Ami Bhatt: Lessons from the microbial world living within us

Russ Altman: Today, on The Future of Everything, the future of the microbiome. Now, the microbiome has gotten a lot of attention in the last few years.

Now, what is a microbiome? I guess we will learn more, but for the purposes of this discussion, it’s the full set of microbial organisms, chiefly bacteria, but maybe others, that live in different niches within our body. Our mouth, nasal cavity, skin folds, everywhere that has contact with the outside world.

The gut microbiome is one of those microbiomes and it’s the community of bacteria living in our digestive system, not necessarily related to disease, but as a normal part of our physiology. We have long known that there is a lot of bacteria in our digestive tract and we know, for example, that they help us digest our food. That’s what we were taught in medical school many decades ago when I was in medical school.

We also know that when we treat infections with antibiotics, it can alter these species because these species are sitting in your gut and they also can be very susceptible to antibiotics. So when I treat a patient for urinary tract infection or for pneumonia, not only am I killing the bacteria, hopefully, that’s causing the infection, but I’m probably altering the microbiome of that patient in ways that might lead to some symptoms. They might have some digestive issues that are associated with that antibiotic.

Now, it’s become clear that the bacteria living in our gut have much more complicated relationship with our health and with our disease. They seem to be involved in our immune system. They seem to be changing sometimes in both acute and chronic disease. The idea has even emerged that there’s a healthy microbiome, the set of bacteria that you would love to have and host in your bowel and that there might be treatments for some diseases that involve changing the microbiome to get it to be more healthy, so to speak. This has gotten probably the most publicity in the idea of fecal transplants. Yes, if you’re not familiar with that, you heard correctly. This is the idea where poop, forgive the terminology, the technical terminology, poop from healthy people is introduced into the digestive tract of people with disease in order to help them normalize their microbiome to hopefully get it back into a healthy state. So this is getting serious.

Ami Bhatt is a Professor of Medicine and Genetics at Stanford University. She has a medical specialty of hematology and studies the human microbiome, mostly in the gut, and has developed new ways to measure the presence of bacteria in the human body and ways to interpret these for health and disease.
Ami, you specialize in hematology, the study of blood and blood diseases. How does a hematologist get interested in bacteria that live in the gut?

Ami Bhatt: So, thanks a lot for having me, Russ. It’s a pleasure to be here. I actually first became interested in the bacteria viruses and fungi that live in and on us, as I think many young people did which was by watching a TV show. I remember being about, I don’t know, nine or ten years old, and I was left at home for the first time, for like ten minutes by myself or something like that, and so I turned on the TV. My younger brother and I were watching a television show about germs and, they showed these horrifying microscopic images of all of the bacteria that are squirming around everywhere. And I thought, “Wow, this is fantastic and also very gross, and we should really learn more about this.”

If you fast forward many years later, part of the reason I became interested as a hematologist and oncologist in viruses and bacteria was because I learned that viruses can cause cancers in some cases. And as you well know, there are viruses that cause well-known cancers like liver cancer. Liver cancer is caused, in some cases, by a hepatitis virus. We know that the human papilloma virus causes cervical cancer and other cancers. And I thought, “Wow, there are all of these relatively simple organisms. They don’t have many genes.” You know, a virus can’t even live by itself. It requires a human cell in these cases in order to replicate. It’s amazing that such simple organisms can alter the biology of such complex organisms like us.
That was how I ended up getting interested in bacteria viruses and fungi that live in and on us. Of course, first I learned about them as kind of bad guys but there are trillions of microorganisms that live in and on us and most of them are probably not bad guys. Many of them are probably actually quite helpful and so I’ve taken a more holistic view of what bugs mean to us.

Russ Altman: So tell me, what are we finding when we look at the microbiome? How many of these are old friends that we’ve known for years and how many surprises are there where we’re saying, “Wow, we had no idea that this bacteria species was living in us.” And then how do we figure out what they’re doing, good or bad?

Ami Bhatt: Yeah, this is an incredibly complex question in part because we don’t even know most of the microbes that live within us. Despite the fact that now, there have been tens of thousands of papers published on the gut microbiome of humans, for example, we know relatively little about who these organisms are. The classical ways of studying microorganisms was by taking them, culturing them, looking at them under the microscope.

Russ Altman: Right, give them a little sugar and they’ll grow.

Ami Bhatt: Exactly. Describing them based on what they grow on, so what they like to eat, what color they stain, what shape they are. But now what we’re understanding is organisms that look really similar under the microscope, and have very similar growth characteristics, for example, can have totally different genomes which means that they can probably do totally different things. So one of the things that we’re learning in the field is that we know relatively little about the organisms even within our own guts. And so a lot of effort has been put into trying to better enumerate who’s there and what they’re doing.

Russ Altman: I also know that these bacteria often, you can’t just grow them on sugar and salt, they actually need each other to live so it’s like a very highly interlinked environment. Is this idea of a healthy microbiome, is that an oversimplification or is it in fact true that you could look at a sample of somebody’s poop and say, “That looks pretty good,” versus, “Oh, we have a problem here.”

Ami Bhatt: You know, I think in general we’re coming to a consensus that for the gut microbiome, at least based on the individuals who’ve been studied to date, having a more diverse community is better. And so having a larger variety of different types of organisms is probably better than the alternative, which is having a handful of organisms that are present at a high abundance.

But in general, what we think we know now is that there isn’t just one healthy microbiome. There isn’t that golden poop out there that we should fecal transplant into everyone and then we’ll all look like a Kardashian and live for 250 years.
Russ Altman: I know a young man in Boston whose name will not be mentioned who’s actually made several thousand dollars donating his poop to research and to microbiome stuff for the last couple of years so he’s in the money.

Ami Bhatt: Yeah, oh yeah. It’s a great way to, you know, turn poop into cold, hard cash.

Russ Altman: Poop into cash. Okay, that was a very distracting idea. So there are many healthy microbiomes. And how can a patient or a person who’s listening, how can they figure out what the state of their microbiome is? You know, it’s interesting. I think if I talk to most laypeople or my patients or family members who aren’t in medicine and I ask them, “How’s your gut health?” Most people can actually tell you. Most people have a very good sense of how their gut is functioning based on their daily bowel movement or bowel movements, how they feel, do they feel bloated, etc. And so I would say most people who don’t have gastrointestinal symptoms, I’m talking about diarrhea, constipation, nausea, vomiting, bloating, those are people who probably have fairly healthy gut microbiomes.

Russ Altman: So that’s good news ’cause that means you can use your normal life experience to kind of self-diagnose if there’s a problem and if things are going well both literally and figuratively, then we’re okay and then there’s no need to worry. So what are the impacts…

Well, this is The Future of Everything. I’m Russ Altman, I’m speaking with Ami Bhatt about microbiomes and healthy and diseased ones.

What about when you take antibiotics? This is a huge insult to the system. Do we know what happens to the gut microbiome and does it bounce back or does it then change forever? Where are we in that knowledge?

Ami Bhatt: Absolutely. So, you know, I liken antibiotic exposure to a forest fire. You’re basically getting rid of the vast majority of life that exists in the gut microbiome. And you don’t get rid of everything because even the most broad-spectrum antibiotics that we use don’t kill off every single microorganism in our gut.

Russ Altman: And that’s also true of the forest fires where those few species come back right away.

Ami Bhatt: Absolutely, absolutely. So it’s very, very similar of a situation. Some of the best work that we have in the field focusing on how antibiotics affect the microbiome have actually come here from Stanford from a colleague named David Roman. He and his colleagues did some really transformative early work in the early 2010s on the exposures of antibiotics to the gut microbiome in healthy individuals. They took a handful of individuals, gave them antibiotics, and studied what happened to their microbiomes. What they found was that, there was definitely a simplification of the microbiomes when people were exposed to antibiotics.

Russ Altman: That loss of the diversity you were talking about.

Ami Bhatt: Exactly, that’s loss of diversity and then basically after the people stop the antibiotics assuming they were living a healthy lifestyle, which they were, they regained their diversity, mostly.

Russ Altman: So that’s good news.

Ami Bhatt: Good news. On repeated exposures to antibiotics, what people have observed is that there may be a point at which you can’t quite get back to your normal and every time you’re exposed to antibiotics, you may be readjusting to a new normal.

Russ Altman: Does the microbiome run in families? Can I assume that my wife and I, our kids are outta the house. That’s a whole different story, and I know nothing about their microbiomes. But do my wife and I have the same microbiome probably because we’re spending a lot of time together or could they be very different even in that home situation?

Ami Bhatt: Yeah, so we call the scientific jargon for this is cohabitating adults.

Russ Altman: That’s what I do with my wife.

Ami Bhatt: Yes, so you and your cohabitating adult, your lovely wife, you probably do have some shared species and strains. So research has suggested that cohabitating adults do share some strains. There has been some limited work to show exciting results that people who own pets, for example dogs, may actually even share a few strains with their pets.

Now this is really exciting because as you know, there’s this hygiene hypothesis out there and the idea that we’ve become too clean as a society that’s why we have, like, asthma and allergies and eczema that are increasing.

Russ Altman: We need more exposures as youths.

Ami Bhatt: Exactly, and we know that people who have animals when they’re young or who live on farms when they’re young actually have a decreased incidence of these diseases. So one question that has arisen is, is it because we’re actually getting microbes from these animals around us?

Russ Altman: That raises an issue that I really, I did wanna get to so I’m glad that you’ve raised this, which is, the role of the gut microbiome with the immune system. In fact, you would think they might be at battle with one another but I think it’s much more complicated and I know you’ve looked into this. So, how should I think about the relationship of my gut bacteria with the health of my immune system?

Ami Bhatt: Yeah, so we know that animals that can be reared without microbes, we call these germ-free animals.

Russ Altman: So like the bubble boy but they’re the bubble cow or the bubble.

Ami Bhatt: Yeah, bubble mouse. All kinds of bubble animals.

Russ Altman: That’s probably easier than the bubble cow.

Ami Bhatt: Yes, but you know, even bubble fish have been generated. You can generate these animals without really any measurable microbes and what we know about them, surprisingly, is that their immune systems are really messed up. That observation actually suggests that the immune system is really dependent on microbial exposures in order to mature properly. We also know, interestingly, and this is more of a correlational relationship, that the immune system develops over the first three years of life. You know, that’s why a lot of kids and babies get their immunizations or vaccinations in that early period of time. That’s actually also when the microbiome develops. So we know that the vast majority of microbiome and immune system development happens in those first three years of life. That suggests that just like having, you know, a sparring partner, someone who urges you.

Russ Altman: Keeps you sharp.

Ami Bhatt: Yeah, absolutely. I think the microbes keep the immune system sharp and I think the immune system keeps the microbes sharp.

Russ Altman: Okay, so we should be rooting for a certain amount of healthy competition between the bacteria and the immune system and it’s part of developing this robust immune system. Taking that idea and combining with your earlier comments about there’s many healthy microbiomes, you’ve made a study of the cultural and geographic diversity of the microbiome including even in places like Africa where I imagine that the lifestyle, the diet, many things are different from the West Coast of the United States. Why are you doing that work and what are we finding?

Ami Bhatt: The reason we’re doing this work which is really trying to broaden our understanding of all of the different types of healthy and diseased microbiomes that exist around the world, is that we know, unlike human genetics, like your human genome doesn’t really change over the course of your life, we know that the microbiome can change over life and that the microbiome is pretty much controlled by your lifestyle and your environment. For example, if you, Russ, were to move to Greenland and take up a diet that was entirely of fish and seals, your microbiome would change dramatically. And that suggests that the variety of lifestyle choices and environmental exposures that people have can really affect their microbiomes and they affect their microbiomes way more than their personal genetics do.

Russ Altman: So it’s the environment that is playing a huge role. Even though I’m the same Russ, after six weeks in Greenland, I’m a different microbiome Russ.

Ami Bhatt: Absolutely, absolutely. So one of the challenges in research has been that we tend to, in my opinion, overstudy kind of the same people over and over, in part ’cause they’re convenient. Honestly, if I was to do a study of a thousand people’s microbiomes, it’d be a lot easier for me to do the study here at Stanford and just to recruit, you know, the incoming freshman class.

Russ Altman: It would be very diverse. It would be both Facebook employees as well as Google employees.

Ami Bhatt: There you go, yeah. And then throw in like a little bit of Apple just for the fun.

Russ Altman: There’s your diversity.

Ami Bhatt: We know that many of these people are gonna have very, very consistent lifestyles. And so we thought that it was really important to broaden our understanding of all of the different types of microbiomes that can exist in the world, both for the purpose of better enumerating what is normal, normal can be a variety of things, but also because, not only should genetic research be done all over the world, we wanna make sure that genetic researchers are being encouraged all over the world. We started this collaboration with a really impressive consortium called the H3 Africa Genomics Consortium. They do a lot of human genetic work and as you know, life originated in Africa, there’s a huge amount of human genetic diversity there and we, being kind of a one-trick pony said, “Hey, we should collect poop and we’ll sequence it and we’ll learn about the microbiomes of these individuals.” Thankfully we have collaborators who are game for that and we’ve been studying the microbiomes of individuals in urban township settings and rural areas and trying to understand how they’re similar and different to each other and similar and different to us.

Russ Altman: This is The Future of Everything. I’m Russ Altman, I’m speaking with Dr. Ami Bhatt about the microbiomes in Africa and fascinating because of the diversity and the history of Africa, it is possible that there will be more diversity of the microbiomes in Africa than there is in the rest of the world or certainly it will be more diverse than what we’re seeing in local areas as you described. And I also totally buy your argument that if there are gonna be in the future treatments of the microbiome, we really need to understand the range of normal so that we don’t start treating people in Africa with microbiomes that are irrelevant or even damaging.

So let me ask that, we hear a lot about when people migrate from one place to another, after a certain amount of time they start getting the diseases of the local milieu. So, you know, we hear about people from China who come to the U.S. They have a certain diet and lifestyle in China, and after a couple of generations, they start getting the same heart disease that has been plaguing all of the U.S. Could there be a microbiome connection to this? Is it that changing your geography is not just the lifestyle and the McDonald’s and dietary considerations, but that you’re also now being exposed to microbiomes that might change your disease risk?

Ami Bhatt: I absolutely believe so. One of the things that we don’t know is whether or not a healthy adult can actually acquire new microbes easily from the environment, but certainly the idea that changing someone’s lifestyle can change their microbiome is well established. There have been migration studies where immigrants have been studied over the course of time. I absolutely think this is related to disease.

One of the things I’m really fascinated about is this observation that my parents, for example. My parents came over from India to the United States for school. They were born and raised in India. They could eat all of the delicious street food that is there. But when we used to go back to visit when I was a kid, my parents would say, “Absolutely no street food for you,” and absolutely no street food for them, because we would get terrible diarrhea, to be honest. Why is that so? My parents have been exposed to that.

Russ Altman: They’ve grown up on it.

Ami Bhatt: Yeah, they’ve grown up on it. Presumably their immune systems have gotten used to it, so why could they suddenly not eat these foods anymore? And I really do think part of it might be that their microbiomes had shifted over time.

Russ Altman: Fantastic. This is The Future of Everything, I’m Russ Altman. More with guest Dr. Ami Bhatt about the microbiome and its significance for both health and disease, next on Sirius XM Insight 121.
Welcome back to The Future of Everything, I’m Russ Altman. I’m speaking with Ami Bhatt about the microbiome. And in the last segment we had a great discussion about health and disease and immune system. People like to manipulate their microbiome and there’s been a lot of popular press about yogurts and probiotics. Is that all real? How should people think about the opportunities for manipulating or improving their bowel health by ingesting foods that modify it?

Ami Bhatt: I think it’s natural for us to wanna improve our bowel health. I think almost every one of us has done this. By the time we’re an adult, we know that there are certain foods we don’t tolerate, certain foods that actually work out better for us. I think many people learn, for example, in their 20s and their 30s that they don’t tolerate lactose anymore, for example.

Russ Altman: Right, so milk is out.

Ami Bhatt: Milk is out. And probiotics are an interesting opportunity for us to try and change that microbiome.

Russ Altman: Can you tell me what is the definition of a probiotic? Because I think there’s even confusion about that. It sounds great. Pro, biotic, I mean what could be wrong with it?

Ami Bhatt: Yeah, it’s a fantastic thing, but, it is actually a moving target, also. So, the idea of a probiotic is it’s live microbial therapy. Right? It’s a compound, not a compound, but organisms that you can ingest or put on you if they’re skin probiotics.

Russ Altman: Oh, so there are skin probiotics?

Ami Bhatt: There are skin probiotics now, too. So you can ingest or put these things on you and that they will somehow improve your health. They can come in a variety of “flavors.” On one extreme, while fecal microbiota transplantation is not technically considered a probiotic, it is one of the most complex live microbial therapies we can administer.

Russ Altman: Yeah, it’s a definitely cousin idea because you’re introducing bacteria on purpose to help.
Ami Bhatt: Exactly. Most probiotics come in either pill form, so you can go to, often like the natural foods store and you’ll find an area where they have a bunch of bottles that are labeled with different complicated Latin and Greek names. Those are probiotics. Alternatively you can have things like foods that actually contain live bacteria or sometimes fungi.

Russ Altman: On purpose.

Ami Bhatt: On purpose. Turns out, this has actually been an important part of cooking for millennia. Bread, for example, is obviously fermented by yeast. In the classical way, it was not just fermented by yeast but also by bacteria that are present in the air and on the grains of wheat.

Russ Altman: I believe that’s part of the sourdough magic is that it’s not just the yeast but a complex. My son teaches me about the complex bacteria required for high-quality sourdough.

Ami Bhatt: Absolutely, so we consume bacteria in these ways. Of course, when we bake bread, the bacteria die but there are things like yogurt. Yogurt is made by actually culturing milk with bacteria, and we can buy live active culture food.

Russ Altman: Now, will yogurt automatically come with bacteria or is it a special type of yogurt that would have bacteria? ’Cause I know that people often think, “I love my yogurt, it’s giving me good probiotics.” I don’t know if that’s true.

Ami Bhatt: The majority of commercial yogurts that are available, the bacteria have been killed. So if you want to go to the store and buy a live active culture yogurt, meaning a yogurt that still has living organisms in it, you’ve gotta look for that. They usually say, “live active culture,” and if you turn the container around to the back, you can actually see the names of the organisms that are included.

Russ Altman: The list of Latin names. Lactobacillus and things like that.

Ami Bhatt: Exactly, exactly. Also if you make it at home, of course, you would also be live active culture. So there are other types of foods that are live active culture. Sauerkraut, kimchi, in fact, almost every culture has some sort of fermented food that’s an important part of their culture and their cuisine.

Russ Altman: Yes, we’re overloading the word culture. Every culture has their favorite bacterial culture. Here’s the big question. Is there evidence for health benefit?

Ami Bhatt: This is really where it gets kind of tricky. It gets tricky because there have been some big studies done on pills, like probiotic pills, used in the medical setting to do things, specific things, like, prevent antibiotic associated diarrhea. For example, many of our listeners have probably gone to the doctor, gotten an antibiotic for a bacterial infection, and have been told by either their doctor or friend, "Hey, eat some yogurt while you’re having this." In that concept there is, we know that antibiotic is killing a lot of the bacteria in your gut, maybe some of these bacteria from the yogurt will fill in the gaps, and prevent you from having the diarrhea that’s associated with having low diversity microbiomes.

Russ Altman: And does that indeed happen?

Ami Bhatt: You know, so, there are studies that say it does, there are studies that say it doesn’t. And I think really, the jury is out. It’s a really complicated topic. As a physician, I would say, there is really limited evidence for the utility of probiotics in the health setting, and in disease management.

Russ Altman: So as a physician, it kind of falls into the, well, I don’t think it’s doing any harm, so I’m not gonna tell you not to do it, but I wouldn’t bet the farm that it’s gonna solve the problem.

Ami Bhatt: Absolutely. And I would say in some extreme circumstances of health, like, you know, for example, there have been studies showing that, immunotherapy, which is a type of treatment that’s used to treat cancer patients, immunotherapy may depend on what the microbiome contains. We know that there may actually be risks associated with taking probiotics when you’re on an immunotherapy agent.

Russ Altman: So that’s a big deal, because now we’re talking about risks. Can you tell me a little bit more about that?

Ami Bhatt: Yeah.

Russ Altman: Sounds like it’s new.

Ami Bhatt: It’s really new. I think none of these data are published yet. But at conferences, at scientific conferences, people have been talking about observations that cancer patients on immunotherapy who are taking probiotics, may actually respond worse than those who are not. Which really begs the question of, you know, could we potentially be doing harm by giving people probiotics.

Russ Altman: So that’s something we’ll have to keep a close eye on. And I’m sure that oncologists will pay close attention, because they don’t wanna undermine their treatments by saying, “Oh, it can hurt,” when in fact, maybe it can hurt. So that’s an important one.

Ami Bhatt: Absolutely.

Russ Altman: This is The Future of Everything. I’m Russ Altman, I’m speaking with Dr. Ami Bhatt, about the microbiome. And I wanted to move to the issue of the microbiome over time and in aging, folks, which we all are. I think you made a reference to this, that it doesn’t stay the same. What do we know about the process of aging? And is there things that elderly people should be thinking about in terms of their microbiome? I was struck when you were talking about the immune system, you were very convincing that people have a good sense of how their bowel is doing when you ask them. I’m not sure people have a good sense of their immune system when you ask them in the same way, maybe they do. So it’s all confounded together in my mind as the aging process, the immune system, what do we know about that? And what should people be thinking about as they age?

Ami Bhatt: Yeah, so it’s interesting, there’s been a lot of focus on the microbiome and the immune system in early life, lots of studies on those first three years. And what we think is that, for the adult period, people to tend to be pretty stable in both of those things until later on in life, and our group and others are actually starting to study, the microbiome of aging individuals. From animal studies, it’s actually been demonstrated in the African killifish fish model.

Russ Altman: Killifish?

Ami Bhatt: Killifish. Yeah. These are really cool, short lived fish. They’re actually the, I believe the shortest live vertebrate animals.

Russ Altman: So what are we talking?

Ami Bhatt: Months.

Russ Altman: Months of life.

Ami Bhatt: Months of life.

Russ Altman: So they really have to go for it.

Ami Bhatt: Yeah, they gotta go big, go big and then they have to go home. So, an interesting study was done, where they took poop from young fish, and then transplanted it into old fish. And they actually find that the old fish can swim faster when they have young poop in them.

Russ Altman: Am so glad you’ve mentioned this, ’cause I’ve heard about these kind of studies, and also like old mice giving their poop to young mice, and vice versa. So yeah, so what’s going on there?
Ami Bhatt: You know, it suggests that there is something within the gut microbiome of these young individuals that can actually alter the biology of these animals, older animals, either through their immune system.

Russ Altman: They are swimming faster. Swimming faster. The older fish. So now we just have to figure out what would that mean for a human, and when do I ask for my young colleague’s, well, I don’t even wanna say it. How do we approach this issue? And do we think that there’s a real hope now for therapies? I mean, are people now thinking about a future, where in addition to the pills that you’re getting from your doctor, they’ll be interventions to try to spruce up your microbiome?

Ami Bhatt: Yeah, I think that there is a great opportunity here. In part because we know that there is this association between the alteration of the microbiome and diminishment of the immune system. I think in the future, although there are no data to support this yet, that older individuals will get things like, microbial therapies or fiber cocktails that will help keep their microbiome healthy, and maybe prevent them from getting things like shingles, you know, a reactivation of a viral infection, maybe that’s related to our gut microbiome, who knows?

Russ Altman: And you’ve made a really important point here, it’s not just introduction of the bacteria, but you need them to be happy, so to speak, and to live. And so you mentioned fiber, because that might be one of the substrates upon which these bacteria live, in order to stay in your bowel after they’ve been introduced.
Ami Bhatt: Absolutely. We can’t just put them there, we’ve got to feed them as well. And so, since fiber is what a lot of these healthy microbes eat, then we’ve got to feed them.

Russ Altman: So when we think about high fiber diets, part of the reason we’re recommending this to patients is not just for the bulk and to help them the musculature of their bowel, it’s also to have a good relationship with the underlying microbiome.

Ami Bhatt: Absolutely.

Russ Altman: Thank you for listening to The Future of Everything. I’m Russ Solomon. If you missed any of this episode, listen anytime on demand with the Sirius XM app.

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