Episode 17: What Bugs Us

Peter 0:15
Hi, welcome back to the Gastronauts podcast. My name is Peter. And my name is Reem Hasnah, and we’ll be your hosts. Here at Gastronauts, we are committed to exploring communication throughout the body with a focus on the crosstalk between gut and brain. We invite speakers in this field to share both their research and their life journeys. So come join me as we explore the steps that go into shaping a scientist on the Gastronauts Podcast. Today, we have two great scientists Dr. Mary Estes and Dr. Dylan Dodd.

Reem 1:06
Dr. Mary Estes is a professor of biology and microbiology in the Department of Medicine at Baylor College of Medicine. She’s a member of the National Academy of Science, the past president of the American Society for biology, a fellow of the American Association of the advancement of science, and has authored over 400 articles. She’s a molecular biologist whose research is focused on understanding viral infections of the gastrointestinal tract. Her research group focus is to study how the viral proteins interact with receptors of the intestinal cells. Welcome, Dr. Mary.

Dr. Mary Estes 1:41
Thank you very much.

Peter 1:42
Dr. Dylan Dodd is an assistant professor at Stanford University. He received his training as a physician scientist at the University of Illinois in Urbana Champaign. his PhD work was done in Professor Isaac Khan’s laboratory, where he looked at the molecular mechanisms that were involved in how energy is captured by gut bacteria. And then he worked in Dr. Sonnenberg laboratory where he studied how gut bacteria contribute to small molecules that impact host physiology. He has leveraged his research to co found a company that engineers bacteria to modulate the immune system. And his research group’s focus is to uncover the chemistry underlying host microbe interactions in the gut.

Reem 2:24
Dr. Mary and Dr. Dylan. So what was the motivation behind you both going into research and studying these microorganisms like the microbiome and the viruses?

Dr. Mary Estes 2:36
So I originally had thought that I would go to medical school because I didn’t know that there were was another career that you could do research. And when I went to undergraduate college at a small girl school, we had a visiting prior graduate from the college come and give a talk. She was doing research in microbiology, and I had liked biology, I thought that I wanted to do immunology and I suddenly discovered that there was this whole other area of research. So I applied to graduate school. And then when I took my first class in microbiology, I learned about viruses. And I was hooked from then on. I worked on different viruses, tumor viruses initially, and then once I came to Baylor, I still worked on tumor viruses for a while, and then changed into gastrointestinal viruses after a few years.

Reem 3:27
So the carrier started with a spark.

Dr. Mary Estes 3:29

Reem 3:32
Yeah. And you Dr. Dylan?

Dr. Dylan Dodd 3:34
Yeah. So I also was very excited about immunology, I actually joined MD PhD program straight out of undergraduate, because I knew I wanted to try to do science that could more broadly impact patient health. Unfortunately, you know, as graduate school goes, sometimes the lab you wanted to go to, there aren’t openings. And so I ended up going to microbiology, which I had never even studied as an undergrad. And I was captivated by it actually worked on trying to identify new enzymes for biofuels, if you could imagine, and the best place to look for enzymes that break down grass and lignocellulose is really the cows for stomach, the rumen. And so I did my PhD in rumen. microbiology. And it was very surprising for a lot of people that were my cohort and MD PhD. They said, Why are you studying the cow, but I immediately made connections between the metabolic activities within the cow’s stomach and what’s happening in our gastrointestinal tract. And so then I switched over to studying human colonic microbiota and their metabolic properties.

Peter 4:46
That’s super neat. It’s just so interesting how people get into their path into science and there’s just so many different paths to it. I guess for me, I had never thought I’d be studying the gut either. I never thought I’d be working on a podcast or the session with Reem. So I think it’s All about that spark.

Reem 5:02
It’s a small world Peter.

Peter 5:05
We’re really excited about the audience being really interested in asking questions. And we are going to start having people in the audience who have typed their questions ask their question,

Reem 5:15
Dr. McCann.

Dr. McCann 5:17
My question is for Dr. Dodd. I’m a research staff scientist in the Rawls lab. And we’re also really interested in microbial metabolism along the gut. And I was just curious actually what you thought about your sample set diversity. I know the Sonnenberg lab has access to tons of diversity as far as fecal samples go, but for your blood metabolites. I know, for instance, we have a hard time in really finding diverse populations and sample sets to look at for microbial metabolites. And I was curious about what you thought about that access? And how important it is?

Dr. Dylan Dodd 5:51
Yeah, thanks. That’s a great question. And I fully admit that our sample is not really capturing great diversity. It’s just capturing sort of the cultural background of the Bay Area, and especially tech companies. And in fact, we don’t have the metadata to say what the background is, or do we have any information on diet? So yeah, as you mentioned, you know, Justin Sonnenberg also at Stanford, in fact, my former mentor, has been studying the hodza, which is a sort of hunter gatherer population. And he’s got extensive metabolomics data that he’s working on in different populations across the world. And, you know, I think he definitely sees large changes in metabolomic profiles that vary across people. And so I think it’ll be really interesting as we start to build up datasets from culturally diverse as well as geographically diverse, as well as people taking diverse diets.

Dr. McCann 6:54

Peter 6:54
With regards to the diversity is that we experienced with our diverse diets and what not married, are you aware of how this diversity affects infections to viral gastroenteritis?

Dr. Mary Estes 7:06
I actually don’t know the answer to that question. Maybe there’s another a bile acid person that studies that this more broadly in different populations, or Victoria, do you have an answer?

Victoria 7:18
I think we’ve had this question, at least with individuals who have deficiencies in bile acid production. They’re more or less susceptible, but I don’t think we have an answer

Peter 7:28
Moving on, we have actually a question from Roy.

Roy 7:32
Hi, Dr. Dodd. I’m a student in Dr. Mary Estes lab, also joining us today. So I was wondering, my question is short, so I was wondering if the caffeine level you’ve just mentioned is now indulgence, right? So [I was wondering] you have some topic to say related to coffee or tea consumption and how affects maybe metabolite composition?

Dr. Dylan Dodd 7:58
Yeah, so I didn’t even mention it. I had caffeine on the far right of my plot of metabolites. And, you know, one, one point I like to make about that is actually 25% of individuals in our population had undetectable levels of caffeine. And that corresponds roughly to the caffeine consumption that we know, for, you know, typical individuals in the population. So 75% of people were positive, and then their concentrations ranged about as dramatically as the microbial metabolites. And so I just like to make that comparison to orient people and then also to say that, you know, that microbial metabolites are drug like molecules, essentially similar to caffeine. And their concentrations are varying as much in the population.

Roy 8:43
And may i ask one more question. So you just mentioned that there’s some potential limitations in metabolomics. So I’m wondering, are people developing a new technique to try to detect all undetectable metabolites so far, or that technique is improving?

Dr. Dylan Dodd 9:02
Yeah, that’s an important question. And, you know, if you look at, say, David Wishart’s group, who has the human metabolome database, you know, when they publish their papers, they go extensively into their samples with multiple different methodologies. And they may get very trace molecules that we would be unable to detect. So, you know, we’re, I do believe that we’re just kind of scraping the surface. But you know, mass spectrometers are sort of the workhorse of metabolomics. They have linear dynamic range on the order of four to five orders of magnitude. So I think it’s a really good approach right now, but I’m sure as we get interested in molecules that are at lower concentrations, we’ll have to change our methodology.

Roy 9:48
Okay, thank you.

Reem 9:49
So people are subjected to several medication and several foods and nutrients. And so how do you establish a stable set of microbial metabolites And how are they altered by pharmacological intervention? So what do you think?

Dr. Dylan Dodd 10:06
Yeah, that’s that’s a great question. It’s such a complex microbial community. And production of these molecules isn’t linear. It’s not one microbe acting on its own to produce these chemicals. It’s the microbial community interacting, exchanging electrons, transferring substrates. And so really, it’s, it’s incredibly challenging to tell how a dietary perturbation is actually going to influence a molecule like an amino acid metabolite. If you give fiber to people, you might actually see an increase in some of these protein metabolites. And it’s really difficult to understand. So I think to get at that, what we really need to start doing is human studies that are, you know, essentially longitudinal, studying each individual and how their metabolism changes over the course of a day over the course of different diets. And if we were able to do large scale studies of those sort of longitudinal analyses, I think we’ll learn an incredible amount about how diet influences microbial metabolites.

Reem 11:12
Yeah, that’s great. What do you believe is the most critical lack in our understanding of the host microbe interaction, to help us get into the precision of us having transplanted microbiome and then getting over specific diseases?

Dr. Dylan Dodd 11:30
Well, I mean, in the in the context of therapeutics, we don’t really know what dictates whether a microbial community will stay after transplantation. So it’s community dynamics, that really we don’t understand. We know that if you do a fecal microbiome transplant, you can actually track donor strains. And you can also track the original strains from the recipient. And you get some sort of mixture of that as assemblage over time. And so I just think that it’s going to be more of these very careful, multi omic types of analyses of FMT, that is going to allow us to understand more about the mechanisms and the dynamics of microbial interventions at the community scale.

Dr. Mary Estes 12:17
I think that what you said is absolutely true. I think the other big challenge at the moment is having technologies to be able to really address host micro biome interactions. I mean, one of the ways we’re doing that is with these cultures, we can put the cultures in anaerobic chambers, and we’re now making platforms or we can add the microbiota. And we do have a few examples. Now we’re putting microbiota in with a virus. microbiota can enhance viral replication, or in other cases where it can reduce viral replication. Now, that’s all in vitro, it’s reductionist, but that may be a way to that to begin to understand some of these more complex communities, perhaps in a simpler system. And then you would certainly have to go back ultimately and tested in animal models or perhaps people

Peter 13:08
Really neat. Andrea Marciniak.

Andrea 13:11
Yes. Hi, I’m a graduate student from the University of Virginia. And I had a quick question for Dr. Dodd, I’m actually studying how microbial metabolites are impacting the CNS. And have been thinking about this question a lot recently, of how likely is it that we will be able to modulate microbial communities long term to mediate their metabolism in chronic disorders? So I’m thinking things like, you know, depression or mood disorders? And is it likely that our work might be used in the future just for drug discovery? And that will actually be using these small molecules in a pill form?

Dr. Dylan Dodd 13:45
Yeah, I think if you look at sort of the biotech space, you know, they’re very much used to working on small molecules. But having biological entities like a microbe that’s anaerobic, and its entire suite of pathways, as well as its interactions with other strains, is really challenging to conceptualize and to bring through sort of the market. So I think the low hanging fruit are the small molecules that have specific receptors that you can actually dose. But a lot of the case in the microbiome is you want to actually deplete some molecules that potentially have a deleterious effect. And in that case, you might be able to block the receptor. But another strategy would be to make a fecal microbiome transplant, if you will, and potentially a synthetic FMT to actually replace the microbes in the community with ones that don’t produce that molecule or take the molecule the substrate down a different pathway. So there’s a lot of approaches people are taking, and I think all of the ones I’ve described, at least a few companies are working on. And so it’ll be super exciting to see what ends up working. And the the nice idea about the fecal microbiome transplant is you could potentially affect a long term change, if you could replace somebody’s microbiome with a synthetic community, but that has yet to be shown to be possible.

Andrea 15:31

Maya 15:31
so my name is Maya Kaelberer. I’m here at Duke University. So we care a lot about good bacteria and bad viruses, if I’m going to generalize. What about good viruses? Are there symbiotic viruses that are symbiotic with like, maybe even the host, the human or even the bacteria? And how is their role different than bacteria? Or is it similar?

Dr. Mary Estes 15:53
I’ll give you two comments about good viruses. One are viruses that infect plants. So the tulips that you enjoy in the spring, and if you go to the Netherlands, there will actually be production facilities, in a greenhouse where a particular plant virus is added to make the white stripes on a red tulip or something. So that’s one example of a really good virus, I think.

Maya 16:18
Beautiful virus, yes.

Dr. Mary Estes 16:21
The other area where people are looking carefully now our bacteria are phage that actually come from infecting bacteria. But they may have some positive effects in the intestine. They’re not fully understood yet. But there’s some suggestion that the levels of phage may be important in outcomes of colitis. I think some of that is from animal models. I don’t know that we have good data in people yet. But I think that’s an area that’s going to be looked at, like carefully and there are beginning to be more and more stories where there are interactions between hosts genetics, bacteria and viruses that can either make disease worse, or trying to they I don’t know that I know of one that’s potentially better, but I think we’ll learn about those in the future.

Dr. Dylan Dodd 17:09
Are you interested in the bad bacteria?

Maya 17:14
I guess that’s true. My, my question was very one sided. But what about the bad bacteria?

Dr. Dylan Dodd 17:20
Yeah, I mean, we like to think a lot about beneficial microbes. And there are a lot of them, but not all microbes are commensals. And I mean, there’s opportunistic pathogens, which we know a lot about, especially esbl, for immunocompromised individuals, that can lead to enteric and systemic infections. But I think, you know, as we learn more about microbial metabolites, there are contexts where those molecules and their signaling pathways are beneficial. And there’s contexts where the same molecule on signaling pathway could actually be detrimental. And I think as we learn more about those specific interactions, we’ll learn about you know, what is sort of a beneficial context and one patient population versus another.

Dr. Mary Estes 18:04
I do know, so there are people in Houston that are studying Cryptosporidium, they also had done volunteer studies, and they had found that the levels of indle in the large intestine actually seemed to protect against crypto infection there are now doing experiments to try to understand exactly how that’s working. But that would be potentially an example where if you had the right bacteria making that you might be resistant to an infection.

Reem 18:33
We have a follow up question.

Elaine 18:35
hi. This is the Elaine Snell from England, London, about to go into lockdown. Question for Mary. So thank you and thank you both actually for your excellent presentations. I really enjoyed them. And Mary, I was immediately struck by the fact that you were talking about norovirus as a pandemic, the G 242 three strains that cause a pandemic that that norovirus kills 200,000 people globally every year. Well, you know, in the current circumstances, with Coronavirus, claiming all the attention whilst I’m not asking you a political question about how it’s been dealt with, I mean, you must have a view on you know, the the ways that norovirus is communicated and managed and lessons that can be learned for, you know, this other virus Coronavirus that also kills hundreds of thousands of people this year, I can imagine it must be quite frustrating for you to see the way it’s being managed in many respects, but I don’t want to put words in

Dr. Mary Estes 19:42
I mean, I think we know how to manage it. The question is whether the population will until we have a vaccine or prevented therapeutics. You know, you need to wear masks social distance. Wash your hands and actually those are the same Same rules for norovirus. So this is a virus that used to be known as the cruise ship virus. I think maybe that’s now taken over by our new pandemic Coronavirus. But it’s the same principles. When you get people in closed semi closed environments. You may have one person come on a cruise ship that’s sick. And if they don’t use good personal hygiene and go around touching surfaces, this is fecal oral spread. They’ll spread the virus very readily and you and you can have thousands of people on a cruise ship that will get sick with this. There have been ships that have been denied entry into ports in the last several years, because so many people are infected. So the principles are the same. I hope that if people will become educated about infectious agents, and how do you handle them, really probably could reduce the level of infection globally for many of these organisms. I mean, even the Coronavirus seems to be having an enteric phase and many people, it’s not clear that it’s actually spread through the feces but it certainly can infect the intestine. There’s been some suggestion that it may cause a pro inflammatory response in the intestine that may actually get into the circulation and affect other organs. That’s not fully proven, but as a hypothesis.

Elaine 21:23
Thank you.

Peter 21:24
Yeah, this is just having me think Reem and I were having a discussion earlier. I think every time before we have our meetings, we talk about how is COVID affected you? Are you doing okay in the time of Coronavirus? I was wondering, a lot of times these research in norovirusi and I guess research in the microbiome is not quite made it to the same degree of the public as Coronavirus has, and I was wondering how do you apply these findings from your research into your personal your day to day lives?

Dr. Mary Estes 21:49
I try to use good personal hygiene to prevent getting the infections and I think in terms of in the era that we’re in with Coronavirus. I think we’re trying to apply all the expertise that we have to maybe trying to answer a question about Coronavirus. So there’s been a lot of discussion about whether Abo blood type may be important or Coronavirus, infections. And there’s you’ll read one report that says that there is another that says it isn’t we have actually submitted a proposal to try to look at that, using our culture’s were so the histo blood group antigens are part of the Abo blood type system. And we have these cultures now that we’ve well characterized, we know what kinds of glycans are on them. And we’re proposing to try and use them to infect with Coronavirus to see if in the in vitro system, we can actually get a clear answer. And if we can to determine what part of the spike protein might be binding to the glycan where it might be binding and see if that might be able to be blocked in some way.

Dr. Dylan Dodd 22:55
Yeah, I can chime in on you know, how we use the microbiome and the metabolites that we’re studying in our day to day lives. You know, I have a six year old, and my wife and I, you know, are conscious about what we eat, and especially coming from Justin Sonnenberg lab, we have a copy of the good gut, on our shelves. And so we incorporate we try to incorporate more fiber into our diet. He’s a huge proponent of that. And there’s a lot of evidence that increasing your fiber intake is beneficial. We actually have a lot of fun picking that recipes randomly from the book. So I encourage you to take a look at it if you haven’t seen it already. It’s just a lot of fun. Justin and Erica Sonnenberg have done an amazing job with that.

Peter 23:36
I feel like the research that we do just definitely lends itself to, you know, impacting our personal life, especially if we study the gut, or viruses that infect our gut or viruses in general means basically like our understanding of our personal hygiene, how we live our daily lives-

Reem 23:52
and also the decisions we make on a daily basis. So whatever we learned in the lab, actually influenced our decisions in the future. I would like to thank our amazing audience who without them, we wouldn’t have this great discussion or these questions. Also a huge thank you from the Gastronauts family, to our guests, Dr. Mary Estes and Dr. Dylan Dodd, thank you for your precious time, and for taking part of today’s discussion.

Dr. Mary Estes 24:16
Thank you for inviting us. It was great to be here.

Dr. Dylan Dodd 24:19
Thank you so much.

Reem 24:33
Today we had a great episode, and a great discussion. And we knew that our body is far more complex than what we expect or know. Thank you all for listening. And we’ll see you on the next episode. We are really excited to announce that Gastronauts Global will take place this year and will start May 11! See you all in the virtual Gastronauts global. For more of our content, you can follow us on Twitter @gutbrainmatters or visit at our website thinkgastronauts.com. The Gastronauts Podcast would be impossible without our incredible team. Meredith Schmehl, our producer and theme music composer, and a special thanks to the founder of Gastronauts: Dr. Diego Bohórquez & the Bohórquez laboratory.