Tonight you’re going to find out just how beautiful science can be. It’s a real pleasure to have Anjali Nayar, who I think is one of the most successful documentary filmmakers in the world here tonight, as well as my own colleague, Sean Gibbons, who was a scientific advisor on the recent documentary on Netflix, Hack Your Health, that we’re going to talk about tonight. Anjali is actually an environmental scientist who was, I suppose, doing filmmaking as a hobby and decided to become a filmmaker doing environmental and other kinds of science as a hobby. She’s been extremely successful. I’m not going to go through all of her filmography, but she’s had several that have made it in probably in your living rooms on Netflix or Amazon or what have you. This one here, which it’s about the gut. Who would’ve thought? It was a top 10 in 77 countries and top one of all Netflix offerings in 19 countries with no advertising by Netflix.

Absolutely awesome. 

Sean Gibbons is my colleague at ISB. He’s an associate professor. Sean worked his way from, let’s see, he was a Fulbright scholar in Europe. He got his undergraduate degree at University of Chicago. He went to this place called MIT on the East Coast and the Broad Institute before we lured him to take a faculty job at ISB. At ISB, Sean has really set up a world-leading program in trying to understand the science and biology of the gut microbiome, and he was the scientific advisor on this film. Sean and Anjali, please come up. 

We’re going to obviously have a discussion about an Anjali’s movie tonight. Anjali, I want to… First congratulations on the great success of this film. Why did you choose this topic? It’s not like your last one was on human health. It’s very different from your previous work.

Anjali Nayar:

Yeah. Well, I think I’m always excited by people saying that you can’t do something. I think that that’s generally my starting point, but something that isn’t the obvious story, something that is hard, something where you have to be really creative about the subject. But it does feel like there were very many things leading to this film. My mom is a doctor and also spent a lot of her time trying to help women continue to breastfeed knowing the improvements on the baby’s health and so on. I was aware of it from that perspective. Then probably about I guess a year before I started making the film, Sean and I were on a national… Tell me what it was? National?

Sean Gibbons:

The National Academy of Sciences.

Anjali Nayar:

Does an exchange-

Sean Gibbons:

Yes.

Anjali Nayar:

… where they invite people like me and people like Sean to go and hang out and cross-pollinate ideas of what could be a particular project. Then the third thing that came along was Netflix was really interested in doing something about how we all interact with food. So many people are confused about food, and so many people have problems either temporarily or long-term, and they knew it was a really big thing for them, they just didn’t know how to make it. That’s when I came into the picture as somebody with a science background and really interested in taking on this topic. It was a whole bunch of different things and I wanted to play with stop-motion felt animation, so it was the perfect thing.

Jim Heath:

Sean, what was your role here as scientific advisor?

Sean Gibbons:

Well. Yeah, like Anjali said, we met at this event. The National Academy of Sciences has this thing called the Scientific Exchange where they catalog all these experts that Hollywood goes to consult on various films, but they also have this young up and comers meeting in Woods Hole where they get together scientists and filmmakers and have them crash together and learn about one another’s work. That’s where we initially met, and you probably knew who I was because of that. Then next thing I know, Anjali was reaching out to me to maybe be a part of this.

Jim Heath:

I want to turn a little bit to the first thing we saw in that clip was the animations, which I think are a pretty defining feature, a defining feature of the film, and one of the most remarkable ways I’ve seen to teach science ever. How did that come about? How did you think about that?

Anjali Nayar:

Yeah. It goes back to the fact that I started my career in science, and so I was a climate scientist and a space scientist studying how our world is changing. It was early 2000s, this is before Inconvenient Truth came out, and I realized that maybe I could be more useful as a communicator than I could be as a pure scientist because there was such a gap in terms of what people understood about the world versus what was actually out there and so on. I think it came from that perspective of struggling with this question of how do you make science reach people, but also not dumb it down to the point that it becomes unhelpful or pseudoscience that it actually harms people? I knew moving through this film that there’s so many questions that we have about these basic functionalities that pretty much like every other animal in the world understands. They know what to eat. They know what not to eat. They know how to take care of themselves, and it’s so confusing for us.

I wanted to do the exact opposite of what a normal science film would do, which is go to graphics and go to statistics and go to everything and try to make it as analog as possible. I think if you go to the far end of analog, then you get into stop-motion animation, which is people moving felt around. That was my happy place. I think it was thinking about how we think of digestion as burping and farting and all these things that are unpalatable. I wanted to make this a place that we were excited about and thinking of Fraggle Rock of my childhood, these exciting worlds that are within us, similar to the worlds that are outside of us. It felt like a perfect medium to just make it fun and make it interesting and rebrand pink. I know that we were talking about that, this color that has all these negative connotations with the intestine track.

Jim Heath:

Well, at ISB because of Sean, we talk a lot about poop soup. We’ve maybe been a little bit indoctrinated into this already. I’ll ask you one more question, then turn to Sean. But you found four individuals who… It is a remarkable quartet of people from around the world. How did you find them?

Anjali Nayar:

Yeah. Just like a couple of weeks ago, I looked back at the credits of the film and how many people we reached out to. It was like something like 290, 294 people that we reached out to to cast the four people in this film. Some of those were scientists, some of those were other people. But by and large, we talked to a lot of people. That was looking at Instagram. It was going into the depths of Reddit, which is where a lot of people talk about their gut problems. It was just thinking about what are the different takes on food. Who eats a lot? Like Kobayashi, who’s the hotdog king. Kobayashi was obviously one of the most famous. He won all the Nathan’s competitions for many years. Kimmie I had seen in a Rihanna advert for her lingerie.

I knew I wanted to have somebody who was maybe trying to get healthy but was also super body positive. I didn’t want this to be a conversation about being slim. Then I think Danielle might’ve been the corners of Reddit, and Maya, she had written a blog about her adventures with sugar and her eating disorders and going through time. We joked about it because they all reached this pinnacle of excellence at a really young age. Julia wrote a New York Times bestseller by the age of 23. Maya got her first Michelin Star by 23. Kobayashi was a world champion hotdog eater by 23. It felt like we were in this room with all these champions, and they kindly agreed to be a part of this film. Because I think the reality is that each and every one of us, if we put up our hand of how many people have been questioning their gut or had problems with their gut, they were all curious about what was going on in their bodies and wanted to be on this adventure with us.

Jim Heath:

Sean, on these individuals and their gut diversity, there’s also a couple of actual scientific graphics. There’s like three-dimensional standing there with a bunch of microbiomes and a UMap or a Principal Component Analysis showing diversity of the gut. What is known about the diversity of the gut? I know there’s… I guess let me maybe-

Sean Gibbons:

How long do you have?

Jim Heath:

… rephrase that or we’re going to be here all night. What is known about the value of having a diverse gut? Based on these people’s stories, do you think you would expect to see diversity from individual to individual to be higher than normal?

Sean Gibbons:

Yeah. It’s a great question. Going back to this issue of so many people suffer from gut issues, I think the stat that I know is about at one third… At any given point in time, one third of all Americans suffer from some form of problem in their gut, whether it’s diagnosable or not. A lot of that can’t be explained by the things we know how to measure like the genome or a lot of other clinical laboratories you can measure. We’re finding that variation in the composition of the microbiome is associated with some of this heterogeneity and how people experience food, but we’re in the early days of really understanding how that’s all mapped out. Diversity, for those of you who aren’t gut microbiome wonks, diversity is the counting the number of species that are living in your gut. There’s another way to measure it, which is the evenness of the abundances of the species in your gut. Oftentimes, at least in the prior decade, people have associated higher diversity with better health.

It intuitively makes sense, a more diverse ecosystem, maybe it’s more resilient to perturbation. If you smack it and one species goes extinct, maybe there’s functional redundancies in the system that can compensate for that loss if there’s enough diversity around to stabilize it again. That’s the common wisdom that higher diversity is better, but also it’s a simplifying way to look at the microbiome. You’re collapsing all this multidimensional complexity down to one number like how many species are there? Our lab has looked into this a bit from a lot of different angles. By and large, if you’re eating a lot of diverse plant substrates, if you have a plant-rich diet and you’re eating a lot of different species of plants, you can largely increase the diversity of your microbiome. That increase has been associated with better health, but there are states in which people have high diversity that aren’t so great. It turns out that if you have constipation, you have a very diverse microbiome. That’s not necessarily a good thing.

I think like any simplified metric, it’s not a perfect metric for assessing health. But in the film, there’s this rule of always be counting that one of the scientists talks about, counting the number of plants you’re eating throughout the week. She suggests between 20 and 30 species of plants you should be eating throughout the week. That’s a good suggestion that the science behind it is there was this paper by Rob Knights group who was the bald guy pointing at plots on the film. They had a project called The American Gut Project where they had people send in their poop, and they had a bunch of questionnaire data. They found that one of the strongest signals in that dataset was the number of plant species you ate increased your diversity, but it plateaued. At around 20 or 30 species, you started to see it level off. I think that’s where that comes from. But that’s all to say that yes, usually diversity is thought to be a good thing, but with the caveat that it’s not always.

Anjali Nayar:

Working with scientists.

Jim Heath:

Maybe I’ll ask you about working with scientists in a minute. One thing you did very carefully in this film is, as we just heard Sean tell us that a lot of the science of the microbiome was just evolving. Yet if you go out and look in the world of products, you would think there’s all kinds of things you can do to improve your microbiome. I think most of it’s probably snake oil, and you avoided that completely. You actually gave the impression that the science is evolving, but it’s not there yet. How did you walk that line? That’s a tough line to walk.

Anjali Nayar:

Yeah. It was actually a really hard line to walk because there’s a lot of scientists too that have their side projects and their startups. Part of crafting the people who would be in this film, it was focused on trying to be as instructive to as general audience as possible, but without making you believe that you have to buy something. That’s because it’s based on science. You don’t actually at this stage need to buy anything to be healthier unless you have… Say if you have some extreme something and actually need a poop transplant of some description, that’s slightly different. But yeah, it was really hard and we said no to a lot of really great science because it was too closely related to a product.

I would say that 99% of what you have out there is probably not based in science or not related to a science group. Certainly when this film came out, a lot of them used the film to promote their work, which I wrote to them about and got them to stop associating the film with their work. It was really important to me. I think it’s the number one question that people ask me is like, “What app was this?” Or, “What tests should I buy?” My answer is always, “You do not need to buy anything at this stage.” If I do know the answer to that, at some stage I will communicate it. We did use many different products. If you do zoom in to the frames, we use several different testing kits and got people to do a number of different things so that we weren’t putting a focus on one specific thing.

Jim Heath:

Yeah. Well, you did a great job. You made a decision right off the bat, we’re going to keep this?

Anjali Nayar:

Yeah, we-

Jim Heath:

We’re not going to-

Anjali Nayar:

Totally.

Jim Heath:

… sell anything but the science.

Anjali Nayar:

Yeah. I think it’s because of one of the core things that people struggle with is understanding the basics. If you don’t understand how the gut works and how the science works, then the next antioxidant that comes up or the next special green smoothie, you’re going to want to buy into that. Then it’ll put into question anything that you were doing before. If you understand the basics, then you have the tools to make decisions about the things that come up next that the film doesn’t talk about. It was really about the basic science, and so we went away from even some of the applied science and focused on mouse experiments and the basic, basic, basic science that was being done in the space.

Jim Heath:

Yeah. It was a great decision. But there is some applied science that is known, and you didn’t touch on it because you didn’t need to. Your four individuals didn’t require it, but how would you talk about that?

Sean Gibbons:

Yeah. What is the state of the field in terms of precision interventions and the microbiome and all of that?

Jim Heath:

Yeah. Exactly.

Sean Gibbons:

Yeah. We’re in a very nascent period. There’s a lot of stuff happening right now that I find very exciting because a scientist, and I’m on the science side of it. It hasn’t yet come to the point where you can go order it and the FDA has approved it for treating this disease and all of that, but I’ll give you a quick rundown of some of what’s out there. I would say the vast majority, like Anjali was saying, of these companies selling you products and things, it’s pretty snake oily. It’s mostly entertainment. These companies tend to have very large marketing budgets and very small science budgets. They’re not running a ton of clinical trials or anything like that.

There are a subset of what I would call golder standard companies that I won’t mention by name, but companies that start with a clinical trial, a human trial, where you collect a bunch of data on a large population of people. So far, those studies have mostly been based on machine learning. The idea is you don’t actually understand how it works, how the biology works, but if you collect enough data on people eating different foods and their microbiomes and blood measurements and you feed that into an algorithm and predict, say, personalized blood glucose responses after a meal, there’s great evidence now showing that you can actually algorithmically design good diets and bad diets for individual humans. This has been done, it’s been tested, and they’ve demonstrated that they can do it.

Some of these companies have spun out of these initial proofs of concept. The way some of those companies have gone forward with translating the science out to the public hasn’t always been the most rigorous, but I’d say that’s the gold standard is we have some proofs of concept that we can actually predict personalized interventions for individuals that do do things like improve your blood glucose response. Beyond that, though, there’s not a lot of general precision nutrition advice except for some very nascent stuff. Our lab’s working on it, and I won’t plug it, but we have a paper coming out in a few weeks on mechanistic modeling to try to come up with precision nutritional interventions. I think in the next five to 10 years, these things will begin to enter a clinical space. But at the moment, it’s not quite there yet.

Anjali Nayar:

I would say all the apps and so on that were used in the course of the film were related to… They’re the gold standard ones that are related to research institutions. Regardless of what they’re telling you, they’re also building this database of information that’s going to help research be better about this in the future.

Jim Heath:

I have two questions. First for Anjali, and then I want to get to the science of what you can and can’t expect and something like that from Sean. Anjali, what was the… That is obviously a therapy, but one based on the… What was your rationale for… We missed the fuzzy animations there. We went straight to the real soup.

Anjali Nayar:

Absolutely. Watching that back, we had so much fun designing what would happen in the animated sequences. I don’t know if you can see, it was just like, “And then they’re going to take over the screen.” Every single moment we did stuff with microbes, it was thinking about the most relatable experience that you could have and then figuring out how to do it with a little fuzzy thing. It reminded me of that. It was just really fun. Why did we show poop soup, as you talked about? Because people are doing it, and we felt like the conversation needed to be had. You can get an FMT of fecal microbiome transplant for C. diff and specific things legally, but there’s a lot of people out there that are doing this.

It felt like it was wrong, specifically because one of our characters was doing this regularly to avoid the conversation about what the potential could be, but also the harms and how far people are going because they’re in so much pain. I think that there were a few different reasons for showing that. We could have shown the one through the FDA. You’re right, we could have shown that one, but we were really making this film through our characters and found the science and the interventions through our characters experience. That was really important to us to represent this in all its positive potentials and also the harms.

Jim Heath:

Let’s talk about the science then. I’ll just let you riff on it. There’s good things. There’s the known, the unknown.

Sean Gibbons:

This is the one that made me most nervous as the scientific advisor. I was like, “Oh, gosh. We’re going to make everybody so mad?”

Anjali Nayar:

What were the conversations we had just to… Do you remember them?

Sean Gibbons:

I remember like, “This has to be couched so carefully in cautionary wording from the scientists, and the viewer has to be scared of doing this themselves, essentially.” That’s how it should be, essentially. To give you a little background, because I have a unique window into fecal transplants to some extent. My colleague, Ali Perrotta, who’s here, was also in the Alm lab a few years back, and our advisor started the first stool bank for high throughput processing of human fecal donors to make material for transplants. Before that, we knew for a while that these transplants could help with these C. diff infections, resolve this terrible disease. Back in the day, like 500,000 Americans are getting sick from C. diff every year and about 30,000 or so were dying because antibiotics, I think 30% or so of people treated with antibiotics recur. Once you recur, it’s very unlikely that those symptoms are going to be resolved by further antibiotic treatment.

These people would have many, many, many rounds of antibiotics before they would have so much damage done to their colonic tissue they’d have to have surgical resections, and then they could die from things like sepsis. We knew that fecal transplants could help resolve the disease, but individual doctors had to go hunt down a donor. Before you give poop from one person to another, many of us are carrying pathogens in this audience tonight. We all harbor pathogens in our guts, and because we have a healthy commensal microbiota, it suppresses those pathogens and keeps them from making us sick. But if I was to take my microbiota and transplant it into someone with a bone marrow transplant who’s very vulnerable and has their immune system wiped out, my pathogens could hurt them, could kill them even. You have to be careful about screening people who are these donors. Doctors would have to go through this very expensive and long process to select and screen.

Oftentimes people would fail the screening, so you’d have to find another person and keep going and going and going until you could finally do the procedure, which made it very long and expensive. OpenBiome, this company, took the difficulty out of that process by making it a factory. You get a bunch of donors who are squeaky clean, that poop three or five times a week for you. They get paid. I think you could make, what? 12,000 bucks a year or something pooping, or maybe it was more than that. Then they would ship their samples out to clinics across the country, and I think even across the world, and they could be used for these procedures. It works great for C. diff infections. For recurrent C. diff, it’s like 85, 90 plus percent efficacy. The first trials done with fecal transplants were actually halted early because the FMTs were so much more efficacious than antibiotics it was considered unethical to keep giving people antibiotics.

They work great for C. diff. But even for treating C. diff, there have been cases where people have died from fecal transplants. The specific cases are people with bone marrow transplants who are really, really, really vulnerable. The FDA kept expanding the screening procedures to find organisms that hadn’t been caught before that are potential pathogens. It’s dangerous, and if you’re not getting your material from some facility that’s being screened actively by a regulator, you’re in a lot of danger in doing these procedures. I’ll quickly say, outside of C. diff, there’s not a ton of evidence that they work for many other diseases. There’s a lot of trials. You can get FMTs for other diseases through clinical trials like for inflammatory bowel disease and many other things, but nothing has been as low hanging fruit as C. diff. It works great for C. diff, and efficacy is middling to not there for a lot of other diseases.

Jim Heath:

In the documentary, there’s animations of the good guys and the bad guys. There’s probably a gray scale. It’s probably… Everybody sits on some scale of one to 10. There’s no truly bad, but still. I know people are thinking about how do you take a given microbe that you know has some metabolic benefit and have a targeted transplant, which seems to me to be maybe one of the frontiers of where the field is at. Is that something that you think would come down the pike in the near future? Is there success there? Is it-

Sean Gibbons:

Yeah. I can say that it’s actually happening now. There are companies right now, these so-called bugs as drugs companies. A big one on the East Coast is named Vedanta. It’s essentially a pharmaceutical company, but instead of manufacturing drugs, they manufacture clinical grade probiotics. There’s now a mixture called VE303 that’s for treating C. diff. It’s an eight species cocktail that can be reproducibly manufactured in a factory. You don’t have to get a person pooping. It can be given to patients, and it does significantly do better than placebo at treating C. diff. It’s now going to phase three trials globally, and it’s on track to be FDA approved in maybe a year or two. The next precision probiotics beyond FMTs, they should be available in the next couple of years.

Jim Heath:

Cool. Okay. Anjali, I want to come back to your four people that you involved in this study because each of those individuals went through a microbiome university experience. What did they get out of it? If you ask them like, “What did you learn? What’s different now?” What would you say?

Anjali Nayar:

Good question. It feels like there’s no finish point with things with the gut. I do check in regularly with each of the characters, and it feels like they’re still on a path and still on a journey to healing. Definitely Kimmie reaches out regularly to me and tells me that she’s working on stuff with her kids and finding a way to be a mom and do everything and find ways to really involve her kids in cooking. Maya’s still on her journey to being better about her body and feeling good about eating food. Danielle has actually gone through some more invasive surgeries, and Kobe is now doing a hot dog competition against-

Jim Heath:

Yeah. I saw that.

Anjali Nayar:

… Joey Chestnut? Joey Chestnut. Which I think is opportunistic a little bit, not by Kobe, but also by Netflix. But I think that the thing about this is is that if you tell me to change my life tomorrow to be better, it’s going to be very hard for me to be better forever. I’m going to revert back to eating chocolate. I’m going to revert back to having a glass of wine. I’m going to have all of these different things. It’s hard to be perfect, and so this learning process for all of us I think is a lifetime thing. It’s changing how we think about life and food and how that interacts over time. I just don’t think it’s… As we talked about, a diet isn’t a two-week thing that you go on to lose weight. It’s a change in lifestyle. I think that that’s not something that there’s a clear end point to. That’s what the film really tried to speak to.

Jim Heath:

Well, one point your film made spectacularly well was illustrating with those marvelous animations the difference between highly processed foods and I guess naturally grown foods. Sean, I’m going to ask you, what does that do to your microbiome? If you are… The highly processed foods is really a diet that I would say a good chunk of our country probably has more often than not. Mary was just in Minnesota where people were cooking at home, but even though they’re cooking at home, they’re putting highly processed foods, and so it was basically just throughout the whole diet. What does that mean for your microbiome?

Sean Gibbons:

Yeah. I think the film actually did an amazing job of explaining this.

Jim Heath:

It does.

Sean Gibbons:

I want to quickly call out, I think Julia was talking about this, where when you eat a processed food, it’s like a flood of sugar. It’s like a sprint. The sugar just floods into your system and the body’s trying to figure out where to put it. Whereas whole foods that are degraded more slowly, it’s more like a long run or a marathon. It’s degraded more slowly, and the body is absorbing it more slowly. I think that alone is a lot of the effect that’s driving a lot of the problems in the physiology and insulin resistance. Having our food be processed more slowly by our microbes is how we evolved, essentially, it’s how we evolved to process food. Going back to how does it change the microbiome? It’s like if you build it, they will come. That’s part of it.

If you eat a lot of fiber… Well, I’ll back up a little bit. At a first approximation, we eat food and we have prime access to that food. We have a stomach and a small intestine that we maintain at really low pH, and we make a lot of antimicrobial compounds that suppress the biomass and the growth of microbes. Then the colon is where we take off the reins and we just let the microbes go hog wild. It’s an evolved fermentor. We absorb what we can on the upper half, and then the lower half for all the things we don’t have the genes to break down, like dietary fibers, we let the microbes eat those. Those microbes turn those dietary fibers, they ferment them into a bunch of organic acids for the most part. Over evolutionary time, our bodies have come to rely on the presence of a fairly high level of these organic acids in our system to function properly.

Many of these act as hormones. Butyrate can affect insulin signaling, it can affect satiety, whether we feel hungry, it can affect systemic inflammation, and it’s the primary energy source of our gut cells, our colonocytes. The modern diet, most Americans eat between 10 and 15 grams of fiber. It’s suggested we eat something like 20 to 30 grams. But if you look at historically what humans probably ate, and as hunter-gatherers, it’s more like 100 grams of dietary fiber a day. We’ve vastly decreased the amount that we’re feeding our microbes, the food that is specifically for them, and it’s reducing these organic acids and is having huge negative effects on our physiology. If we starve the microbes, guess what happens? Anybody?

Audience member:

They die.

Sean Gibbons:

They die. That’s part of it. But if you remember in the film, there were these little green guys with their arms locked, the mucus layer. We actually produce polysaccharides or fibrous material that’s in our mucus, and microbes can break that down. They can eat it. But many microbes in our gut can switch, they can either eat dietary fiber or they can eat our fiber. They’ll start eating you. If you’re not eating enough dietary fiber, they’ll start eating you. If that layer thins too much, that’s the wall that maintains the détente between your immune system and your microbes. If it gets too thin, your immune system goes crazy. You get inflammation. Things like inflammatory bowel disease start to happen and it’s bad news. When you’re eating your next meal, remember you’re not just eating for you, you should eat for your microbes too.

Anjali Nayar:

That’s actually one of the things that some of the scientists in the film told me was how they talk to their kids about this was just like, “You have these pets in your belly, and so you can’t just eat what you want to eat because you also have to feed the pets in your belly,” which I thought was a really sweet way of getting your kids not to ask for pets, but also eating their vegetables.

Jim Heath:

Is that how these folks are getting their kids to eat right? By telling them that …

Anjali Nayar:

Completely. The Sonenbergs. Yeah. Legends.

Jim Heath:

That’s a great idea. What did you learn from making this movie?

Anjali Nayar:

Yeah. I feel like I learned so much. It’s hard to put my finger on one thing, and similar to the other characters in the film, I feel like I’m still learning. All the time, I’m constantly learning and relearning. I think the biggest thing is about intention with food. I think that like many people probably in this room, I eat a lot of my meals in front of a screen or I eat it with a group of people and we’re chatting and we’re talking and I’m stuffing my face. I don’t always feel the signals that my body is trying to tell me like when I’m full. There’s all this cultural conditioning that goes around it. When I was a kid, I was always told to finish my plate.

Even now as an adult, if somebody serves me and it’s too much food, I’ll still finish it even though I’m full. I would hate to say that that’s any food restriction behavior. I do think that it’s important to listen to your body and know what your body is telling you when you are hungry, when you are full, what you feel like eating. I think I’m getting even better about now that I’ve figured out how much… If my body’s telling me to eat something, I go and eat it. I’m like, “I actually need more protein right now. Okay, I’ll go eat that.” I think it’s about listening. That’s the biggest thing that I’ve learned is to listen to my body and to trust that it’s telling me the right thing.

Jim Heath:

Cool. And Sean?

Sean Gibbons:

Well, and the consequences, just to follow up on that Kobayashi story. If you’re doing these extreme behaviors and then ignoring those signals, maybe someday those signals stop working. Then you don’t have that intuitive experience with eating. What did I learn? I learned from a masterful storyteller, honestly, the ways to convey these complex messages about what’s going on in the gut, like the sprint versus the marathon for explaining processed foods versus whole foods. There’s all these brilliant little pieces throughout the film that I think subtly convey really complex messages to a wide audience. Science often lacks that, and being really good at that is really special.

Jim Heath:

Yeah. It’s actually awesome. I think all of us scientists think of ourselves as teachers. As I told you, I felt like I was in kindergarten when I was watching your skills there. It was amazing. Last question, Anjali, what’s next?

Anjali Nayar:

I am making a docuseries with the Golden State Warriors Senior Dance Team, which is a group of 55 to 78-year-old senior professional dancers. They are awesome. It’s like… I don’t know if you guys have seen Cheer or any of these other types of shows. It’s still life, but it’s not problems of 18 year olds. It’s the problems of 70 year olds with way more baked goods and way more insight and wisdom. It is like sitting with your parents all the time, or your kid. Whatever age group you are. I am learning so much, and it’s just such a fabulous experience. Again, it’s a bit of a left turn, but I think that that’s what’s so fun about this business is that I get to learn. I get to be in a world and immerse myself fully and learn from incredible people around me and be an expert for a moment in that one thing. I forget it shortly thereafter. But for that one moment, I get to be an expert and try to put it all together into something that is a story.

Jim Heath:

Cool. Well, good luck with the… You call them the-

Anjali Nayar:

Yeah. They’re called the Hardwood Classics.

Jim Heath:

The Hardwood Classics.

Anjali Nayar:

Yeah. They’re amazing. Go check them out.

Jim Heath:

Okay. I think now we can take questions. I know there must be questions out there for either Anjali or Sean. If you have a question, you can use the QR code and some nice person out there with an iPad will read it out loud. If you want to shout it out, you can shout it out. I’ll repeat it.

Sean Gibbons:

There’s a microphone.

Jim Heath:

But there is a microphone right there. You’re going to have to go to the microphone because you could have your hand up and I can’t call on you. I can’t see anything out there. It is all glary.

Anjali Nayar:

Oh, that one.

Jim Heath:

Perfect.

Audience member:

I have two questions. The panel talked about clinical probiotics, and I guess my question is… The first question would be is there any benefit at all to some of the over-the-counter probiotics? Kombucha is one of them, kombucha drinks. Or if there’s no benefit is there at least no harm? My second question has to do with the individual who was a hot dog eating champion. That’s very processed food. That can’t be healthy. What did he suffer as a result of eating billions of hot dogs over the years? Thank you.

Anjali Nayar:

You want to take the first one?

Sean Gibbons:

Sure. I’ll take the first one. Probiotics. Okay. Most probiotics that you can buy at the store are these organisms that are present in cheese and kombucha and sauerkraut. They are on a list that the FDA has called generally regarded as safe, and they’re considered food items. You can legally sell them to people as long as you don’t make strong health claims because they’re considered food. However, the organisms that I would’ve loved to give you as probiotics as a scientist, the ones that actually reside in the adult human gut, those are not on the grass list.

In order for me to give you say Faecalibacterium prausnitzii, which is this butyrate producing taxon that’s really good for you. When you don’t have it, you tend to be sick for different reasons. I would’ve to do a phase one clinical trial to prove its safety, and then other trials to prove efficacy and things like this. To take these next generation probiotics that are actually the efficacious ones that I think will be important in the future, there’s a lot of money and time and science that has to be spent to get approvals for them to be used. There are a first wave of them available. Bugs like Akkermansia muciniphila, Clostridium butyricum, they are out there and available commercially. These are the actual bugs that I think are important.

Now, the classic probiotics, a few of them have been tested in trials like lactobacilli and bifidobacteria. They do have their place and they are efficacious in some areas, especially infant health and things like that. But the big problem is it’s often very heterogeneous what their effects are. There’s non-responders and responders, just like there are to drugs there are for probiotics, and precision targeting of probiotics I think is the next major thing that will make them more effective. Even the bugs as drugs companies now aren’t doing it precision, they’re just making one cocktail for C. diff, and then just giving that to everybody. But I think in another 10 years, we’ll start to actually create different cocktails for different people, make it more precision.

Anjali Nayar:

Yes. It is not good to eat all those hot dogs. That’s the general answer. I don’t know. Was that you who asked the question? Oh, okay. Sorry. I couldn’t see you originally you were behind the podium. It is not good to eat all those hot dogs. I think, like in the film, if you watch the film, you’ll see that Kobe suffers from issues with his satiety, like hunger and fullness. He goes days without remembering to eat, essentially, because he never feels hungry. What I would say about the system is is probably… I’m just jumping to conclusions.

It might not only be the hot dogs, but also the sheer abundance and stuffing your system and not listening to your body signals. I think that that probably also has to do with it. Interestingly, Kobe has a very diverse microbiome because in addition to hot dogs when he is eating, he’s eating a traditional Japanese diet. Perhaps more than say his American counterparts that might be eating pizza even on the weekends or hot dogs on the weekends, he’s actually getting an incredible amount of fermented foods and diversity of foods within his diet. Lots of misos and various pickled things.

Sean Gibbons:

I’ll quickly follow onto that for whether fermented foods are good for you, there’s actually a lot of work showing that they are. The Sonnenburg Lab at Stanford has some cool trials showing that eating fermented foods does decrease systemic inflammation in the body. Drink your kombucha, eat your sauerkraut. That’s good.

Audience member:

Hello. I’ve been sitting in the audience thinking about how I can phrase this question in an impartial scientific way, but I’ve decided that the most direct way is to ask you a question that is deeply personal. It has to do with the microbiome and the effect on mental health. My child has resistant to therapy, obsessive compulsive disorder. When I watched this film, it really struck me that though he has an incredibly healthy diet by his own choice, and that’s actually part of his obsession is being extremely healthy and eating a ton of vegetables. It hasn’t changed anything with his degree of severity from OCD. If you were a family dealing with something like this and there was a possibility of fecal transplant or other research, clinical trials or resources for mental health in general, or OCD specifically, what would you do in my place?

Sean Gibbons:

Yeah. That’s a tough question and a tough situation. I’m not a medical doctor, and I cannot give medical advice, so I should preface all of that. Honestly, the science really isn’t there to help you right now, I would say. There’s a lot of people out there who are preying on families like yours to try to sell that type of a thing. I’ll give you one example, and I think I can call this company out because it was a story in Bloomberg recently. But Viome is a company that’s out there, and there was a partnership with that company and a clinician who had been sanctioned by a Canadian court and had his medical license stripped away from him for…

He was essentially making fecal transplant material in his basement with material from his own nephew, unregulated, not screening it for pathogens, anything like that. Then giving it to parents for a fee to try to treat autism. He didn’t have a good mechanistic explanation for what it was doing. He got kicked out of Canada, went to Mexico, set up a clinic there, and was selling I think these FMTs for something like tens of thousands of dollars a pop to American families who would take their kids south of the border to get the treatment. Viome was partnering with them on a study to study the effects of FMT on autism. There are clinicians out there, and there are companies out there that try to sell this stuff, so beware and just try to follow accredited clinical people with this type of thing.

Jim Heath:

But everything you said is right, but there are things known about the microbiome brain health axis.

Sean Gibbons:

Yeah. The gut brain axis is real, and there are several examples where it’s been validated. If you’re not familiar, epileptic seizures, it’s known that the ketogenic diet is preventative of epileptic seizures. There’s a great researcher at UCLA, Elaine Chao, who showed the mechanism was microbially mediated so that the microbes were actually producing a lipid byproduct from the diet that was affecting the propensity for these seizures. There’s many examples of this. There’s a condition called PANDAS, which you maybe have heard of.

Audience member:

That’s how his mental health started with PANS/PANDAS.

Sean Gibbons:

Interesting. Yeah. Where it’s like a strep infection?

Audience member:

Strep infection. Or with PANS, it’s just not necessarily strep related.

Sean Gibbons:

Yeah. I think-

Audience member:

[inaudible 00:49:55] an onset of OCD symptoms.

Sean Gibbons:

That’s right. That’s right. You don’t get the classic strep symptoms, but you have OCD. I think if they catch it early enough with antibiotics, it can reverse the symptoms. But perhaps if they don’t catch it early enough, it can have more long-

Audience member:

[inaudible 00:50:09] rarely it can help it, and then they come back as a teenager.

Sean Gibbons:

I see. Yeah. Yeah. I don’t want to also oversell the effect of the microbiome on the host. There’s a lot of host processes that are independent of what’s going on in the microbiome. They’re clearly coupled, and sadly, we just don’t quite know enough yet about the complexity of it to be able to engineer it.

Anjali Nayar:

Yeah. Just to follow that I wanted to say there were so many incredible studies that went beyond this film, and what we talked about in this film were the basics, I would say, but it was also what our characters were going through. There’s incredible science out there with regards to basically the effectiveness of cancer treatment. I guess it was mainly chemotherapy, but for melanomas and what diet could do to that, and various different microbiome interventions. We didn’t have anybody older in our film, mainly because we were filming during COVID, and it was very difficult to film in a cancer hospital during COVID. But there’s so many other things like what you just mentioned that are out there and that are still in research, and this is an incredibly interesting but emerging science.

Jim Heath:

Yeah. I think it’s fair to say that it’s only recently that people have been able to even begin to resolve mechanistic relationships, which is really what you need to do something as interventional and targeted.

Audience member:

I think I read that our lower intestine is home of not just bacteria but also viruses, archaea and eukaryotic cells also part of this population.

Sean Gibbons:

You know your microbes. Yeah. There’s bacteria. Bacteria are the by mass, the most dominant in the system. There’s archaea, so those are the methanogens. Some of us burp methane and some of us don’t. The difference is some of us have methanogens and some don’t. There’s a bunch of viruses. There’s a bunch of phage, which infect bacteria and fungi and eukaryotes, so any parasite, like there’s worms and there’s single cellular eukaryotic parasites that also reside in the gut. That’s all happening. It’s a crazy complicated ecosystem. What’s known about it? It’s the Wild West right now. We’re learning a lot as we go. There’s a postdoc at ISB now, Nate Ritz, who’s from John Kyron’s lab, who is the Irish gentleman in the film. A portly guy with the brown hair in the glasses.

Anjali Nayar:

They know him as the person that was lying down in the gut.

Sean Gibbons:

Yes. Yes. That guy. Nate was in his lab, and they had a recent paper out where they did a viral fecal transplant. They just transplanted the phage from, let’s see, what was it? People with social anxiety into mice. They found that they could transfer this social anxiety phenotype just with the viruses, which was super interesting. There’s all kinds of things we don’t know yet.

Anjali Nayar:

Yeah. I think John Kyron’s a pretty big proponent of phages is the next big part of this.

Jim Heath:

Wow. That’s amazing. Okay. One more… Time for one more.

Audience member:

I have the pleasure of being from the science world and now transitioned into teaching. I teach at local high school, and we got to watch your documentary over these last couple of days and they loved it. It was awesome. Thank you for making something that’s accessible. They loved all of the animation. It was beautiful. One of the questions, so I’m bringing their questions to you, is they want to know when is this type of approach going to be accessible in just general medical care? They were like, “I want to get my microbiome tested and see what organisms that I have.” My question is where are we at with that? When they go get their annual exam, can they go and get their microbiome tested anytime?

Anjali Nayar:

Thank you so much for showing this in your class, firstly. It starts with… Think of us, if we all watched this film when we were in school, how different our choices might be, so thank you so much for bringing it to the folks that can be most affected at a really young age. I’m going to pass it over to you because it’s a hard question.

Sean Gibbons:

Yeah. What can you do now? There’s several companies that will sequence your microbiome for you that are out there, and many of them are great and fine. There’s even some academic organizations. At UCSD where Jack Gilbert and Rob Knight are at, there’s this thing called The Microsetta Initiative. It used to be called the American Gut, and it’s a nonprofit initiative where it’s a citizen science initiative essentially. You can send in your poop, and they will give you back some educational information about that poop. Your data will be contributed to science. They will give you a questionnaire about what you’re eating and your lifestyle. They’ll use that data for their scientific research, but what you’re getting back is essentially entertainment. It’s not so much an actionable thing you can use in the clinic. That’s, I think, where we’re at right now.

There are a few companies, Precision Nutrition companies that I don’t know if they’re actually still in operation anymore. Some of them are actually going out of business, sadly. But if they’re still out there, you can get your gut sequenced and get precision nutritional advice. I will say that both of those companies recently had pretty cool validation. One company compared their intervention against the Mediterranean diet and they beat the Mediterranean diet. That’s a good validation. The other one, Nature Medicine a couple of weeks ago, had a comparison against the USDA suggested healthy diet versus theirs. They did slightly better for a few different markers in the blood, like LDL cholesterol and a few other things. There’s good evidence now that some of these kind of work, so there’s a few companies that give you that ability. Beyond that, beyond entertainment, there’s not a lot more than that at the moment, but it’s coming. It’s coming in maybe the next-

Anjali Nayar:

What can they do? They can eat their fruits and vegetables.

Sean Gibbons:

Exactly.

Anjali Nayar:

They can try to reduce the amount of sugar they take in. They can move their bodies. They can do meditations and other lifestyle things that will help them in the longer term.

Sean Gibbons:

Feed your microbes.

Anjali Nayar:

They’re pets.

Jim Heath:

And stop processed foods.

Anjali Nayar:

We can reduce the amount of or stop processed foods. There’s another thing that I learned, any vegan meat is still processed food.

Jim Heath:

Oh, yeah.

Anjali Nayar:

I think that… I don’t know why I didn’t know that before I started working on this film. But it’s processed food, it’s made in a lab.

Sean Gibbons:

It’s a lot of sodium, a lot of sugar and all these things. Yeah.

Jim Heath:

Okay. Well, we’ll let you go home with those thoughts.

Anjali Nayar:

Starting on that one.

Jim Heath:

Anjali and Sean, thank you very much.