The future of gut health

0:00Justin Sonnenburg:This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. Since we started this show eight years ago, it's become an archive of amazing and impactful work by my Stanford colleagues. Research is not something that just happens in the lab, and as you'll hear on this show, the research at Stanford can impact areas like health, technology, law, and business, and many other topics that can affect everyday life. We hope you'll tune in to learn more about how research has the potential to help your life and to help the lives of people you care about in your family and your community.

0:32I think the past 10 years of doing these dietary intervention studies has really shown us that on the one hand, diet can do a lot. That's one of the powerful messages of the gut microbiome field is that this isn't restricted to just therapeutics and us having to do a lot of science first. Like we kind of know what people should be eating. And I think people can really, you know, take the reins of their own health and fostering a healthy gut microbiome.

0:59Justin Sonnenburg:This is Stanford Engineering, the future of everything, and I'm your host, Russ Altman. If you like what you hear today, please follow the show. Your future self will thank you. Today, Justin Sonnenberg will tell us that bacteria in your gut are critical for your well-being. Not only that, but we can modulate our health by what we eat and change the bacteria that are living in our gut. That means that in the future, we may be even able to manipulate what we eat in order to help us respond and do better with specific diseases. It's the future of fiber and fermentation. Today, we're continuing our feature called The Future in a Minute.

1:34Justin Sonnenburg:At the end of my conversation, I will ask Justin some pointed questions and he'll give me some pointed answers. Before we get started, a reminder to follow the show and make sure that you get alerted to every episode so you never miss the future of anything. So many of us know that there are bacteria that live in our gut. A lot of times we think that these are dangerous, that we have to worry about bacteria because they can cause infections, which they can. And that's what antibiotics are for, for killing those bad bacteria. But what is sometimes lost is the fact that there are a huge number and diversity of normal bacteria in our gut that are not just okay, they're critical for our health.

2:12Justin Sonnenburg:They help us digest food, they release molecules that interact with our immune system, our nervous system, and our metabolism. And so they're absolutely critical for health. And the bad news is that with industrialization, there's been a change in our microbiome, in the bacteria that live in our gut. And this can adversely affect our health and has been connected with increasing rates of inflammatory and autoimmune diseases. Well, Justin Sonnenberg is a professor of microbiology and immunology at Stanford University, and he's an expert on the health consequences of manipulating the human microbiome in the gut.

2:48Justin Sonnenburg:He'll tell us that we have a better understanding now of how to eat more healthy and have the right bacteria so that we can maximize our health generally. And he'll also tell us that there may be specific diseases that we can improve the treatments by modifying diet or bacteria. Justin, how did you decide to focus your research on how the bacteria that live in the gut influence our health? Yeah, great question. First of all, thank you for the invitation. It's great to be here. I got very interested. I did my PhD in glycobiology, and I got very interested in all the carbohydrate motifs that coat all of our cells and started realizing that these were an interface for interaction, particularly with pathogens.

3:31That's kind of where it's best studied. Cholera toxin, flu, all these pathogens and their toxins bind to these carbohydrate motifs. And so I started looking into postdocs and what was I going to spend my career doing. And it really was a new spin on this to think about these carbohydrate motifs being important in recruiting and maintaining interactions with friendly microbes rather than harmful ones. And these, of course, are the commensals and what we refer to as oftentimes symbionts or mutualists that live in and on our body and our need to both escape pathogens. So changing these motifs so that we don't get attacked by the bad guys, but not changing them too much to where we lose interactions with the good guys.

4:15And those ideas really started to pique my interest. And then I found Jeff Gordon's lab at Wash U that was studying all of these topics. And that's where I went for my postdoc and the rest is history.

4:26Justin Sonnenburg:And the rest is history. Okay, so what does somebody need to know who doesn't think about the gut microbiome all the time about like the normal state of the and I know that even the definition of normal is somewhat contested, but what how should we think about the bacteria in our gut? And I think people may be surprised to learn, first of all, that they're there and that they are friendly. But secondly, how much they are part of the ecosystem of health in the body. So maybe can you give us an overview you for people who say, what are you talking about? I thought bacteria were the kinds of things we killed with antibiotics.

4:58Completely. And I think that is kind of the challenge of this field is we've all been raised in a universe where bacteria are the bad guys. We're trying to get rid of them. We have antibiotics. Those are obviously miracle medicines in terms of saving lives and preventing disease. But there is this other side of the story where we have evolved over millions of years, long before our species even arose, with microbes in the equation and microbes that actually aren't necessarily trying to cause disease. They're just, you know, microbes are just interested in making more of themselves. And many of them found a good living just living in and on our bodies without causing disease, getting transmitted from one person to another.

5:38Over the course of evolution, this has resulted in what we refer to as a mutualism, where we benefit from having these microbes and the microbes benefit from having this wonderful ecosystem where they get nutrients and can prosper and divide and all the things they like to do. And so now we are fully dependent upon these microbes. I mean, it is like an organ, this complement of microbes that we have in and on our bodies. And they're everywhere. They're not in our organs or in our bloodstream. They shouldn't be there in the parts that should be sterile, but on our body surfaces, in our nose, in the vagina.

6:12But most of them reside in the GI tract. And that's what we study in my lab, the gut microbiome and most of the microbes there reside in the far reaches of the gut in the colon.

6:23Justin Sonnenburg:Great. So now when you write about the microbiome, three of the big ones, and this is not exclusive, but three of the big kind of systems in the body that you talk about are the immune system, the metabolite system, small molecules in the body from nutrition and the nervous system. So could you just connect each of those quickly? I mean, it's ridiculous requests, but welcome to the future of everything. Could you quickly connect those to like, okay, I have bacteria. How does that affect my immune system, my metabolism and my nervous system? Yeah. And I think this really is the counterintuitive part for a lot of people, because if you have a lot of bacteria in your gut and I should, we studied bacteria, but there's all sorts of microbes there.

7:00So there are viruses attacking the bacteria. There's eukaryotes there. It's just this really, there's archaea, this completely different domain of life. And so it really is this complex ecosystem. You can think about it almost like a rainforest and all the different layers and interactions that are occurring. But I think it's intuitive for people to think about these microbes being important in digestion and gut health. But what's remarkable is, you know, these microbes are sending chemical signals into our bloodstream. They're making little chemicals that are secreting molecules off their cell surfaces.

7:35Those interact with our cells that get absorbed into our blood system, circulate throughout our bodies and have access then to all of our tissues. And so that means when you change your gut microbes, when you change the composition or function of this community, those changes ripple through metabolism, through your immune system, and through your central nervous system, which may be hard to believe, but these microbes are even impacting neurodegeneration, moods, behavior. So it really is a full body impact that our gut microbes are having.

8:08Justin Sonnenburg:So that's great. And really the key thing you said there, and I think we're going to talk about this more, is that they secrete molecules. And those molecules, once they enter the bloodstream, can of course affect almost anything, in fact, anything in our physiology. And so in a funny way, immune, metabolism, and nervous are just the three big ones that you're able to measure. Okay. So thank you. That was, now we have set the stage and I want to get right to it because you've written about the industrialization of the gut microbiome. And that could mean a lot of things, but tell me what you mean when you talk about that our microbiome, that the bacteria that live in our bacteria have been industrialized.

8:45I think one of the incredible features of the gut microbiome is that it's malleable, And so it's this component of our biology that probably on the ancient savanna, we benefited from this plasticity. As foods fluctuated over the seasons, our microbiome could adjust, help us digest what was coming down the pipe during that specific moment. And in fact, we've studied the Hadza hunter-gatherers in Tanzania and shown that their microbiome fluctuates seasonally, which of course has been totally lost in industrialized societies. But I think this malleability is a feature, but it also is a bug. So it means that in the extreme circumstance, the microbiome can deteriorate at a really rapid rate when it experiences new insults like antibiotics or a food supply that has been industrialized that no longer contains the nutrients that support the microbiome and instead contains crazy chemicals and weird artificial things to light up our taste buds, but maybe not feed our gut bacteria.

9:46And so, you know, the factors are many. I've just named two there, but, you know, everything from C-sections to baby formula to, you know, there's just all sorts of things in our modern world, you know, sanitation of the water supply, I think wonderful for controlling infectious disease, but maybe it has a negative impact on us being able to share beneficial microbes with one another. So there really are these plus minuses, again, antibiotics, beautiful medicines, but this negative impact with all this collateral damage, because they're meant to be broad spectrum killers where they just will wipe out broad sections of bacteria because I think when these medicines were developed, it wasn't really recognized the importance of the gut microbiome and that there would be this negative impact.

10:25So taking together this picture, surveying across a lot of different lifestyles, what we understand is that ancestrally for tens of thousands, probably hundreds of thousands of millions of years, we had a relatively constricted set of bacteria that we would pass from generation to generation. And just over a legacy. Exactly. Yeah, it really is.

10:50Justin Sonnenburg:I would like to give you this microbiota for your life going forward. You know, and that's the thing is we see and we've modeled this in mice, you know, we can take mice and just over four generations of giving them a Western diet, we see their microbiome whittles down to like a third of the species that it started with. There's just this massive, you know, kind of compounding extinctions that occur in the gut microbiome. And you can't bring those microbes back just by feeding a good diet at the end of that experiment, you actually have to purposefully reintroduce the microbes that you've lost.

11:21And maybe we can come back to this and how we recover health in our gut microbiome. But basically, we are like those fourth generation mice where it's very clear, we just not only whittled down the diversity of this gut microbiome and lost a lot of the community members that we evolved with for thousands of years. We have replaced them with other microbes. And these microbes appear to be pro-inflammatory in some of the early tests that are going on in the field right now. So we've replaced this co-evolved microbiome. And that's not to say that all those microbes are beneficial and great, but they're certainly the microbes that our body has become accustomed to.

11:58We've replaced those with another set of microbes that appear to be propagating inflammation. And we actually think this may be at the basis of a lot of chronic inflammatory disease.

12:08Justin Sonnenburg:So what you say is extremely attractive. It's even somewhat intuitive. And I'm sure that the number one question you get then is, well, I'm in an industrialized society and there's a lot of things I can't change, but I can change what I eat. And I know this is something that you've been looking at. And you went all the way back, even in your origin story, you were looking at the sugars that are attached to proteins and to cells. So, and as you know, a huge market has arisen for health foods that are going to help our microbiota. So I hope it's not premature because I do want to get to the serious precision health applications that you're studying.

12:41Justin Sonnenburg:But I think now is a good time because I think people are asking, what should I be eating? Because you also made reference to our diet changing and the seasonal diets in Tanzania. So maybe let's, let me ask you about that. What are the kinds of things that we're not eating that at least you have seen probably historically, we were eating much more. Yeah, completely. So one of the insights that I think the field had early on was that most of the gut microbes live at the far reaches of the digestive tract, which means that if you're eating a diet that's rich in like sugar and protein and fat, like a Western diet, most of that gets absorbed in the small intestine up at the top of the, right after the stomach.

13:21And so if you're eating a Western diet, there's no food left over for the gut microbes in the colon. And historically, we ate diets that were, you know, I think hunter gathers, quite often people have images of them killing game and eating a lot of meat. Actually, if you go to the Hadza, the studies that have been done, it looks like that they eat mostly plants because those staples are always available. That's kind of what they rely on. But they just have to flux a lot of this plant material to get the nutritional value and calories out of it. So they're eating on the order of 100 to 150 grams of dietary fiber per day.

13:55This is complex, you know, dietary fiber is a crude term, but complex carbohydrates that we can't digest most of them, which means that they pass through the small intestine. And that is what the gut microbiome is adapted to, is digesting these complex carbohydrates that are present in plant foods. In the industrialized world, we eat on the order of 15 to 20 grams of dietary fiber. So almost a tenfold decrease in this nutrient that fuels our gut microbiome. Now, that dietary fiber in the gut microbiome actually does two important things. It, on the one hand, serves as the fuel that allows the bacteria to produce beneficial metabolites, so things like butyrate that actually fuel colonocytes, enforce the barrier, regulate the immune system in positive ways, regulate metabolism in positive ways.

14:41That's gone missing. and the flip side of that is that our gut bacteria have started to eat the mucus layer as a backup food source these carbohydrates that i mentioned at the beginning we're literally devouring ourselves exactly and and these these studies are just it's one of the themes that it has persisted you know the um this was first described actually during my postdoc work it's what you got what got me the job here at stanford was discovering that these microbes can switch over to eating mucus if you deprive them of dietary fiber. And it's one of the themes that has just been very solid in the field.

15:15And we not only see that they devour the mucus, but that inflammation goes up. And then, you know, this is happening at the same time that we're watching inflammatory bowel disease rates, early onset colorectal cancer, all of these rates go through the roof that we know are directly related to inflammation in the gut. So I think there's a direct connection there that's inferred, but really the studies need to be done to hammer this home.

15:38Justin Sonnenburg:And a great thing that you've made clear is that there's two things we need. Like, yes, eating more fiber is good, but you have to make sure you have the bacteria that can help you process that. So there's two things you need, perhaps. You need the fiber at whatever appropriate level, and you need those bacteria that, as you've said, because of industrialization, may be lost and hard to get back. Is that - Actually, perfect. So that actually, I want to reinforce that point because about 10 years ago, we started the Center for Human Microbiome Studies at Stanford to do human studies focused on diet.

16:09We did this with a close collaborator, Christopher Gardner. We use the immune monitoring center here run by Holden Maker, Mark Davis, a beautiful system that allows us to monitor the immune system in really high dimensional ways so we can understand what's happening to somebody's inflammatory tone as they're on different diets longitudinally. And so with Christopher Gardner, we have done dietary fiber interventions. And what we see is, and we've done about 10 or so dietary interventions over the past 10 years in human cohorts, different human cohorts. And what's been remarkable is that for dietary fiber, only about a third of the healthy adults that we enroll in these trials can respond positively to the dietary fiber.

16:51That is, they actually make butyrate, they actually decrease their inflammation, exactly the signal we'd want to see. Two-thirds of them cannot. Those two-thirds of the population actually have the lowest diversity, most deteriorated gut microbiome, and a lot of fiber coming through in their stool. So really, the implication there is exactly what you're saying. You not only need to have fiber, but you need to have the right microbes. Now, just to interject one thing here, because I think it's an important side point, we have also studied a lot of other diets. And the big signal that we didn't really expect and wasn't really appreciated in the field before, fermented foods have an incredibly positive impact on the gut microbiome.

17:31Justin Sonnenburg:That was exactly where I was going to go. Can you tell us what does it mean? I mean, when we think of fermentation, most of us think about people in Kentucky making bourbon. But what's the definition of fermented for you? Yeah, so fermented foods that we used in this study, and that's a very good point. We get asked the alcohol question quite often. And we'd be happy to do a bourbon study if somebody wants to fund it. I would enroll. I have a friend named Johnny who might want to fund us. Okay, great, great. You know, we took this to mean for fermented foods, basically like yogurt, kimchi, sauerkraut, kombucha.

18:09So these are foods that are transformed by microbes. You buy them in the refrigerated section in the market or you make them at home. They contain not only the live microbes, but they also contain all the metabolites that the microbes have made while they've been fermenting. So like lactic acid is a common one that people think about. But there's hundreds of different molecules in there that are produced by the microbes. And then the other important point is they actually have reduced glycemic index because all the microbes have consumed all the simple carbohydrates. So they're really wonderful foods.

18:39and we've now conducted a couple trials with these with just magnificent results in terms of the impact on the microbiome and on host biology.

18:48Justin Sonnenburg:Because they're bringing both the bacteria and the kind of nutrients that you would want to the party. It's not just half the story. It's the whole shebang, so to speak. Exactly, but we still don't know all the mechanisms of this and that's the really, there's just a lot of science to do here that's really interesting, but we know we're on the right track. What we see is when we give people fermented foods, their microbiome diversity increases. So the signal we'd want to see to counter the deterioration that occurred during industrialization and not only increased diversity, but we see recruitment of butyrate producing bacteria and, you know, exactly the kind of strict anaerobic fermenters that we'd want to see.

19:25We see a decrease in many inflammatory markers. So over two dozen different inflammatory markers go down. So, you know, exactly what we'd want to see to counter the rise of chronic inflammatory diseases. And now we're actually performing this. So that was originally a study that we did in healthy adults. Now we're doing this study in pregnant women to see if we can cultivate a more diverse gut microbiome in them that then they pass to their infants with the idea that we can reverse what I described before without four generation. The legacy is back. Exactly. Can we reverse this?

19:58Justin Sonnenburg:This is the future of everything. I'm Russ Altman, and I'm speaking with Justin Sonnenberg from Stanford University. We've been discussing the gut microbiome and its relationship to health, immune system, nervous system, metabolism, everything you can think of could be affected by the bugs that are secreting small molecules into your bloodstream. We're going to now move to therapeutic approaches. How can we use this to improve people's health, either in general or in the context of specific diseases? But before that, don't forget at the end of the episode, we're going to have the future in a minute where I'll ask Justin five pointed questions and he will give me five pointed answers.

20:36Justin Sonnenburg:So Justin, you've worked us up into a frenzy and we're excited about these, the dietary things, the fermentation of bacteria working on us, but what's the opportunity for actually using this to improve health? You know, I think the past 10 years of doing these dietary intervention studies has really shown us that on the one hand, diet can do a lot. So I encourage everybody out there, That's one of the powerful messages of the gut microbiome field is that this isn't restricted to just therapeutics and us having to do a lot of science first. We kind of know what people should be eating. And I think people can really take the reins of their own health in fostering a healthy gut microbiome.

21:13Now, it's a long road. It's a habitual thing. It doesn't all happen within a six-week dietary intervention. So diet's powerful. But I do think that if you use diet alone, it can be a slow road. because we have to acquire from around us all the right microbes if we have a deteriorated microbiome. And in our sanitized world, that can be a slow process. So I think that the opportunity for the field right now is to bring back functions that have been lost in the industrialized microbiome. And there's a lot of them out there, but one of the key ones that we've been focusing on is this ability of the microbiome to consume dietary fiber, break it down, and turn it into short chain fatty acids like butyrate.

21:55So if we can reinstall that function into everybody's gut microbiome, it's such a critical node of homeostasis in the gut that I think that that would have a really big role. We've just gotten a grant from the NIH to do this. We've been supported by philanthropy through Stanford Development, wonderful kind of team effort here from the community. And we are now building microbial consortia that we can give back to people and feed them fibers.