really had a lot of the infrastructure that we have now was to feed patients who have a prior history of colorectal cancer or colorectal adenomatous polyps dry beans. And dry beans are not actually dry. They are cooked beans, particularly navy beans. And the reason why I chose that is because they contain multiple types of prebiotic fibers, protein and different bioactive compounds that have been shown to be effective in preclinical models for handling this condition that we see in our patients and terms of them being both overweight or obese, but also having a high level of inflammation. And so that's what we were targeting through the gut microbiome with the consumption of navy beans. And so we allowed patients to eat whatever they wanted in their normal diet and measured that very carefully. And then they worked with a dietitian to incorporate a cup of beans into their diet each day. And we did that for four weeks and eight weeks and measured the gut microbiome at both time points. And we saw these amazing increases in a lot of the gut bacteria that we were seeing in the cancer patient population in terms of response to immunotherapy, like an increase in diversity and an increase in Faecalibacterium and Bifidobacterium and some of the other bacteria that are known to be really strong promoters of a healthy gut microbiome community. So, they may have actions all on their own, but what they really do is cross-feed or take care of other bugs within the community and crowd out some of the other bacteria that we like to see go down. And so that is really what we saw and that's really what I would call a prebiotic effect.  

Jennifer Wargo, M.D. So, Carrie, tell me, what kind of beans did you use in that study?  

Carrie Daniel-MacDougall, Ph.D. (Host) So, we actually use canned navy beans. I will tell you that canned beans are cooked very quickly and a very special pressure cooking process that breaks down some of the different compounds that can be difficult for people to digest. Now, other people may be excellent at making homemade beans in terms of proper cooking and soaking techniques to achieve that. But because this was a research study, we wanted uniformity and we also wanted to control some of those other variables that can impact their side effects. And so we actually did use canned beans. And after the fact, I really saw that this, you know, this really resonated with people because you can live in any neighborhood in Houston and go to a gas station or a grocery store. You don't have to live next to a Whole Foods and you don't have to be a, you know, particularly rich family in order to afford a can of beans. And I think the other thing that's kind of interesting is people are really obsessed with protein right now and how many hundreds of grams of protein they need. And I just remind people that that can be achieved through foods like beans as well. There's eight grams of fiber and eight grams of protein in a half cup of navy beans. That's a pretty big punch for a half cup of some kind of food.  

Jennifer Wargo, M.D. Yeah, definitely. Now, can how about the fiber aspect? You know, can you talk a little bit more about, certainly we had seen together that a lot of the microbes that were associated with response to treatment with immunotherapy were actually fiber-fermenting bacteria. And can you talk about how that led us, you know, a. What we found in observational studies and patients who reported taking more fiber. And then, b. Also, on how you and Jen McQuade and others then designed clinical trials in patients with cancer who were going on to immunotherapy and kind of give us a little hint as to what we're seeing with that.  

Carrie Daniel-MacDougall, Ph.D. (Host) Well, I mean, really that the first paper that you had coming out showing that the gut microbiome and these particular microbes were really sort of predictive of who was going to respond to immunotherapy was really inspiring. And it made me think, why aren't we measuring diet in cancer patients? And the reason why is because it's hard. And so I really appreciated that I had the support of you all to give it a try and go on that wild ride with me. And what we basically found is that patients who reported higher amounts of dietary fiber on our little questionnaires that we gave them were more likely to respond to immunotherapy and had extended progression-free survival. So, durable response to therapy.  

Jennifer Wargo, M.D. And there was at least 20 grams of fiber per day.  

Carrie Daniel-MacDougall, Ph.D. (Host) Yes, it was 20 grams. We knew we wanted it to be really tightly controlled so we could get very clear answers in those patients. And so we designed these menus, really, where we gave patients at first 20 grams, then 30 grams, then 40 grams, then 50 grams, kind of ramping them up with whole foods. So, kind of like, you know, you start with white rice and switched to brown rice or you start with this small amount of beans and you increase the amount of beans. So, we did this all through whole foods. And we did that according to the patient's tolerance. And this was, really, a challenging study to do. And we provided all of the food for up to 11 weeks in these patients.  

Jennifer Wargo, M.D. And tell us, you know, I think some people will wonder, can I buy it in a pill? You know, will the fiber pills help me or do I need a whole foods-based?  

Carrie Daniel-MacDougall, Ph.D. (Host) Sure. So, as someone who's been the nutrition field for a very long time, you can almost never get what you can get from a healthy whole foods diet in a pill. And that's because, you know, we just talked about the beans, there is multiple nutrients within a single food. And if we kind of want to think about this multipronged approach, we know everybody has a different gut microbiome to begin with. So, we can't just throw one thing at it and expect that everyone is going to have the same response. But we basically have a gut microbiome that evolved on a whole food diet. And so it's really optimized, in my opinion, to respond to food. And those foods will contain not just one kind of fiber, but often insoluble fiber, soluble fiber, resistant starch, bioactive compounds like polyphenols, which are also prebiotic properties within the gut microbiome and even specific amino acids that stimulate the gut microbiome and may have an effect on the immune system.