Stanford microbiologist Dr Justin Sonnenburg discusses gut microbiome health with Andrew Huberman
Andrew Huberman interviews Stanford microbiologist Dr Justin Sonnenburg on the Huberman Lab podcast.
Summary
Andrew Huberman interviews Dr Justin Sonnenburg, a microbiologist at Stanford, about the gut microbiome — what it is, how it develops, and how diet shapes it throughout life. Sonnenburg argues that the industrialized microbiome may be in a state of progressive deterioration driven by antibiotic use, processed food, and reduced microbial exposure — and that this deterioration is likely setting the immune system toward chronic inflammation and metabolic disease. He presents findings from a landmark Stanford dietary intervention study showing that a high-fermented-food diet significantly increased microbiome diversity and reduced multiple inflammatory markers, while a high-fiber diet produced more variable results, particularly in people who had already lost the fiber-degrading microbes needed to benefit from it. Sonnenburg also cautions that probiotics and purified prebiotic fibers carry real limitations, and that diverse whole-plant foods remain the most reliable dietary strategy for microbiome health.
Key Takeaways
FULL TRANSCRIPT
What the microbiome is and where it lives
Dr Justin Sonnenburg: Just to start off with clarifying terminology — microbiome and microbiota are quite often used interchangeably to refer to our microbial community, and I'll probably switch between those two terms. The other important thing to realize is that these microbes are not just in our gut but all over our body — in our nose, in our mouths, on our skin. Basically anywhere that the environment can get to in our body, which includes inside our digestive tract, is colonized with microbes. The vast majority of these are in our distal gut and in our colon. This is the gut microbiota, or gut microbiome.
The density of this community is astounding. If you start with a zoomed-out view you see something that looks like fecal material — the digest inside the gut — and you zoom in to the microscopic level and see the microbes. They are just packed side to side, end to end. It's a super dense bacterial community, almost like a biofilm, to the point where it's thought that around 30 to 50% of fecal matter is actually microbes. We're talking trillions of microbial cells, and if you start to get to know them and see who they are, they break out in the gut to probably hundreds to a thousand species. Most of these are bacteria, but there are a lot of other life forms there. There are archaea, which are bacteria-like microbes but different. There are eukaryotes — we commonly think of eukaryotes in the gut as something like a parasite, but there are also fungi. And there are little viruses, bacteriophages that infect bacterial cells, and those actually outnumber the bacteria ten to one. They kill bacteria, so there are really interesting predator-prey interactions. Overall, it's just a really dense, complex, dynamic ecosystem.
How the microbiome is established in early life
Andrew Huberman: Is our microbiota seen in newborns? Where does it come from?
Dr. Sonnenburg: There have been some studies looking at whether there are microbes in the womb colonizing the fetus, and there's some debate about this, but overall it looks like that's not a big part of the equation. So each time an infant is born, it's a new ecosystem — like an island rising up out of the ocean with no species on it, and suddenly there's this land rush for open territory.
There are also a lot of different trajectories that developmental process can take, because our microbiota is so malleable and plastic, and those trajectories can be affected by all sorts of factors in early life. An example is whether an infant is born by C-section or vaginally. Infants born by C-section actually have a gut microbiota that looks more like human skin than like either the birth canal microbiota or the mother's stool microbiota. Compound on top of that whether you're breastfed or formula-fed, whether your family has a pet, whether you're exposed to antibiotics — all these factors can really change that developmental process and change your microbial identity in later life. We know from animal studies that depending upon the microbes you get early in life, you can send the immune system or metabolism of an organism in totally different developmental trajectories. What microbes you're colonized with early in life can really change your biology.
How to assess whether a microbiome is healthy
Andrew Huberman: How do I know if my microbiome is healthy or unhealthy?
Dr. Sonnenburg: Context matters a lot. What's healthy for one person or one population may not be healthy for another. There's no single answer to this, but there are some really important considerations.
Perhaps the best way to start is to go back to the inception of the Human Microbiome Project — a program that the NIH started, investing a lot of money in 2008 and 2009 to really propel the field of gut microbiome research. It was becoming evident at that point that this was not just a curiosity of human biology but was probably really important for our health. Through those studies, we really started to get the image that there is tremendous individuality in the gut microbiome, making it really hard to draw conclusions after an initial pass of that project about what a healthy microbiome looks like.
At the same time, there were studies going on documenting the gut microbiome of traditional populations — hunter-gatherers, rural agricultural populations — and those studies were really mind-blowing. All these people are healthy, living very different lifestyles, and their microbiome doesn't look anything like a healthy American microbiome. One possibility is that in the industrialized world we have a different microbiome from traditional populations and that microbiome is well adapted to our current lifestyle, and therefore healthy in the context of an industrialized society. There probably are elements of that that are true. But another possibility is that this is a microbiome that's gone off the rails — deteriorating in the face of antibiotic use and all the problems associated with an industrialized, western diet — and that even though the Human Microbiome Project documented the microbiome of healthy Americans, what they may really have been documenting is a perturbed microbiota that's predisposing people to a variety of inflammatory and metabolic diseases.
Whether a disrupted microbiome can recover
Andrew Huberman: If my gut microbiome was dysbiotic early in life, can I rescue that through proper conditions and exercise, or is there some fixed pattern that's going to be hard to escape from?
Dr. Sonnenburg: There's a big field emerging now that we refer to as reprogramming the gut microbiome. The issue is that microbiomes, whether diseased or healthy, quite often exist in stable states — they tend toward a well with a kind of biological gravity, where it's really hard to dislodge that community from that state.
Even individuals who get antibiotics: you take oral antibiotics, the community takes a huge hit, a bunch of microbes die, composition changes, and that represents a period of vulnerability where pathogens can come in and cause disease. But if that doesn't happen, the microbiota kind of works its way back to something that is not exactly, but similar to, the pre-antibiotic state. With dietary perturbations, you'll often see a really rapid change to the gut microbiome, and then it's almost like a memory where it snaps back to something very similar to the original state even though the diet remains different. There's what we refer to as resilience of the gut microbiome — resistance to change, or at least resistance to establishing a new stable state.
That doesn't mean it's hopeless to change an unhealthy microbiome. But it does mean we need to think carefully about restructuring these communities in ways where we can achieve a new stable state that will resist the community getting pulled back to the original state.
One of the simplest examples of this is an experiment we performed with mice. We fed mice a normal mouse diet — lots of nutrients for the gut microbiota including dietary fiber — then switched half the mice to a low-fiber diet. We were asking: if you switch to a western-like diet, a low-fiber, higher-fat diet, what happens to the gut microbiota? We saw the microbiota change. It lost diversity, very similar to what we see in the difference between industrialized and traditional populations. But when we brought back a healthy diet, a lot of the microbes returned — there was this kind of memory where it went back to very similar to its original state.
The difference is when we put mice on a low-fiber, high-fat diet and kept them on that for multiple generations. We saw progressive deterioration over the course of generations where by the fourth generation the gut microbiome was a fraction of what it originally was — let's say 30% of the species remained and something like 70% of the species had gone extinct or appeared to have gone extinct. We then put those mice back onto a high-fiber diet and we didn't see recovery. A new stable state had been achieved, probably because those mice no longer had access to the microbes they'd lost.
We did the control experiment: mice on a high-fiber diet for four generations maintained all their microbes. If we took those fourth-generation mice with all the diversity and did a fecal transplant into the mice that had lost their microbes but had been returned to a high-fiber diet, all of the diversity was reconstituted. So the answer to how we establish new stable states — how we get back to a healthy microbiota after taking a lot of antibiotics or having a deteriorated microbiota — is probably a combination of having access to the right microbes and nourishing those microbes with the proper diet. There are a lot of companies working on creating cocktails of healthy microbes, but it'll be a combination of access to the right microbes and nourishing those microbes with the proper diet.
Cleanses, fasting, and microbial reconstitution
Andrew Huberman: What's the thinking about cleanses and fasting as they relate to the health or dysbiosis of the microbiota?
Dr. Sonnenburg: In studies being done now to reprogram the gut microbiota and install a completely new microbial community, the first step is to wash away the resident microbial community that's there. So if you're in the process of acquiring a really good microbiota and you know how to do that, flushing everything out is great. Otherwise, what's happening is you're leaving the rebuilding of the community to chance — what microbes are going to colonize, who's going to take up space after you do this flush or cleanse. It's a little bit like playing Russian roulette. You may end up with a good microbial community afterwards, or you may not. You certainly want to pay close attention to what you're eating while the community is reconstituting after you do something like that.
Processed foods and the microbiome
Andrew Huberman: It sounds to me that avoiding processed foods — or heavily processed foods — is a good idea. Consuming processed foods is just bad for the microbiome. Can we say that categorically?
Dr. Sonnenburg: For sure. We can break down why different components of processed food are so bad for us and so bad for our microbiome. The flip side of this: if you're eating a bunch of complex plant-based fibers that feed your gut microbiota, your gut microbiota produces substances called short-chain fatty acids — things like butyrate. These short-chain fatty acids play really essential roles in fueling colonocytes, reinforcing the barrier, keeping inflammation low, regulating the immune system, and regulating metabolism. Your gut microbiota is producing this vast array of fermentation end-products that get absorbed into our bloodstream and have tremendous cascading effects that appear to be largely beneficial on our biology.
Processed foods represent a different dimension, where you have all these unusual chemicals — artificial sweeteners, unusual fats, a lot of refined simple nutrients. We know that artificial sweeteners can have a massive negative impact on the gut microbiome and can lead towards metabolic syndrome. There's been beautiful work out of the Weizmann Institute on this. And then emulsifiers — compounds put in processed foods to help maintain shelf stability so things don't separate and moisture content is retained — many of these are known to disrupt the mucous layer. As soon as you start disrupting that barrier, it can lead in the direction of inflammation, and in animal models we know that can lead towards metabolic syndrome as well. So there are components of processed food that, when studied in isolation, are known to have a direct negative impact on gut biology and the microbiota.
Artificial versus plant-based non-caloric sweeteners
Andrew Huberman: I want to make sure we distinguish artificial sweeteners from non-caloric plant-based sweeteners. Do we know anything about plant-based, non-caloric or low-caloric sweeteners?
Dr. Sonnenburg: Very little. A lot of those have a lot more bang for the buck — they're incredibly sweet, so it takes a really small amount to trigger a huge amount of sweetness. Depending upon the mechanism by which these non-sugar sweeteners impact our biology, it may be that those are actually less negative or more healthy than artificial ones, just because it requires less of them for us to perceive that sweet taste. Historically, there are traditional populations that use these to sweeten different foods, and our bodies probably know how to deal with those compounds better than synthetic ones. But the studies still need to be done.
Andrew Huberman: Do you actively avoid artificial sweeteners — sucralose, aspartame, saccharin — personally?
Dr. Sonnenburg: I do avoid them, but I'm not rigid about it. I think doing things in moderation and doing things slowly makes it a lot easier. There are very few hard and fast rules I have. I'm a pretty flexible eater. I don't believe that having a diet coke will somehow cascade into some terrible disease.
The Stanford fiber and fermented food intervention study
Andrew Huberman: I'd love to talk about fiber and fermented foods, because you and Chris had what I think is a really interesting and exciting paper comparing inflammatory markers of people who ate a certain amount of fiber versus a certain amount of fermented foods.
Dr. Sonnenburg: Let me take a step back first, because I think the reason we did this study goes back to an epiphany we had while studying the gut microbiome. When we started studying it at Stanford, we were thinking about it as this newly appreciated aspect of our biology — almost like finding an organ we didn't know was there — and thinking about all the drug targets, whether we could go in with small molecule drugs and manipulate this community to ameliorate disease. This is largely the mindset of western medicine, born out of the era of infectious disease: you wait for an infection, treat with antibiotics. That paradigm has become less successful as we've moved into this era of inflammatory western diseases.
We started to think about how we could get out in front of this — how we could think about preventative ways of dealing with this crisis of metabolic and inflammatory diseases. A tremendous body of literature started to show that the gut microbiome is absolutely critical to modulating our immune status. If you change the microbiome, you can fundamentally change how the immune system operates. And the immune system is at the basis of a lot of these chronic inflammatory diseases.
This brought up the possibility that maybe the fact that we're not nourishing this community well enough, maybe the fact that it's deteriorated over time due to antibiotic use and industrialized lifestyle, means we have a microbiome right now that is setting our immune system at a set point of simmering inflammation that's driving us towards inflammatory diseases. Wouldn't it be wonderful if we could learn the rules of how to reconfigure both the composition and function of our gut microbiome so that inflammation was different in our bodies and each one of us was less likely to develop an inflammatory disease.
In our flagship study, we wanted to understand: if we put people on a high-fiber diet, how would that affect their microbiome and immune system? And if we put them on a high-fermented-food diet — rich in live microbes and all the metabolites present from fermentation — how would that change the microbiome and immune system?
For the high-fiber diet, we increased plant-based fiber: more whole grains, more legumes, more vegetables, nuts — pushing fiber intake from around 15 to 20 grams per day up to over 40 grams per day, more than doubling the amount consumed.
For the fermented food diet, people were instructed to eat foods they could buy at a grocery store that were naturally fermented and contain live microbes: yogurt, kefir, sauerkraut, kimchi. We instructed people to eat unsweetened yogurts — a huge pitfall in this area is that you can have a yogurt loaded with bacteria, a healthy base, and then a ton of artificial flavoring and sugar loaded on top. Manufacturers put a ton of sugar in after the fact to mask the sour taste of fermented foods, which is hard for some people to become accustomed to. Getting used to that sour flavor is difficult, but people really should try to stay away from fermented foods loaded with sugar, and that's what we instructed people in this study.
A lot of people shy away from high-quality fermented foods because they can be quite costly. I'll just refer people to a resource in Tim Ferriss's book, The 4-Hour Chef. He gives an excellent recipe for making your own sauerkraut, which basically involves cabbage, water, and salt. You have to do it properly because you can grow some somewhat dangerous bacteria if you don't scrape off the top layer, but he gives beautiful instructions for making large amounts of truly fermented sauerkraut from just those three ingredients.
If you can get your hands on a SCOBY, kombucha is another one that's super simple to make yourself. I constantly have a batch going at home. It's a symbiotic community of bacteria and yeast — you brew tea, add sugar, put the SCOBY in, wait a week or two depending on temperature, then move the SCOBY over to a new batch, and what the SCOBY was in is kombucha.
Andrew Huberman: How much fermented food were they consuming in servings — how many times a day?
Dr. Sonnenburg: The general instructions were to eat as much fermented food as possible — more is better. During the height of the intervention phase, people were up to over six servings on average per day, roughly two servings at each meal. The size really depended on what the fermented food was. We told them to stick to what was a recommended dose on the package — for kombucha, a six to eight ounce glass; for sauerkraut, about a half cup; same with yogurt.
The big signal was really in the fermented food group. We saw all the things you would hope to see: an increase in microbiota diversity over the course of the six weeks while they were consuming the fermented foods. We can't always say that higher diversity is better — we know there are cases where higher diversity is indicative of a disease state, like bacterial vaginosis. But in the context of the gut for people living in the industrialized world, higher diversity is generally better. People with higher diversity generally are healthier, and if you can push your diversity higher, you're in better shape.
Then the major question was what happened to the immune system as these people were increasing their gut microbiota diversity through fermented foods. We did massive immune profiling and saw a couple dozen immune markers and inflammatory markers decrease over the course of the study. There's a step-wise reduction in things like interleukin-6 and interleukin-12 — a variety of famous inflammatory mediators. And even when you go into the immune cells and look at their signaling cascades, those signaling cascades are less activated at the end of the study compared to the beginning, indicating an attenuation of inflammation — exactly what we would hypothesize would lead to less propensity for inflammatory disease over time.
Andrew Huberman: Did people say they were feeling better in any way?
Dr. Sonnenburg: Tons of people said they had more energy, thought more clearly, slept better. It's really hard to uncouple whether this is because these people have taken charge of what they're eating and just feel better in general for being in control, or whether there's a cascading set of effects actually emanating from the gut-brain axis. The list goes on — people claim their complexion improves, their allergies improve, and there are probably all sorts of ripple effects if you can affect your inflammation. We know that you can affect cognition. We know that you can affect inflammation occurring on your skin. I really think there is a basis for a lot of those anecdotes — it may just be hard to see in a short study with a small cohort over a short period of time.
We also have a standardized stool measure that people use, and there was less constipation and better bowel movements over the course of both of these interventions. Bowel habits improved, which a lot of times can lead to better moods, though we weren't able to measure that directly.
Results in the fiber group and the limits of fiber without the right microbes
Andrew Huberman: What sorts of interesting things did you observe in the fiber group?
Dr. Sonnenburg: The data seem to be telling us that if you start off with a diverse microbiota — one that's better equipped to degrade a wide variety of dietary fiber — you're more likely to respond positively to it. If you have a very depleted gut microbiome, you're not as likely to be able to respond to it.
Thinking back to that multigenerational experiment with mice fed a western diet and losing fiber-fermenting microbes — it may be that many of us in the industrialized world have a microbiome so depleted that even if we consume a high-fiber diet, at least for a short period of time, we don't have the right microbes in our gut to degrade that fiber. This has actually been observed by other groups. There's a beautiful study out of the University of Minnesota looking at immigrants coming to the United States: within nine months, and certainly over the course of years, immigrants who come here lose a lot of the diversity in their gut microbiome, and a lot of the fiber-degrading capacity too.
It could be that over time this becomes a one-way street and it's hard for us to recover the microbes that can actually degrade fiber. I think this probably intersects with sanitation in our environment and the fact that we don't have access to new microbes — that we've lost these microbes and they're in some ways irrecoverable without deliberate reintroduction of fiber-degrading microbes.
Children, dirt, pets, and environmental microbial exposure
Andrew Huberman: You have children. Do you encourage them to interact with pets and dirt and stuff in the environment, provided that stuff wasn't immediately toxic?
Dr. Sonnenburg: Absolutely. Certainly, with infectious diseases in general, it's really important to be aware of the possibility of compromising your health through the spread of germs. Handwashing is important. But I do think that the sanitization of our environment has gone overboard — various things being impregnated with antibiotics, shopping carts, toothbrushes. Antibiotics and things for killing microbes are everywhere.
When our daughters were young and we were making these decisions, the calculations we would make were: how likely are they to encounter a disease-causing microbe? If we've been out on a hike or in our garden working in the dirt, maybe it's not as important to wash hands before lunch even if there's a little dirt on them. If they've been in a public playground where maybe there are other kids with germs, or maybe even chemicals like pesticides and herbicides, then maybe it's more important to wash hands. Certainly if you've been in a grocery store or on the subway, probably a good idea to wash your hands. You really need to think about the context. Exposure to microbes from the environment is likely an important part of educating our immune system and keeping the proper balance, and it's just a matter of figuring out the right way to do that safely.
Probiotics: what to look for and buyer-beware
Andrew Huberman: What's the thought about probiotics for the typical person who is not recovering from a round of antibiotics?
Dr. Sonnenburg: The first thing to say is buyer beware, because it's a supplement market. It's largely unregulated, which means there are a lot of bad products out there and a lot of products that, even though they're not intended to be bad, just don't have great quality control. There have been several studies that have taken off-the-shelf probiotics, surveyed what's in there based on sequencing, and shown that what is in there does not match what's on the label.
There are places that probiotic companies can send their product to have it independently validated, so you want to look for that sort of validation on a product. There also are names that are very well known, and their reputations are on the line, so they probably invest a little bit more in quality control than some lesser-known names.
Because there's such a huge range of products and because each person is their own little case when it comes to the microbiome, it's really hard to know whether there are great products for a given indication. The really good advice I've heard is to try to find a well-designed study that supports a specific probiotic doing whatever it is you're looking for, and then sticking with that probiotic. If you're experiencing a medical problem, consulting a doctor would be helpful. But finding a study where a specific probiotic has successfully done what you're looking for and then sticking with that probiotic is really the best recipe as a place to start in this space.
Prebiotics: benefits, risks, and the case for diverse whole plants
Andrew Huberman: What about prebiotics?
Dr. Sonnenburg: The studies that have been done on prebiotics present a really mixed bag of results. There have been studies done with purified fibers where you actually see microbiota diversity plummet over the course of the study, because you get a very specific bloom in a small number of bacteria that are good at using that one type of fiber, and that's at the expense of all the other microbes in the gut. So it's really hard to replicate with purified fiber what you'd get at a salad bar in terms of the array of complex carbohydrates you'd be exposing your microbiota to.
The broad view in the field is that consuming a wide variety of plants and all the diverse fiber that comes with that is probably better for fostering diversity in your microbiota than purified fibers. There are people who benefit from purified fibers for GI motility or for other GI health problems, and it's the type of thing where you have to try to find what's right for you.
There are also studies suggesting that if you layer rapidly fermentable fibers on top of a western diet, you can actually result in unusual metabolism happening in your liver, because you have this incredibly rapid fermentation of fiber along with a lot of fat coming into the system. In a mouse study published a few years ago, a subset of the mice actually developed hepatocellular carcinoma — liver cancer — when fed a high-dose prebiotic on top of a western diet. Whether that's representative of human biology, we don't know. But purified fibers are definitely very different from whole plant fibers, both in terms of the diversity of structures and in terms of how rapidly they're fermented in the gut. If you're eating plants, the complex structures really slow the microbes down in terms of fermentation, and you end up with a slow rate of fermentation over the length of your colon, as opposed to a big burst of fermentation that can happen if you eat something that is highly soluble and easily accessed by the microbes.
Resources and the Sonnenburg Lab
Andrew Huberman: Where can people find out more about the work that you're doing? You have a book on this topic — could you tell us about it and where we can learn more about the Sonnenburg Lab?
Dr. Sonnenburg: My wife Erica and I wrote a book called The Good Gut. That really was a response to how we were changing our own lives in response to being in the field, being very familiar with the research, and seeing that a lot of our friends who weren't studying the gut microbiome but were very well-informed — many of them scientists — were not doing the same things we were doing. It was very clear that it was just the lack of information funneling out of the field to other people, and we wanted to make that accessible to people who are not microbiome scientists.
In terms of connecting with our research, there is the Center for Human Microbiome Studies at Stanford, which is our home base for doing a lot of these dietary interventions. We list our studies there, give more information on what we're doing, and we're always looking for participants.