The ‘microbiome’ is very trendy right now. Maybe you’ve seen supplements marketed on social media or on store shelves that supposedly “support a healthy gut microbiome.” But what exactly is a microbiome? What does it have to do with your health? And is your gut microbiome actually connected to your brain?!
Transcript of this Episode
Deboki Chakravarti: When it comes to microorganisms like bacteria, viruses, and fungi, we usually paint them in a negative light—in the context of antibiotic resistance or viral infections. I mean a virus just caused a pandemic and microorganisms before it have caused diseases like HIV, typhoid fever, and the bubonic plague.
But have you heard about this thing called the microbiome?
Sam Jones: You probably have, whether in a science setting or in a Whole Foods. Talking about the ‘microbiome’ is very trendy right now. Maybe you’ve seen supplements or food on store shelves that’s marketed as “supporting a healthy microbiome.” But what exactly is a microbiome? And what does it have to do with your health?
Welcome to Tiny Matters. I’m Sam Jones and I’m joined by my co-host Deboki Chakravarti.
Deboki, just so you know, you are at this very second teeming with microorganisms. In fact, you have as many microorganisms as you do your own cells. How does that make you feel?
Deboki: I feel great about it, thank you for asking. And I think, after this episode, our listeners will feel great about it too.
Sam: And we should also say a big thank you to listener Saara Goldhorn for suggesting an episode about the microbiome.
Deboki: Yes, thank you Saara! So today we’re going to talk about the human microbiome, some of what researchers are learning about its impact on our health, how our gut microbiome is linked to our brain, and why when we talk about the microbiome it often comes back to… poop.
Sam: Fecal transplants! Yes!
Deboki: But before we get into fecal transplant of it all, let’s start with an essential question: what exactly is a microbiome? To find out, we called up Emily Balskus, a professor of chemistry and chemical biology at Harvard University.
Emily Balskus: A microbiome is basically another word for a community of microorganisms. I'm talking about invisible creatures like bacteria, archaea, fungi. Also viruses are often considered to be microorganisms. And when we refer to the human microbiome, we're talking about the microbes that live together in and on various parts of the human body. The most prominent human microbiome is the gut microbiome. So the trillions of microbes that inhabit the gastrointestinal tract.
Sam: The surface of your skin also has a microbiome, as does your mouth and airways and other parts of your body. And all of these smaller microbiome worlds put together are what Emily refers to as the human microbiome.
Deboki: Emily studies microbial metabolism: the chemistry that’s happening inside of the microbes.
Emily: Microbes are really amazing chemists and, like all living organisms, in order to survive they have to perform a lot of chemistry to reproduce, to maintain a healthy state of their cells, to produce energy, to fuel their growth. All of this chemistry is their metabolism.
Deboki: And that metabolism is strongly linked to human health and disease.
Emily: A great example of that is how these organisms help us to digest food. Food contains many, many complex molecules, and a good portion of the molecules in the food we eat actually can't be broken down by our own cells. It can be, however, broken down by our gut microbiome. And so our gut microbiome actually plays a critical role in helping us to get the full nutritional benefits of our diet. The microbiome is also known to metabolize drugs that we take—medications—that can sometimes be critical for having a medication work properly. It can also have detrimental effects. They can inactivate the medication or turn it into something that's toxic.
Sam: But here’s the thing—how our microbes do stuff, both good and bad, isn’t well understood.
Emily: What drew me and my research group to this area is the fact that we don't understand how a lot of this important chemistry is happening within the microbiome. So while we may be aware that microbes are carrying out a chemical process in the human gut, for the majority of those processes, we don't actually know how it's happening. So microbes and other organisms use enzymes—these are protein-based catalysts—to do chemistry. And for most of the chemistry performed by the gut microbiome, we actually don't know which organisms, which enzymes, and what genes encode those enzymes in the microbiome.
Sam: Emily also told us that the products of microbial metabolism—the actual molecules that microbes are making—aren’t well understood either and that chemists can't actually assign a chemical structure to a huge fraction of the molecules they suspect are coming from our microbiome.
Emily: So both in terms of understanding how microbes are doing chemistry and just understanding the fine details of the chemistry they're performing in the gut, there's big knowledge gaps. And so that was a big motivation for our research.
Deboki: Let’s talk about some of that research. One of the lab’s projects focuses on cholesterol. Cholesterol is a lipid, a fat that’s made up of carbon, hydrogen and oxygen. Cells in your liver make cholesterol, but you can also get it from your diet. Cholesterol is important for your body to make different hormones and vitamins as well as cell membranes. But too much cholesterol is bad and can cause plaque to build up in your arteries, restricting blood flow, putting you at a higher risk for things like heart attack and stroke.
Emily: Many of us take drugs to lower cholesterol levels, and those work by preventing our body from making cholesterol. We obviously still consume a lot of cholesterol in our diet. And it turns out that the human gut is a really central location for management of cholesterol in the human body because that's where cholesterol derived from our bodies and cholesterol derived from our diets meet.
Sam: Emily told us that it has been known for nearly a century that gut microbes can change the structure of cholesterol, turning it into another molecule called coprostanol, which you just excrete, it doesn’t get taken back up into your body. Because of this, for a long time it has been thought that having a microbiome that’s really great at turning cholesterol into coprostanol could lower your cholesterol levels.
Emily: You'd think this is a really important process to understand. No one had really figured out how this happened. We didn't know exactly which gut bacteria in humans were doing this. We didn't know what the genes and enzymes were that were responsible for the reactions that converted cholesterol to coprostanol. And so my students and I got interested in this problem. We were able to discover an enzyme that's involved in cholesterol metabolism and really show that it's involved in this process.
Sam: And once they were able to link that chemistry back to an enzyme and then back to the gene that encodes the enzyme, they could start understanding the link between cholesterol metabolism by microbes in our gut and cholesterol levels in humans.
Emily: Now, for the first time, we could look at DNA sequences from gut microbiomes from different patients. We observed that if you have cholesterol-metabolizing bacteria in your gut microbiome, you're more likely to have lower total cholesterol levels. So it's still just a correlation at this point, but it's consistent with the idea that there could be a role for this microbial chemistry in helping to lower cholesterol levels. And so that's very exciting, it suggests maybe if we could introduce this activity into the gut microbiome or enhance it in people, we might have a new way to potentially prevent heart disease.
Deboki: Using our own microbiomes to prevent heart disease would be amazing. A lot of what the microbiome does is really amazing but… not everything your microbiome does is good for you.
Emily: Another discovery from my lab focused on a complex metabolite that causes DNA damage in human cells. So it is a chemically reactive metabolite that's made by certain gut bacteria and it forms covalent bonds with DNA.
Deboki: This metabolite made by bacteria in your gut is named colibactin, and when it binds to DNA in cells it causes genetic mutations. Emily told us that it was known that gut bacteria with the genes needed to make colibactin had been linked with colorectal cancer. But a link is just a link, it’s not proof that colibactin-producing microbes in our gut could cause cancer. So Emily and her lab are still working to see if they can more directly connect the two.
Emily: And so now that we have been able to, as a community detect mutations that come from exposure to colibactin, we actually see those mutations in the genomes of colorectal cancers and various other cancers suggesting that humans are in fact exposed to colibactin and that the mutations that are inflicted by this microbial molecule could maybe be playing a causal role in cancer development.
Sam: Maybe you’re thinking: just kill the bacteria that make colibactin! Unfortunately, it’s not that simple. Killing off colibactin-producing microbes would also mean killing off tons of good microbes because antibiotics just aren’t very specific. They kinda hit everything. With that in mind, Emily and her lab are taking a different approach.
Emily: The approach my lab is taking to try to prevent harmful chemistry is to try to inhibit the activity of enzymes. So we're actually trying to develop small molecule drugs that would stop gut microbial enzymes from doing potentially harmful chemistry.
Deboki: Imagine being able to block the production of a toxin that, in all likelihood, causes colon cancer. That would be incredible.
Sam: It really would.
Now before we move on to the next thing I want to rewind to what I just mentioned about antibiotics and how they aren’t very specific which means you kill off tons of bacteria, not just the bacteria you’re aiming to kill. That can allow bad microbes to multiply. One example: Clostridioides difficile—better known as C. diff. Chances are, you’ve got some C. diff in your gut right now, but good bacteria is keeping it in check so you don’t have a full blown infection, which by the way you do not want. With a C. diff infection, best case scenario you get diarrhea. Worst case, your colon swells, your kidneys fail, and you die.
Deboki: One solution to dealing with a C. diff infection is to introduce more good bacteria to your gut by fecal transplant. A fecal transplant is exactly what it sounds like—someone’s poop—which has been screened for dangerous bacteria, viruses, you name it—is put into another person. There’s the oral fecal capsule option but also a poop enema option or a feeding tube option, where healthy poop is sent in a tube directly to your intestine. I will not be going through the steps of that process.
Sam: With that said, fecal transplants have not yet been approved by the FDA and there is still a lot to learn. But, as of right now, they do seem like the most effective of the probiotics out there. With other commonly marketed probiotics like kombucha or different supplements, there just isn’t any conclusive data showing that they make any serious changes to your gut. They just don’t stick around all that long.
Emily: The consensus on how most probiotics at the moment work is through transient interactions with the host. There is great interest in trying to engineer probiotics that could become longer term stable members of the microbiome. And essentially that's sort of what a fecal transplant is, at least for some of the strains that come in. They become long term colonizers. But as a field, we don't necessarily understand how that process works yet. We can't predict when a patient's given a fecal transplant which strains will end up being those long-term colonizers.
Emily: One vision I have potentially for some of my lab's work in the long term is the idea of trying to incorporate beneficial chemistry into probiotics. Either selecting natural strains that have desirable chemical abilities or potentially engineering probiotics specifically to perform beneficial chemistry and administering them as medications.
Emily: So we're still at the very beginning of understanding how to really develop that type of microbial-based therapeutic.
Deboki: I love how solving this problem brings in such an interesting mix of biochemistry, genetics, and engineering.
Sam: Yeah this field of research has so much going on. I mean I guess that makes sense if we’re swarming with microbes that seem to be impacting our health. If we understood them better, you’d think that would make a huge impact on our lives.
Deboki: So now I want to talk a bit about our gut microbiome in a different context. Our listener Saara, who we mentioned at the top of the episode, asked us about something called the gut-brain connection or gut-brain axis. Is your gut actually connected to your brain? Yes, yes it is.
Sam: You actually have two thin layers of more than 100 million nerve cells that line your intestinal tract, running from top to bottom—esophagus to rectum. These layers of nerve cells are called your enteric nervous system and are connected to your brain by what’s called the vagus nerve.
Livia Hecke Morais: So this is the first link between our gut and the brain and the most direct one. But there are also several indirect pathways between the gut and brain. There are chemical signaling for example, coming from our immune system and the production of cytokines that can bypass the blood brain barrier and communicate with your brain and moderate brain function and brain cells as well as metabolites and neurotransmitters that are produced or modified by the gut microbiome.
Deboki: That’s Livia Hecke Morais, a postdoctoral researcher studying the gut-brain axis at Caltech. Livia told Sam and I that many years ago, at the start of college, she became interested in how different parts of the body influence or are influenced by the brain. She was intrigued by questions like, ‘why do we feel physically ill when we’re stressed?’ And then, nearing college graduation in 2010, she heard about a connection between the gut and the brain when it came to neurological disease.
Livia: What I'm really interested in is to understand the importance of the gut microorganisms to development and aging. And one of the aging-related diseases that I am interested in looking at is Parkinson's disease. So my current research is looking at how gut microbes and gut microbial metabolites can actually modulate brain metabolism in animal models of Parkinson's disease. So during aging, our brain cells undergo a lot of metabolic changes and one of the things that happen in Parkinson’s disease as well in aging is that our mitochondria stop functioning well.
Sam: Mitochondria are the energy generators in your cells. Livia is interested in seeing if gut microbes known to modulate mitochondria in the brain are in fact causing Parkinson’s.
So far, her research in mice has shown that gut microbes seem to affect the function of mitochondria in certain regions of the brain, not equally across the entire brain. Now Livia is trying to figure out if those regions are more vulnerable to Parkinson’s disease.
Livia: I’m very curious to know exactly how this may be happening. Is this happening via microbial metabolites or other products or by direct interactions? So I feel like that's a remaining question in our field.
Deboki: Hearing from both Livia and Emily it became clear that there are so many indicators of the microbiome’s importance in…. kind of everything, but more studies need to be done to take that evidence from correlation to causation.
Sam: Although what researchers have learned so far about the microbiome is very promising, Emily says that because there’s still so much work to be done it’s important to remain skeptical when it comes to companies trying to sell you supplements or probiotic tonics or even asking to sequence your microbiome so they can tell you what species of bacteria you have in your gut.
Emily: Companies that may say, “sequence your microbiome and you'll learn a lot about your health”—I think we're still at a very early stage in actually doing that and doing that well. And especially with thinking about bacterial species, knowing who a microbe is actually doesn't tell you much about what it can do because microbes are swapping and losing genes all the time. Their genomes are very plastic and dynamic.
Emily: We also just don't know what the vast majority of genes in the microbiome and even in any bacterial genome are actually doing. I think it's 85% of the genes in the healthy human gut microbiome can't be confidently assigned a function. So there's a lot of that sequencing information that really means nothing to us at the moment. So it's just the tip of the iceberg in terms of what we can actually get from that type of information about one's gut microbiome.
Sam: Tiny show and tell. Geez, I feel like it's been a little while since we did a tiny show and tell because we've had these other episodes going on, so I'm happy to just kick things off if you want.
Deboki: Yeah, go for it.
Sam: My tiny show and tell today actually relates very closely to our episode because it's about the microbiome. There was a microbiome study in monkeys living on the island of Cayo Santiago, off Puerto Rico's Eastern coast. Researchers found that sociable monkeys in this population of monkeys have a higher abundance of beneficial gut bacteria and a lower abundance of potentially disease causing bacteria. So before we talk about it, let's talk about how they actually did this research, how they made that connection. So these researchers focused on a single social group of rhesus macaques, which are a species of monkey that was made up of 22 males, 16 females ranging in age between six and 20 years old.
So what they did was between 2012 and 2013, they collected 50 uncontaminated stool samples from the group, and then they at the same time, were recording the amount of time that the monkeys were spending either grooming other monkeys or being groomed. So they're really trying to, in addition to collecting these stool samples, they're also taking all of these notes on behaviors of these monkeys. I should also say that the rhesus macaques are super social animals. So grooming is really a way that they maintain relationships. And so they took grooming to be the indicator of sociability. And so then what they did was they analyzed DNA from the poop to look at the diversity of the microbes present and what ones were around. And then they tried to compare gut microbes found in monkeys that were more or less social.
And what they found was that in the sociable monkeys, there were certain gut microbes that are known to be beneficial for different immunological functions. For example, one called Faecalibacterium, which just sounds like fecal bacterium. But that's an example of one that it's known for its anti-inflammatory properties. It's associated, again, associated. It doesn't cause good health. It's associated with. And then they found that bacteria, one's like strep, different strep bacteria that cause pneumonia, strep throat, those seem to be more abundant in the less sociable monkeys.
I wanted to bring in this study because before we did this episode, before doing all this research for this episode, I would've taken this study more or less at face value. I would've said, "Oh, that's really cool. There are these bacteria that are present that seem to be associated with good things. And in the monkeys that are less social, there are these ones that are associated with bad things." But now, after talking with Emily in particular, who brought up the fact that just because you know what bacteria are present in your gut doesn't mean they're necessarily doing all the things that you think they would be doing.
I will say that the researchers are pretty transparent about saying, we're not saying that there's anything causal going on here. This is an interesting finding. However, we definitely need to do more. We need to investigate this more. I was just so excited to see that this came out just a couple days ago as I was already in the microbiome mode and I was like, "Wait, wait. I don't know if we can say that much. Just because we know the species of bacteria doesn't mean we can say that much." I'm not trying to hate on the study, but it was like, "Oh my gosh, wait, I can actually be more critical of this now that I have more information." So that was exciting.
Deboki: And I think that's one of the cool things about being able to read critique too. I think like you're saying, it's not about removing what's interesting. In fact, I feel like being able to critique it probably raises new questions about what makes it interesting in a way that'll give you something new. If these stories are all just exciting in this very rote, one dimensional way, it becomes really simplistic. These are the nuances around the results and that's where all the excitement actually is.
Sam: Absolutely. Well, that's it for me.
Deboki: Well, I am coming in again with one of my more long form article recommendation, so I won't be able to neatly summarize a story. This is more a recommendation for an article that I thought was really interesting. And it's also timely because when we're recording this, we're a week out from the midterm elections and so there have been a lot of conversations around election security and stuff. Some of those conversations are done in good faith, some of them less good faith. And this article that I want to talk about today is titled A Scientist's Quest For an Accessible Unhackable Voting Machine. It was written by Spenser Mestel and was published Undark at the end of October.
And so the article is centered around a computer science professor named Juan Gilbert who is at the University of Florida, who is working on creating a more secure voting machine. But the article is really using his work as this focal point for a bigger story about what even goes into making an electronic voting machine, why do we want them, what is the advantage of being able to switch over? There's questions about accessibility, about language, about just making sure that people know that they voted for everything. So that's why a lot of people are really interested in making electronic voting machines more of a thing, because there's a lot of things that they'll be able to do that are sometimes difficult to do with paper ballots.
But the big concern obviously is security and how hackable are they? So that's really what the story is centered around. And the author gets into Gilbert's design and it was really interesting to read about the considerations that he took into account like there's a whole system around giving people a way to actually see the ballot being submitted so that they don't have to question that their ballot has actually been correctly filled out. So it's about that, but it's also about how do we even try to prove that something's unhackable? What does it mean for something to be unhackable? Is that something we can realistically strive for? Is unhackable like a distracting conversation? Is it something that then gets us hung up on something that maybe we shouldn't really be focusing on? I just found this article really interesting overall, so that's why I would recommend it.
Sam: Because the midterms just happened about a week ago. It's all so fresh and I feel like these conversations are circulating, continue to circulate, right?
Deboki: Yeah.
Sam: As ballots are still being recounted for certain states. I'm so excited to read this. Thanks, Deboki.
Thanks for tuning in to this week’s episode of Tiny Matters, a production of the American Chemical Society, a non-profit scientific society based in Washington, DC.
Deboki: This week’s script was written by Sam who is also our exec producer and was edited by me and by Matt Radcliff who’s the Executive Producer of ACS Productions. It was fact-checked by Michelle Boucher. The Tiny Matters theme and episode sound design are by Michael Simonelli and the Charts & Leisure team. Our artwork was created by Derek Bressler.
Sam: Thanks so much to Emily Balskus and Livia Hecke Morais for joining us.
Deboki: If you have thoughts, questions, ideas about future Tiny Matters episodes, send us an email at tinymatters@acs.org.
You can find me on Twitter at okidoki_boki
Sam: And you can find me on Twitter at samjscience. See you next time.
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