Examining the Forgotten Organ

Speaker 1: Welcome to BenchToBedside, a weekly series of live conversations about recent advances in cancer from the research bench to treatment at the patient's bedside. And now, your host, and the Director of the University of Kansas Cancer Center: Dr. Roy Jensen.

Roy Jensen: Hi, I'm Dr. Roy Jensen. Thanks for joining us for today's episode of Bench to Bedside. With me is Dr. Shahid Umar, Professor and Vice-Chair of Research in the Department of Surgery at the University of Kansas Medical Center, and a gastrointestinal researcher at the University of Kansas Cancer Center. Today we're talking about microbes, specifically the bacteria in our gut and their connection to cancer and our health. Dr. Umar, thanks for joining us today. Let's start with an overview of the human microbiome. What exactly is that?

Shahid Umar: So microbiome seems to be the buzzword these days, and I will start by saying that we are never alone. Now what does it mean? It means that our bodies are inhabited by trillions of tiny friends that we collectively call microbiota. These are bacteria, viruses, fungi, and archaea, to name a few of these microbes, actually. The name microbiome is given to the genes, all the genes that are present within the cells of these microorganisms. These bacteria are transferred from parents to offspring just as we inherit genes from our parents and from their parents. These vertical transfers that we call are the bacteria that we inherit when we are babies born from the mother. Now, 90% of these bacteria live in our gut, so it's almost called a forgotten organ. There are other places, such as skin, lung, reproductive organs, for example, that have a distinct microbiome of their own, and they are very different. Then, there are places such as liver and pancreas that do not have a microbiome of their own; however, they are influenced by the metabolites which are generated as the result of our gut activity, and therefore, these metabolites could be absorbed systemically, and therefore go to these organs to help in terms of affecting the outcome of various activities.

Roy Jensen: Okay. So the microbiome has kind of exploded on the research front. And why is it so important for our overall health?

Shahid Umar: Right. So they do a lot of things that our bodies can't. First of all, humans provide a niche for these microbes. We also provide a nutrient  the mucous which is present in the lumen. And this mucous acts as not only a reservoir, as far as a shelter for these microbes, but it also provides nutrients to these microbes. So the microbes then return the favor by digesting the food that we eat, they absorb nutrients, they produce vitamins that our bodies can't produce, and then they calibrate the immune system. But more importantly, they protect us from environmental pathogens. Now, the numbers of the microbes that we carry in our gut, I said 92, 95% are in the gut. That number is usually very unstable from the time a child is born, to around two years of age, but after that it just stabilizes. However, the composition evolves continuously and is influenced by diet, the type of maternal colonization for example, use of pre and post natal antibiotics for example. So in a nutshell, they do lot of heavy lifting for us, and we don't even realize that they are really doing us a favor. So basically, the saying that what we eat is what we are, and it's true, but what is also true is what we eat is what they eat, so we have to be very, very cognizant of the fact that if these microbes are not healthy, then they will affect our health sooner or later. Roy Jensen: Exactly. Expanding on that a bit, what is the microbiome's connection to colon cancer?

Shahid Umar: Sure, that's a great question. Colon cancer, as we all know, is a very complex and heterogeneous disease. There are several factors including homogenetics, and mutations in those genes, diet, immune system, as well as, of course, microbiome. They all play very important roles in the whole process. Now, these factors not necessarily mutually exclusive. Now what does it mean? It means that they ... If you have a genetic susceptibility, for example, if there is a propensity or predisposition within a family, you know, if there's someone who has a history of cancers in the ... Then there are, it is possible that they may have an underlying defect in terms of the type of bacteria they would be carrying in their gut. And so if you look at the numbers, for example, the upper GI, since 90% of these live in the gut, upper GI is predominately still. It's not until you reach the terminal ilium, which is the last part of this small intestine, and then the colon which is the large intestine, that's when you get to a point where it's almost a trillion bacteria. So with that kind of bacterial load, it's not unusual to expect that microbiota may be providing the missing link. Now, with that being said, the single most important factor that dictates the type of bacteria, and the bacterial metabolites that will be generated, is diet. So I will give you two examples: number one, we have a high fat diet, so these are the diets that are rich in red and processed meat, for example. What they will do is they change the microenvironment in a way that causes these bacterial profiles to change, and then, therefore, the metabolites that are generated, can cause inflammation, can generate a lot of [inaudible 00:07:23], and therefore can damage the DNA, which will culminate in a state where you have massive inflammation, DNA damage, & therefore, onset of the process of carcinogenesis. On the other extreme is a diet which is rich in fiber, and so a fiber diet, what it does is, depending on the type of fiber that we consume, whether soluble or insoluble, mostly soluble fiber generates metabolites that actually boost our immune system. Therefore, they increase the immune surveillance, in those situations, which will then help a person fight cancer. So there are 2 extremes, really, one where you have an [inaudible 00:08:11] immune system due to high fat diet, at the same time, that's where there is massive activity of the immune cells. At the same time, cancer is where you have almost lack of immune surveillance. So you can connect the dots, by choosing a type of diet that a person should be given, and there is a recent report that, even if someone is diagnosed--God forbid, with cancer, for example--you can still manage these diseases by putting them on a proper diet, a regimen. So I think it has a huge potential in terms of how we can cash on the possibilities, where you can manipulate these microbiota to help us fight these [inaudible 00:08:59] diseases. Roy Jensen: Over the last couple of decades, cancer incidences in many cases has been falling, but one notable exception to that, is the fact that more and more young people are being diagnosed with colon cancer. One result of that is that the American Cancer Society now advises that adults 45 years in age, or over, to undergo colon cancer screening. So that's a change from a few years ago, when the value was 50. So why is this change come about, why is this increased incidence of colon cancer in younger people, [crosstalk 00:09:49] and all that?

Shahid Umar: Excellent, excellent question. Let me go back to the state of microbial profile in Western population. If you look at humans in general, compared to any other primates in the Western world, we have the least diversity of the microbiota that you can imagine, so it's almost like an apocalypse, and that the microbiome could be the 5th horseman. Now, with that being said, I think it's several factors. Number one, a sedentary lifestyle, the type of diet we use. And the excessive use of antibiotics, particularly in the developmental years. So now there are two examples that I can tell you: Robert Wood Johnson Foundation recently came out with a very freaky kind of statistics, where they found that 16% of children, age 10 to 17, are obese. That puts them at twice the risk of developing cancer at a very early stage. That's the report. The second report came out from Journal of American Medical Association, or JAMA, where they found that young women, aged 20-49, are either overweight or obese. Now, that also puts them at almost twice the risk for cancer, particularly colon cancer. Now, how are they associated, how are these changes reflecting in terms of microbial profile, we are still in the very early stage to understand. If all of this is eventually related to the changes in microbiome, but those are some of the factors you can very easily focus on, is trying to prevent these changes, because obesity causes significant inflammation, and inflammation can lead to DNA damage, and therefore, eventually causing these onsets to happen very early during that process. I think there are a lot of avenues for us to help stratify these patient populations, and I have always been a big proponent of prevention, rather than trying to cure a disease, and so my take on this is that we should go out and spread the message in the community in a way, so that they can start looking at this seriously. Because again, the lifestyle of these younger kids these days, with the smartphones and everything, they're changing or decreasing the latency period for most of these diseases, and therefore we have more and more incidences of these. Now, with that being said, obviously, what is not known, however, is these are just incidence reports. Whether it's really happening, and is it advantageous to screen patients at 45 compared to 50 and higher, for example, we just have to wait and see, but there are indications that can help us fight this disease. Roy Jensen: So if you're just joining us, we're here with Dr. Shahid Umar, and we are discussing gut health and the microbiome. Alicia Miller is here in the studio to take your questions, and I believe we have a question from our internet audience, [crosstalk 00:13:34] so Alicia, please go ahead. Alicia Miller: We do, the first question is do you recommend a plant-based diet? Shahid Umar: That's a great question, and the answer is yes, because plants and fresh leafy vegetables, they are one of the best sources of antioxidants and fiber content, which will then increase the ratio of good bacteria versus bad bacteria. So the idea is, again, to be able to fight, or boost, our own body's defense system in a way that they can fight on their own. Roy Jensen: Please remember, if you want to share this discussion with friends or people you think might be interested or benefit from this, and use the hashtag #BenchToBedside. Dr. Umar, you've been studying the role of bacterial infection in colitis in colon cancer, for more than 20 years now. Could you tell us about your research in this area? Shahid Umar: Absolutely. I have always been fascinated by the tiny world of microbes, which cause about 20% of all the cancers that's actually out there. The role of viruses in this thing is very well-known, because they cause well-known cancer etiologies, such as hepatocellular carcinoma, head and neck cancers, cerebral cancer, and so on and so forth, for example. When it comes to the role of bacteria in cancer, there are a lot of skepticism, and for the simple reason that these infections are transient, and therefore, they can be treated with antibiotics and therefore, they don't cause any trouble. What we don't realize is that cancer is not a disease that happens overnight. Some of these pathogens are strong enough to cause changes in our gut. These bacteria are eventually gone, but they may have caused the damage that will be then reflected 10, 15, 20 years down the road. My lab has been extensively involved in working on a group of bacteria called driver bacteria, that actually are sort of positive in this situation. So these bacteria cause infection, they can also cause inflammation and colitis, and with that kind of inflammatory background, it sort of increases the chances, or decreases the latency period, for cancer. So my lab, along with the lab at MIT, has been extensively involved in this function. What the field is basically struggling with, however, is a simple concept that all the changes that we see are a result, a cause of the disease, or a consequence of the disease. What we have been able to do is using specific mouse models. We have very easily and very effectively showed that we can increase these tumor incidents in the colon, particularly, by infecting with these driver bacteria. Now what does it do then? You infect a mouse with a driver bacteria, it then leads to changes in the microbiome in a way that, some of them, even though they are command cells, and helpful for you, they are opportunistic pathogens, so we call them pathobionts. When there is an initiation, this then leads to changes in the microbiome in a way, that then can work them into potential pathobionts, so they become the passenger bacteria. A combination of driver, passenger, then causes a situation where you have a full-blown disease. Now, one of my grants will also focus on the simple premise that, God forbid, if somebody is diagnosed with colon cancer early, what if that person gets infected with some of these pathogens, which are called the driver bacteria? Is it possible to expedite the whole process? Now for that to happen, eventually what we are working on, and I'm collaborating with a lot of other investigators, and the field in general is doing a prospective longitudinal study, because most of the studies that you see, the changes that you see, as I said before, are during early stages of cellular transformation, maybe lost 20 years down the road. So the idea is to do a longitudinal study where we can establish the cause and effect, and therefore, definitively link the microbiome to colon cancer. Roy Jensen: Okay. Alicia, it looks like we have a couple of questions from our audience? Alicia Miller: We do. The first one I'll give you is how can you get your microbiome back on track?

Shahid Umar: There are a lot of ways that you can do, and I will be discussing this more as we go along, but there are several food that you can eat, there are lifestyle changes that you can obviously avoid, such as sitting on a couch, for example. Get enough sleep, don't be stressed, because what actually happens is these bacteria can make us thin or fat, they can make us sick or healthy, or they can make us happy or sad. So it all depends on how are we really prioritizing our day to day activities. If you really have a combination of good work ethics, there are ways that you can improve, even if you have an altered microbiota, there are several ways to get back on track. Roy Jensen: Okay. So our second question, Alicia? Alicia Miller: Yes, the next question is what is your recommendation for someone who has an instance of bacterial colitis? Shahid Umar: There are several ways you can do this. Obviously, again, number one is diet, but now, more and more, we are moving towards ... because what happens in these patient populations, there is a severe, severe change in bacterial composition that we call dysbiosis. Our gut, in those patients, harbor bacteria which are more harmful than helpful. And one of the ways, very recently, this technique has taken off, is called the fecal microbiota transplantation, or FMTs. It has worked beautifully for C. Diff. patients, patients who are suffering from C. Diff. diarrhea, for example, particularly in those patients that are resistant to antibiotics. After 3 different recurring infections, the only available strategy is fecal microbiota transplantation. Now, it works very well, almost like a panacea in those patients, 95 to 98% with no side effects, no safety problem. However, for colitis patients, FMT may or may not work. It depends on the state of the disease, the time of FMT, and then the follow-up. There are pills that people can use, we call it "crapsules," so there are several ways, obviously, the full potential of fecal microbiota transplantation, or FMTs, will not be recognized until we have considered all the efficacy data, all the safety data. Children, usually, when they are young, they have colitis. You don't want to give them a transplant, which has pathogens, for example, so you don't want to put them at risk later in life. So there are ways to counter that, but that's where the field is moving. Roy Jensen: Okay. So it looks like we have another question? Alicia Miller: Yes we do. What are your thoughts on using essential oils as natural supplements? Shahid Umar: Right, so I think it all depends on an individual basis, because you and I can eat the same food, and we can generate very different metabolites, because the type of bacteria we're carrying are very different. So whether a person will respond to a particular intervention will be dependent or dictated by the type of bacteria we are carrying. We obviously have to stay healthy in a lot of ways, but at the end of the day, what will really determine is, a kind of approach which is known as the precision medicine, where you give a prescription to a patient based on his or her microbial profile. I'm not sure, but the medical profession is really moving to a stage where this will be a standard of care. As a big proponent of microbial research, that's what I will really convey the message to, because every patient is different, and so the type of food that we take will depend on the type of bacteria we are carrying in our gut. Roy Jensen: So just as a follow-up into that, what is the evidence for the use of probiotics in normal individuals, and is there or is there not evidence that that has beneficial effects? Shahid Umar: This, again, is a great question. So, what are probiotics? Probiotics are a group of bacteria which are, when given in a sufficient amount, will cause a health benefit. There are at least 2 different issues with probiotics: number one, one size doesn't fit all, okay? And number 2, it takes a village. Now, if you look at most of the probiotics which are out there, most of them are a group of 10 to 15 bacteria. In our gut is an ecosystem, which is a consortium. So, it's possible that you can choose the perfect probiotic. The problem is, although they are very helpful, they are healthy, we still don't have the safety data, number one. Number two, these probiotics have to be taken continuously, because they don't colonize the gut, unfortunately. So there's a paper in [inaudible 00:24:51], that just came out, actually, where they took patients on a two antibiotics regimen. In one case, it was just given to these patients who were either obese or on a high fat diet, for example, and most of these bacteria were recovered in the stool. So that means that these are the bacteria that are present in the lumen of the gut, and don't really necessarily associate with the epithelial cells of the gut. In situations where the patients were given antibiotics and then were put on a probiotic regimen, there was very little recovery within that stool, which suggests that the host flora sort of provides significant resistance to the intake of these probiotic, or colonization of the probiotics. At the same time, when these patients stop taking probiotics, is there a possibility for the effect to persist? At the end of the day, that's what we need, basically. That will again depend on the level of dysbiosis, or alteration in the microbiota, and whether our bodies are able to sort of respond efficiently to these probiotics. I think there are, obviously, all the evidence so far hint towards a health benefit, but again, what we don't have is a prospective longitudinal study where we can really magnify the potential of these probiotics. I'm a big proponent of good bacteria, at the same time, what is also important is to keep in mind that nutrition, which is known as a prebiotic, so the dietary part, why don't we try to keep patients on, or even a healthy person, on a diet regimen which will promote the level of good bacteria. In other words, you are basically directly promoting the growth, and you're not even depending on a supplement.[crosstalk 00:27:02]

Roy Jensen: Looks like we have an additional few questions here, Alicia. Alicia Miller: Yes we do, we have 4 questions now. If colon cancer runs in the family, can changes to your diet make a significant effect?

Shahid Umar: Absolutely. It's not all lost, even if you are diagnosed with, God forbid, with cancer, there is still several ways you can keep yourself from falling into a doomsday. Cancer diagnosis is not necessarily the death sentence, and there are several ways you can improve your microbiome, in a way, that will help you, again, the immune system is a big player, if you can teach the gut, or teach your bacteria, to boost the immune system in a way. And for example, one of the major regulatory cell in our bodies is called the regulatory T-cells. These cells are significantly attenuated in patients who have cancer, and so, if you have a high fiber diet, for example, it generates these metabolites called short chain fatty acids, or butyrate, and butyrate can significantly up-regulate these regulatory T-cells. It also helps in terms of mucous production, so you can see all the barrier function in the gut, therefore the bacteria won't be allowed to become systemic. At the same time, you're boosting the immune system to fight dysbiotic bacteria, or opportunistic pathogens, so there are several ways we can help these patients who have been diagnosed with cancer. Roy Jensen: I would add to that, obviously, any patients that have a family history of cancer, you need to make sure that they're following the screening recommendations of their physicians, and it's great to try to supplement or change things to influence the outcome, but that doesn't replace the need for continued screening.

Shahid Umar: Absolutely.

Roy Jensen: So what's our next question, Alicia? Alicia Miller: The next question is, how does drinking plenty of water or other liquids affect our gut health?

Shahid Umar: That's again, an excellent point. We are 90% water in our bodies, so it helps, in terms of lubricating, because let's say you continuously eat a high fat diet, and there is very little fiber, probably the insoluble fiber. So what insoluble fiber does, it's basically roughage, so it absorbs water and keeps our stool moist. Usually, we have a habit of going to the bathroom on a regular basis. Let's say you miss or skip a cycle, what happens then, is the water gets reabsorbed, and therefore that makes the stool harder. That can cause constipation. These dietary agents, when you have plenty of water, it will help in lowering the transit time, and therefore your bowel movement will be easier. That means that your bacteria, even if they have some changes within them, they will not be stored for a long time within the rectum, because that's where the stool is kept before it is passed on. You don't have to allow these bacteria to stay longer in contact with your cells of the body, therefore, drinking plenty of water helps recover that process.

Roy Jensen: I'll drink to that. Just kidding. What's our next question, Alicia? Alicia Miller: The next question is, are there other supplements or interventions beyond weight and obesity that will positively alter gut biota?

Shahid Umar: There are several supplements, but one has to be very careful, and I would suggest that you talk to your primary care physician, or your oncologist, before you start ... I would never recommend anything over the counter without talking with your physician, first of all. Because number one, we don't know how they were stored, we don't know what is the compilation of. Let's say they're probiotic supplements, for example, or they're food supplements, for example what is the efficacy? What is the amount that you need for a sufficient health benefit? So, before really embarking on these supplements, I would be very careful and talk to my physician so that he or she can prescribe based on your situation. Everybody's different, obviously, in terms of what the type of bacteria we carry in our gut, so I would be very careful.

Roy Jensen: Okay. So maybe you could just summarize, what are some recommendations that you have at a practical level, in terms of keeping a healthy gut?

Shahid Umar: We, in the western world, have come to a stage we're literally starving our microbial self. It's about time. By its very nature, the microbiome, or microbiota, is extremely susceptible to, the way it is shaped involves significant plasticity. Now, what does it mean? It means that you have to have boundaries, and what happens when these boundaries are crossed? To what extent these microbiomes, or microbiota, are susceptible to perturbations. I will give you 2 examples. Pregnancy is one of the major regulator of microbiome dynamics, so 2 periods are important: one, before pregnancy, during pregnancy, and after the child is born. During that period, the use of antibiotics is very important. There has been so many literature, scientific findings now available, where what they find is that these children, when they are born, if they are C-section, the type of birth would determine the type of bacteria we carry in our gut. Babies that are born with C-section, they miss the birth canal transit. That means that they will be colonized by bacteria, which is whatever is present in the environment at that time. That means that they will not be inheriting the fair share of microbiome from a mother's bodies. So, what are the consequences of this? These children, some of them are colic, for example, some of them receive a significant amount of antibiotics. There is a population of children, sometimes they are preterm, that have necrotizing endocolitis, for example. All of these are based on a very altered microbiome. What we need to do eventually is cut down on the use of antibiotics, either prenatal or postnatal, because these children, when they are given excessive antibiotics, there are reports that when they receive antibiotics at an early stage, these children go on to develop allergies, asthma, obesity, and all those later in life. If you can cut down on the use of antibiotics, that's one thing. Number two, if you can limit the C-sections, only in those cases where it is unavoidable, for example. Speaking of that C-section, there is a fascinating study that was just published. A family in Virginia went through a C-section, but what the physicians did then, was they took the birth canal fluid, and then wiped it on baby's bodies, and the idea was to promote, or jumpstart the bodies. People are calling it a bacterial baptism. That's a fascinating development in this field, obviously in cases where these C-sections are unavoidable, then those strategies can be very helpful. Roy Jensen: Looks like we have some additional questions. Alicia Miller: We do. How effective are fermented foods?

Shahid Umar: That's a great question because our bodies, particularly the food that we eat, mostly soluble fiber, that does not get digested in the upper GI, it goes to the colon, which is the large intestine, and that's where it gets fermented. Now, whether supplements, which are available over the counter, whether they will be able to replace the healthy lifestyle that we can have, I would rather recommend use of yogurt, for example, which has live cultures; use of foods that are rich in whole grains. Cut down on red and processed meats, for example, increase soluble fiber, and all those strategies can help certify, or rectify, some of these issues.

Roy Jensen: As we approach the end of today's Bench to Bedside session, Dr. Umar, what key takeaways would you like to leave with our Facebook audience?

Shahid Umar: I think what we will have to do is give up on our sedentary lifestyles, we have to eat a lot of fruits and vegetables, and what we really need to do is, we owe a good microbiome to our next future generation, something that our ancestors have colonized for over 200,000 years. I think we have to start before it is too late. It's a good way to end this discussion. If you keep your bacteria healthy, trust me, they will be dancing in your gut.

Roy Jensen: That's good. First of all, I want to say thank you to our Facebook audience for a lot of great questions today. Have we covered everything, Alicia? Alicia Miller: There are 2 more here. One is, is there evidence of diet helping other gastro cancers, for example, stomach or small intestinal cancers?

Shahid Umar: Yes, again, that's an excellent question. The entire GI tract, where 90% of the bacteria are there, they may be at some point in time altered in a way that will cause diseases at this time, particularly there is now evidence of duodenal cancers caused by changes in microbiome. Now, H. pylori, for example, that's what sort of solidified peoples' belief in bacteria causing cancer, because it was discovered to cause gastric cancer. There are several ways we can still maintain a level of healthy microbiome, and therefore, some of these approaches are very meaningful in terms of keeping us healthy overall.

Roy Jensen: Okay. I think we have one additional question? Alicia Miller: One more question: let's see here. Are products like Plexus, BioCleanse, and Probio5 helpful? Are you familiar with these products?

Shahid Umar: Yes and no. I am familiar with them. Whether they provide health benefits, that, again, depends on every person is different. There are several products that are available in the market, Bio-25 is also one one of them. There are some very good probiotics, but we still don't have a safety and efficacy data and a longitudinal study, which would suggest in the long term that they will really provide benefits. But all the evidence against favors our approach. There is at least no harm in taking these supplements, except that you have to be cognizant of your situation, number one, and then talk to your physician before you take any supplement.

Roy Jensen: Okay. Well thank you, Dr. Umar, for a fascinating session today. That's all for now. For more information on colon cancer, please visit kucancercenter.org. We appreciate you joining us and we invite you to tune in next week, Wednesday at 10am, for Bench to Bedside. Thanks for watching.