How to Build, Maintain & Repair Gut Health | Dr. Justin Sonnenburg

Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of Neurobiology and Ophthalmology at Stanford School of Medicine. Today my guest is Dr. Justin Sonnenberg.

Dr. Sonnenberg is a professor of Microbiology and Immunology at Stanford School of Medicine, and one of the world's leading experts on the gut microbiome. The gut microbiome is the existence of trillions of little microorganisms throughout your gut. And by your gut, I don't just mean your stomach, I mean your entire digestive tract.

Turns out we also have a microbiome that exists in our nose, in any other location in which our body interfaces with the outside world. In fact, there's a microbiome on your skin. And while it might seem kind of intrusive, when it's disgusting to have all these little microorganisms, they can be immensely beneficial for our health, meaning our hormonal health, our brain health, and our immune system function. Dr.

Sonnenberg teaches us about the gut microbiome, how it's organized spatially, meaning which microbiota live where. He teaches us about these incredible things called crypts and niches, which are little caves within our digestive tract that certain microbiota take residence. And at that premier real estate, they're able to do incredible things to support our health. He also talks about the things that we can all do to support our microbiome, in order for our microbiome to support our brain and body health.

Dr. Sonnenberg co-runs his laboratory with his spouse, Dr. Erica Sonnenberg, and together they've also written a terrific and highly informative book called The Good Gut, Taking Control of Your Weight, Your Mood, and Your Long-Term Health. Even though that book was written a few years back, the information still holds up very nicely.

And today he also builds on that information informing us about recent studies that, for instance, point to the important role of fermented foods and the role of fiber in supporting a healthy gut microbiome. So if you've heard about the gut microbiome, or even if you haven't, today you're going to hear about it from one of the world's leading experts. He makes it immensely clear as to what it is, how it functions, and how to support it for your brain and body health. During today's discussion, we don't just talk about nutrition, we also talk about the impact of behaviors and the microbiome.

Behaviors such as who you touch, who you kiss, who you hug, whether or not you interact with or avoid animals, whether those animals belong to you, or whether they belong to somebody else. If all that sounds a little bit bizarre, you'll soon understand that your microbiome is constantly being modified by the behavioral interactions, the nutritional interactions, and indeed, your mood and internal reactions to the outside world. This is an incredible system. Everyone has one.

Everyone should know how it works, and everyone should know how to optimize it. And today, you're going to learn all of that from Dr. Sonnenberg. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford.

It is, however, part of my desire and effort to bring zero-cost consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. And now for my discussion with Dr. Justin Sonnenberg.

Justin, thanks so much for being here. Great to be here. I am a true novice when it comes to the microbiome. So I'd like to start off with a really basic question, which is, what is the microbiome?

I imagine lots of little bugs running around in my gut, and I don't quite like the image of that. But I'm aware that our microbiome can be good for us, but we can also have an unhealthy microbiome. So if I were to look at the microbiome at the scale, and I could see the meaningful things, what would it look like, and what's going on in there? Yeah, I mean, essentially, you're correct.

I mean, we have all of these little microorganisms running around in our gut. I think, you know, just to start off with clarifying terminology, microbiome and microbiota quite often are referred to, or used to refer to our microbial community interchangeably, and I'll probably switch between those two terms today. Not just in our gut, but they're all over our body. They're in our nose, they're in our mouths, they're on our skin, and so basically anywhere that the environment can get to in our body, which includes inside our digestive tract, of course, is, you know, colonized with microbes.

And the vast majority of these are in our distal gut and in our colon, and so this is the gut microbiota or gut microbiome. And the density of this community is astounding. I mean, it really is. If you get down to the scale of, you know, being able to see individual microbes, you know, you start off with a zoomed out view, and you see something that looks like, you know, fecal material that adjusts inside the gut, and you zoom in, and you start to, you know, get to the microscopic level and see the microbes, they are just packed, you know, side to side, and it's a super dense bacterial community, almost like a biofilm, you know, something that's just made up of microbes, to the point where it's thought that, you know, around 30% of fecal matter is microbes, 30 to 50%.

So, you know, it's an incredibly dense microbial community. We're talking of, you know, trillions of microbial cells, and all those microbial cells, if you start to get to know them and see who they are, break out in the gut probably to hundreds to a thousand species, depending upon how you define a microbial species. And then most of these are bacteria, but there are a lot of other life forms there. There are archaea, which are little microbes that are bacterial-like, but they're different.

There are eukaryotes. So, you know, we commonly think of eukaryotes in the gut as, you know, something like a parasite, but there are eukaryotes, there are fungi, there are also little viruses. There are these bacteriophages that infect bacterial cells. And so, and those actually outnumber the bacteria like 10 to 1.

So they're just everywhere there. They kill bacteria. And so there's these really interesting predator-prey interactions. But overall, it's just this really dense, complex, dynamic ecosystem.

And so, you know, we're talking about the human as a single species, but we're also thinking of the human as this complex, integrated ecosystem of hundreds to thousands of species interacting in concert to do all the fantastic things that we know happen in the human body. Amazing. So we've got a lot of cargo. Well, hey, we're the cargo.

Yeah, I mean, there have been people that have likened humans to just a really elaborate culturing flask for microbes, and that we've actually been designed over the course of evolution, designed to just efficiently propagate this microbial culture from person to person, from generation to generation. So it's a different way of thinking of the human body. Interesting. I believe that our pH, or the pH of our digestive system varies as you descend, as you go from mouth to, you know, to throat and stomach.

And you said that most of the microbiota are in the distal colon. Are there distinct forms of microbiota all along the length of the digestive tract and within these other interfaces with the outside world? Totally, yeah. So it starts, like, with our teeth and in our mouth and saliva, there's an oral microbiota.

These microbial species are very different than the ones you find in the digestive tract. They're usually, you know, built to deal with oxygen very well. They're, you know, in an area that is exposed to a lot of oxygen. They, of course, see different nutrients than, for instance, a colonic bacteria would see.

And they grow quite often in mats that live, you know, on teeth. So they're very structured in terms of, and not moving around a lot. So they're very fairly stationary. As you move down the digestive tract, there are microbes in our esophagus and our stomach.

But those are, you know, those communities are not very dense and actually not very well studied. We know of a very, you know, there's a very famous stomach bacteria known as Helicobacter pylori, which can cause stomach ulcers and cause gastric cancer in some, you know, less frequent situations. But, you know, this is a very different set of microbes. They have to be adapted to a different environment in the stomach, especially an incredibly acidic environment, but also very different in terms of their ability to interact with other microbes just because the communities are less dense.

They're less dynamic. There's less nutrients that stay there and passage through the community. So a lot of times those communities are reliant upon nutrients derived from the host as opposed to nutrients derived from our diet. As you move down out of the stomach into the small intestine, you start to see these communities, which are the ones that are becoming more well studied.

Small intestine is still a bit of a black box just because it's hard to access. And so there's some really cool technologies out there for using, for instance, capsules to do sampling as the capsule passes through the digestive tract so that we have a better idea of what's going on in the small intestine. And then you get to the colon. And this is the community that's just so incredibly, you know, densely packed, doing a ton of, there's a ton of metabolic activity happening there and a bunch of interaction with the host.

And that's the study, that's the community that's really the best studied. Part of the reason for that is because stool is so easy to obtain compared to, for instance, something in the stomach or small intestine. And that stool is fairly representative. We know from studies that have been done using colonoscopies and so forth, stool is fairly representative of what's happening in the colon.

So, again, super exciting community, but also the best study just because it's the easiest to access in a lower digestive tract. Very interesting. I imagine these microbiota have to get in there at some point. Are microbiota seen in newborns?

In other words, where do they come from? And dare I ask, what direction do they enter the body? Or is it from multiple directions? Yeah, great question.

So, you know, one of the burning questions we can come back to at the end of this is where does our microbiota come from? Because it is this kind of, you know, existential question in the field, like where is this community assembling from? And the reason that it's such an interesting question is that, you know, a fetus, when it's in the womb, that's actually a sterile environment. There have been some studies that have looked at whether there are microbes in the womb and microbes colonizing the fetus at that point.

There's some debate about this, but overall, it looks like that's not a big part of the equation of microbial colonization. And so each time an infant is born, it's this new ecosystem. It's like an island rising up out of the ocean that has no species on it. And suddenly there's this like land rush for, you know, this open territory.

And so, you know, we know that infants go through this really complex process of microbiota assembly over the first days, weeks, months, years of life. And then, you know, you get into switching to solid food, two to three years of age. There's some changes in childhood, adolescence, working into adulthood. But that first, you know, zero to one year is a super dynamic time with really kind of stereotypical developmental changes in the gut microbiota that appear to have the possibility of going wrong and causing problems for infants in some instances.

But, you know, if you step away from that extreme side of things going wrong, there also are a lot of different trajectories that developmental process can take because our microbiota is so malleable and so plastic. And those trajectories can be affected by all sorts of factors in early life. So an example is whether an infant is born by C-section or born vaginally. We know from beautiful work that's been done in the field that infants that are born by C-section actually have a gut microbiota that looks more like human skin than it does like either the birth canal, the vagina microbiota, or the mother's stool microbiota.

Babies that are born through the birth canal have initial colonization of vaginal microbes and of stool microbes from their mother. And so just these first days, whether you're born by C-section or through natural childbirth, your gut microbiota looks very different. And then compound on top of that, whether you're breastfed or formula fed, whether your family has a pet or doesn't have a pet, whether you're exposed to antibiotics, there are all these factors that really can change that developmental process and really change your microbial identity eventually in life. The reason that this is, that the field is paying really close attention to this and studying this right now is because we know from animal studies that depending upon the microbes that you get early in life, you can send the immune system or metabolism of an organism or other parts of their biology in totally different developmental trajectories.

So what microbes you're colonized with early in life can really change your biology. We can come back to that later. But getting back to that original question of where your microbes come from, you'd think because you're born through your mother's birth canal or exposed to her skin microbes that a lot of your microbes would come from your mother. But it actually turns out that we can certainly detect that signal.

We certainly see maternal microbes in the infant, but there are a lot of microbes that are coming from other places, surfaces, other people, perhaps other caregivers, but perhaps strangers as well. So we acquire our microbes from a variety of sources. The first ones are from our mom or from our caregivers from the hospital, but then we add to that tremendously over the first year or so of life. You even said pets.

So if there's a dog in the home or a parakeet in the home, that clearly they have a microbiome also and potentially the child is deriving microbiota species from those pets. Exactly. Yeah. And so the best studies that have been done have just looked at pets in the household as a factor and whether that changes the group of infants that have a pet to look slightly different than the group of infants that don't have a pet.

And the question is, what is the pet doing to change those microbes? And some of it is probably actually contributing to direct members of the microbiota. Actually, I have a dog. That dog occasionally will lick my mouth without me paying attention, and that's probably introducing microbes.

We also know that pets are down in the dirt. They're outside. They're being exposed to a lot of environmental microbes. And so just pets serving as a conduit for a bunch of microbes that we wouldn't otherwise come in contact with is a possibility as well.

We will return to Petson in particular, your dog. An amazing dog, by the way. I met your dog just the other day, and I had to force myself. I had to pry myself away from the Havanese, right?

What was your dog's name? Louis. Louis Pasteur. Louis Pasteur.

How appropriate. Amazing dog. What a personality on the dog. The issue that I think a lot of people are probably wondering is, what is a healthy microbiome?

What is it supporting? We hear that you need a healthy microbiome to support the immune system or metabolism or even the gut-brain axis. How do we define a healthy versus an unhealthy microbiome? I encounter in the literature, but given that there's so many species of microbiota, and given that we probably each have a signature pattern of microbiota, how do we define healthy versus unhealthy microbiota?

Is there a test for this? Later, we'll talk about technologies for testing microbiota. There are a lot of companies now. A lot of people sending stool samples in the mail.

Never look at the postal service the same way again, but it's out there, and it's getting analyzed. So how should I think about this? I can think about things like heart rate, heart rate variability, BMI, all sorts of metrics of health. How should I think about the microbiota?

How do I know if my microbiome is healthy or unhealthy? Yeah, it's a million-dollar question right now in the field, and there's a lot of different ways of thinking about that, and I can talk about some of those. But I would say that there are sessions at conferences. There are review articles being commissioned.

There are all sorts of thought pieces about this right now, like what is a healthy microbiota? What are the features that define it? And I think before diving into this, the important thing to realize is it's a complex topic. Context matters a lot.

What's healthy for one person or one population may not be healthy for another person or population, and the microbiota is malleable. It's plastic. It changes our human biology, which I think is how we think about health bite off and BMI and longevity, reproductive success, however you want to define it. But it certainly can accommodate a variety of configurations of gut microbiota, and it's really hard to untangle all of the different factors of what could be very healthy versus a little bit less healthy.

So I will say that there's no single answer to this, but there's some really important considerations. And perhaps the best way to start talking about this is to go back to the inception of the Human Microbiome Project, which was this program that NIH started. They invested a lot of money in 2008-2009 for really propelling the field of gut microbiome research. It was becoming evident at that point that this was not just a curiosity of human biology, that it was probably really important for our health.

And they have this wonderful sequencing technology from the Human Genome Sequencing Project. And with the Human Genome Complete at that point, they started turning that technology to sequencing our gut microbes. And it's important to contextualize the amount of information that they're trying to document. The collective genome of our gut microbes is on the order of 100 to 500 times larger than our human genome.

So it's just... in terms of the number of genes so it's just this vast number of genes and then if you start getting into some of the fine variation it's you know scales by 10 to 100 fold so really a huge amount of information they're trying to document and and uh and so it's a oh it was a wonderful investment and it continues to pay dividends to this day um but one of their goals of that project was to try to define what a healthy microbiome is versus a disease microbiome in different contexts and so they started um enrolling a bunch of healthy people and a bunch of people with for instance inflammatory bowel disease and other diseases um and the idea was let's let's document those microbiomes what microbes are there what genes are there and then we can start to get a sense of what are the commonalities of the healthy people and and what you know how can that go wrong in these different disease states and um you know they there were some answers from that but you um through those studies we really started to get the image that there is this tremendous individuality in the gut microbiome and um and so it's really hard to um start drawing um you know conclusions after initial pass of that project of what is a healthy microbiome but the other thing that we started to realize at the same time there were studies going on documenting the gut microbiome of traditional populations of humans hunter-gatherers uh rural agricultural populations and um those studies were really mind-blowing from the perspective of you know all these people are healthy they're living very different lifestyles and their microbiome doesn't look anything like a healthy american microbiome so does that mean that the healthy american microbiome is healthy but only in the context of living in the united states and consuming what's consumed here um or is it that there is a superior microbiome signature somewhere in our history or currently in the world yeah you know i think that's that's kind of a big question right now i think you know um there's a great quote from that says nothing in biology makes sense except in the light of evolution and you know that these traditional populations are all modern people um living on the planet now but their lifestyle does represent um uh you know the closest approximation to how our ancestors um early humans lived and so those microbiomes and now we know from sequencing of paleo feces the microbiome of these traditional populations is representative more representative of the microbiome that we evolved with that that potentially shaped our human genome and so 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 and there probably are elements of that that are true um but another possibility is that this is a microbiome that's gone off the rails that it is um you know deteriorating in the face of antibiotic use and um all the problems associated with an industrialized diet western diet um and that even though the human microbiome um project documented the microbiome of healthy people healthy americans that what they really may have been documenting there is a perturbed microbiota that's really predisposing people to a variety of inflammatory and metabolic diseases it reminds me of the um as a neurobiologist i was weaned in the landscape of so-called critical periods where early life environment uh very strongly shapes the brain and so many studies were done on animals raised in traditional cages with a water bottle and some food maybe a few other animals of the same species and then people came along and said wait normally these species in the wild would have things like things to climb over and things to go through and you provide those very basic elements and all of a sudden the architecture of neural circuits looks very different and you realize that you were studying in a deprived condition um and earlier you actually referred to if i understood correctly to critical periods for gut microbiome development um is it fair to say that there are critical periods meaning if my let's say my let's aim at me if my if my gut microbiome was um dysbiotic it was off um early in life can i rescue that through proper conditions and exercise or is there some sort of um fixed pattern that's gonna be hard for me to escape from yeah the there's a big field that's emerging now that um you know we refer to as kind of reprogramming the gut microbiome and you know i think if we want to conceptualize humans as this aggregate human microbial biology um you know most people have heard of crispr and the ability to potentially change our human genome in ways that correct um genetic problems um that's a wonderful technology um and has kind of put on the table you know genetic engineering for curing disease but it's much easier to change gut microbes for a problem just because that community is is malleable um the issue that i think we're seeing in the field is that uh microbiomes quite often whether they're diseased or healthy exist in stable states they kind of tend towards this um well that has gravity to it in a way biological gravity where um it's really hard to dislodge that community from that state so even individuals for instance that get antibiotics um you know you take oral antibiotics the community takes this huge hit we know that a bunch of microbes die the composition changes and you know that represents a period of vulnerability where pathogens can come in and take over and cause disease but if that doesn't happen the microbiota kind of works its way back to something that is not exactly like but similar to the pre-antibiotic treatment uh we know with dietary perturbations um quite often you'll see a really rapid change to the gut microbiome and then this it's almost like a memory where it snaps back to this something that's very similar to the original state even though the diet remains different and so there's this incredible what we refer to as resilience of the gut microbiome and resistance to change or at least resistance to establishing a new stable state so that doesn't mean it's hopeless to change an unhealthy microbiome to a healthy microbiome but it does mean that we need to think carefully about um you know restructuring these communities in ways where we can achieve a new stable state that will resist the microbial community getting pulled back to that original state and you know one of the really kind of simplest and nicest examples of this is an experiment that we performed uh with with mice where we you know we're feeding mice a normal mouse diet um a lot of nutrients there for the gut microbiota things like dietary fiber and um we switch those mice half the mice to a low fiber diet and we're basically asking the question that you know if you switch to kind of a western like diet a low fiber higher fat diet what happens to the gut microbiota and we saw the microbiota change it lost diversity it was very similar to what we see in um in the difference between industrialized and traditional populations but when we brought back a healthy diet a lot of the microbes returned you know it's fairly you know there was this kind of memory where it went back to very similar to its original state the difference is that when we put the mice on a low fiber high fat diet and then kept them on that for multiple generations um we saw this progressive deterioration over the course of generations whereby the fourth generation the gut microbiome was a you know a fraction of what it originally was let's say 30% of the species only remained um 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 so in that case it's a situation where a new stable state has been achieved um in that case it's probably because those mice don't actually have access to the microbes they've lost and we actually know that we did a control experiment of mice on a high fiber diet for four generations they maintain all their microbes if we take those fourth generation mice with all the diversity and do 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 it was um you know so your question of like how do we establish new stable states how do we get back to a healthy microbiota if we have taken a lot of antibiotics or have a deteriorated microbiota it's probably a combination of having access to the right microbes and we can talk about what that access looks like it may look like therapeutics in the future there are a lot of companies working on creating cocktails and healthy microbes but it'll be a combination of access to the right microbes and um nourishing those microbes with the proper diet also reminds me of something that i was told early in my training which was that uh it takes a long time for a trait to evolve but not a long time for traits to devolve exactly which generally um is true of a human behavior too although um it depends we all do better nonetheless so i have a puzzle or a bit of a conundrum um around this notion of species of microbiota so if the if the ph if the acidity is differs along the digestive tract but it's more or less fixed for a given location right unless something's really off the ph of the stomach is within a particular range and the intestine and so forth and certain microbiota thrive in a given station a given location along the digestive tract and the ph is sort of fixed um more or less i'm trying to figure out what what is allowing certain microbiota to stay in a given location why don't they migrate up or down so are they ph sensitive and that's what they're selecting for along with the tract and um i'm also trying to figure out how these changes in food so robustly change the microbiome it's the way you describe it almost makes it sound like food is the variable that's going to dictate the quality of the microbiome although i'm sure there are other factors as well and then in the back of my mind i don't know that i want to ask this question but i really want to ask this question which is where are they in there exactly and why don't they all get flushed out right um if that 30 percent of fecal matter is um microbiota um then where are they living are they in are they along the the lining and the little microvilli of the intestine and what are they attaching to and interacting with and we know there are neurons in there um especially within the stomach there's a lot of work now being done on the gut neurons and how they signal to the brain and so forth but who are they talking to in terms of the the host cells and um because if it's just from food i imagine that they're in there having a good time or not and then some are getting flushed out or not but how do they actually stay in there who are they attaching to what are they talking about what are they doing for fun and so forth yeah yeah super super interesting so um i'll come back to the attachment question and kind of like why they don't get washed out because it's a super fascinating question and um you know i think your initial point of like the the kind of regional differences in what's happening in terms of physiology biochemistry along the length of the gut is really interesting there certainly is a ph gradient along the length of the gut there is um actually bicarbonate that's secreted into the small intestine to try to neutralize stomach acid there also is bile that's secreted um that creates a different chemical environment and they're bile loving bacteria that kind of live in that region of the gut um and then you know there there is a nutrient gradient just because as food leaves the stomach it um you know a lot of the simple nutrients are absorbed and so you might see microbes in the small intestine for instance that are better at consuming simple sugars but you won't find many microbes in the colon like that because all the simple sugars have been depleted at that point um and then the immune system is a big factor as well and the immune system is incredibly active in the small intestine um the small intestine is this really interesting challenge for the host because it's a tissue that's been you know its purpose is mainly absorptive and so there has to be flow of um a lot of things you know a lot of nutrients from the luminal contents into host cells and so that means the barrier can't be as fortified and so the immune system is incredibly active in the small intestine to make sure the microbes aren't getting so close and if they are getting close there's a response to them to put them back in the right location um so there's you know and then you know along this whole kind of architecture of the gut there's the longitudinal gradients um things like like ph and so forth and i should say that you know ph starts to drop again in the colon because a lot of those microbes are fermenting things and producing acids and so you actually end up with uh you know the ph starting to drop not as low as the stomach but starting to drop again if there's a lot of fermentation happening in the colon in addition you also have a gradient from the host surface epithelium out to the middle of the gut and that is likely the key for what is retained in the gut and how the community isn't washed out so lining the gut we have epithelial cells in the small intestine they're largely absorptive um in the colon there's a lot of mucus production and we also see this in the small intestine and this mucus lining is this um you know substance that we secrete largely made of carbohydrate actually and the purpose of that is to keep microbes in the right spot and to allow nutrients and water to be absorbed in the small intestine and large intestine so it's this meshwork that is supposed to keep out large things like bacteria and small things like like nutrients um that mucus layer is um it turns over more slowly than the luminal contents passing by and so um if a microbe learns to hold on to that mucus layer it can actually resist the flow of the the contents of the gut and so there's a many microbes in the gut that are not just good at attaching to mucus but also good at nibbling on it at eating it and you know there are these bacteria like acromansia mucinifla mucus loving it's um one of its main things it does is actually eat mucus in the gut that's its lifestyle and and so there's you know an incredible um gradient of of activity from the host tissue working your way out to the middle of the gut what's amazing is some microbes actually do penetrate past the mucus and there are these invaginations in the intestine known as crypts actually where the stem cells live that produce the epithelium and there are microbial communities that can form in those crypts and we don't know completely what their function is but we've done some studies that appear to indicate that if you can localize to a crypt you've hit the jackpot as a microbe for being able to maintain dominance in the gut so if you sit in the crypt and something similar to you another microbe that's similar to you comes into the gut you can actually exclude that microbe and the thinking is that it can't find a spot to resist being washed out of the gut so there probably are these little niches close to host tissue in the mucus that are absolutely essential for um for resisting getting washed out with the with the flow of all the contents incredible that raises a question about two things that are reasonably popular one is this notion of cleanses um from either direction people consume things by mouth to try and cleanse their digestive tract there's a long history of this um i'm not recommending this there are differing opinions on whether or not this is good or bad and the other is um fasting or time-restricted feeding uh the reason uh i ask about time-restricted feeding is my understanding is that after a prolonged period of fasting there's some um autoabsorption or um digestion of one's own uh digestive tract that then gets renewed in other words you're testing the stomach start eating its own lining to some extent in the absence of food so what do we know about cleanses oh and i suppose there's cleanses from the other direction too right which are less popular but um i've never run the statistics but i um but certainly exist out there uh what's the idea about cleanses and fasting as it relates to the health or the dysbiosis of the microbiota yeah you know there hasn't been a lot of high quality science in this area and so it's really hard to conclude whether these are good for health or bad for health you know i think the the fasting you know we're in a really interesting situation in the industrialized world because we have so many problems associated with our digestive tract and that probably has to do with our highly processed diet and perhaps having a microbiota that's fairly perturbed as well and so you know um whether doing things like this are good or bad um it's really hard to define because we may be starting off in a fairly bad state anyway there's so many diseases that we're dealing with metabolic syndrome inflammatory bowel disease that just put a massive portion of the population in a very different category than people that are thinking about how do i maintain health how do i live a long life um from starting off in what we consider a fairly healthy state and so things like you know fasting um and a lot of other therapies that have been developed in the field um you know i think ketogenic diet may be kind of in this category as well there can be tremendous benefits in terms of um their impact in the context of metabolic syndrome and for people that are battling um you know eating a continual bad diet or something like that so and adherence i think one of the one reasons for the popularity of intermittent fasting um time-restricted feeding uh and sort of what they call them now um exclusion diets where you entirely exclude meat or you entirely exclude plants or whatever it is that adherence is sometimes easier in the all or none um as normal as we think of as a go no-go circuitry it's harder to make uh decisions nuanced decisions often about food than it is to just eliminate entire categories of food not eating for many people yeah it's easier than eating smaller portions yeah um yeah yeah and some of it i think is neurobiological and psychological absolutely and we've had you know gastroenterology fellows in our lab that come in and we kind of you know i think that to kind of slice through the nuance of all this there's a very simple recipe and really well accepted um kind of broad definition of what a healthy diet is you know kind of the mediterranean diet plant-based diet um is you know there's just a ton of data that particularly people of european ancestry but there's a you know a pretty broad acceptance that if you eat mostly plants for most people that's going to be very healthy to the point where um you know a wonderful colleague of ours christopher gardner who studied diet his whole life i'm trying to establish what a healthy diet is and people was giving advice i'm giving advice to a dietitian who was trying to get all the rules of like what she should be recommending to people that she deals with that are interested in a healthy diet and she said so number one i'm going to say plant-based fiber is probably super important and that should be you know very high on the list and she goes on to number two and he said stop he said if people do number one well you don't need to know any other rules i mean it's basically like if you can have a high fiber plant-based diet um for most people at least you know talking about the bucket of people that are already in a healthy state you don't really need to think about other things because you can't eat too much meat you can't eat too many sweets you've already eaten a huge amount of plant-based fiber your gut is full you're not going to be hungry um and it kind of takes care of worrying about what should i eat or what should i just eat a ton of whole plant you know whole grains legumes um vegetables uh fruit that's that's high fiber completely exclude meat and fish in there and he was saying like you know people can add their own spins on this but i think that the the main rule is just start off with you know it kind of gets back to michael pollin's mantra you know um eat food not too much mostly plants you know i think if you stick with kind of these simple rules and don't overthink like should i have this you know can i eat eggs can i eat you know just kind of stick to these simple rules it makes it very approachable but i agree like so these gastroenterology fellows we've had in our lab say that they it's really hard for you we kind of say them why won't you give this dietary advice it's really well known and they just said well it's really hard to get people to change their diet unless you're doing either a go no go sort of thing like or eliminating something so you know carrots are giving you problems don't eat carrots and that's a very simple easy instruction to follow but um doesn't really deal with the root problem of why can't you eat carrots because you should be able to eat carrots most people can eat carrots and um and so i so i think that you know there we um yeah we when we're thinking about things like um fasting and you know all these different dietary regimes and cleanses that people do um we have to step back for a moment and say okay well what are really the the big high level rules that we should take home and then if you are experiencing problems and you want to think about how to deal with them it's good to go to an evidence-based method where there's actually data to back it up the you know the data in the field really shows that with like fasting particularly if you go to like animals that hibernate or things like that where there's really extended fast you actually have a microbiota come up that's that blooms in the absence of food coming in through diet that's really good at eating mucus so you have um you know bacteria that's that specialize in eating nutrients derived from the host because there's no other nutrients to live on now whether this is good or bad we don't know but it it seems like um the you know consumption of mucus in excess is a problem from the standpoint of microbes getting too close to host tissue and inciting inflammation which is what we see in animal models when we deprive of dietary fiber we see these mucus utilizers become abundant and inflammatory markers start to come on so so fasting short term might be fine probably um you know there's definitely benefits that are seen metabolically um in terms of what it means for long-term health from the standpoint of the gut microbiota i would say we don't have the answer to that yet in terms of the you know the cleanses and the flushes and all this uh personally i think it's a terrible idea i mean we know that like if um you know studies that are being done now to reprogram the gut microbiota to 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 then the fleshing everything out is great um otherwise what is happening is you're kind of leaving rebuilding of the community to chance like what is it and so um you know what microbes are going to colonize who's going to take up space after you do this flush or cleanse and um you know that i think it's a little bit like playing russian roulette you may end up with a good microbial community in there afterwards you may not um you certainly want to pay close attention to what you're eating while you're doing the reconstitution of the community after you do something like that yeah uh thank you for that i know a lot of people are interested in these kinds of elimination diets and intermittent fasting um time-restricted feeding seems to be getting some traction in part because at some level we are all doing this when we sleep most of us aren't eating when we sleep anyway and um adjusting the numbers seems um more accessible for a lot of people we have a lot of colleagues at stanford who i know happen to follow that regimen um or a time-restricted feeding regimen but um also who's all the most traditional meal spacing as well of course the one of the things that i wonder about as we talk about i'm primarily plant-based with some you know what you said the pollen thing was it was uh mostly plants um and then maybe some meat but not too much yeah not too much eat food mostly plants not too much or sorry eat food not too much mostly got it um you know and uh just i i hear this again again i know um there are a number of people who do seem to do well on a lower carbohydrate um you know even some people report feeling much better on a like really strictly almost meat organ only diet and the only reason i raise this is not i don't participate in i'm one of those omnivores that out there um i do eat some meat um and i do eat plants as well but the reason i raised this is earlier you were talking about um communities that may have microbiota that are um healthier than ours or at least different than ours and there are communities in the world that uh that subsist largely on animal products or for which unprocessed animal products are considered the richest nutrient foods in those communities protein is very scarce and uh ancestrally protein was more scarce so eggs and meat and things of that sort so could there be a genetic component in other words if we fast forward 10 years and we actually can make sense of all this human genome stuff are we going to find that someone who has um scandinavian uh roots or somebody who has south american roots or somebody descended from a different tribe will do better on one particular diet versus another and thereby where i should say and in parallel with that that their gut microbiome will have different signatures that are so your microbiome might thrive on plants and mine might thrive on organ meats and as i say this i'm not a consumer of organ meats i'm just laying this out for sake of example yeah yeah great um so um a few notes uh the first one has to do with the carbohydrates and restriction of carbohydrates and some people feeling healthier when they cut carbohydrates out my guess is this is this is my theory um to be tested um that people feel better cutting carbohydrates out because the diet that we eat in the united states and in industrialized countries the carbohydrates are largely crap they're processed they're like starch simple sugar um it's things that contribute to glycemic index it's it's the sugars that that we eat they make it to our small intestine they get chopped up into simple sugars absorbed into our bloodstream and we have a ton of glucose then coursing through our veins which we know is bad and can lead to things like diabetes um if the carbohydrates that were in our diet were complex carbohydrates dietary fiber and we like to refer to the subset of dietary fiber that the microbiota can actually access as microbiota accessible carbohydrates and the reason that we like that term is it has the word carbohydrate in it and it's to point out that not all carbs are bad it's just there are bad carbs or carbs that are bad if you consume them in too high quantity things like you know table sugar and simple starches but there are good carbs as well and these microbiota accessible carbohydrates are the complex ones that we can't digest and fuel um our gut microbiota our gut microbiota to ferment them and um so the you know i think i think um we probably all would be better off with less of the carbs that were typically served but most of us and probably the vast majority of us would be better off by consuming a lot more carbs that were complex that were microbiota accessible um and i'll come back to why that's important in terms of our biology there's some mechanisms that are known as to why those complex carbohydrates are so important for our health for most of us um i think this aspect of human genetic adaptation to diet is super interesting and then layer on top of that gut microbiota adaptation to diet which is another layer of this that is also fascinating it's very clear that over very short periods of time humans can adapt to differences in their diet lactase persistence is kind of a classic example of this just over the past 10,000 years um humans you know certain groups of humans have adapted to being able to consume dairy by taking this enzyme lactase that normally is just expressed in most of the world's population early in life to be able to metabolize lactose in breast milk um by extending the expression of that throughout life now you can consume milk for your whole life and so that is an example of specific populations of humans um human genome genetically adapting to diet in a very short period of time and this there are other examples of this and undoubtedly this has happened um throughout the world to various aspects of diet so certainly um it's important to remember that there will be um different diets that are better for different groups based on what genes you you harbor and have in your human genome the other aspect on top of that is that um you know there are um good examples of the gut microbiome adapting to cultural differences in diet and the classic example of this is the degradation of seaweed so we know that most americans if you eat sushi and there's nori there and you you eat um some of this the seaweed it has a dietary fiber in it known as porphyrin that porphyrin will shoot through most of us untransformed inert substance you know it'll do other things like retain water and serve as kind of something like cellulose not be um fermented at a high level um if somebody from southeast asia that's always consumed um seaweed and is part of a culture that consumes seaweed eats seaweed they have a gut microbe that can now metabolize porphyrin and so there are these very specific gene transfer events where the genes for breaking down porphyrin have been imported into the microbiome of many people in southeast asia to um you know we can think of it as helping digest porphyrin but it's really just a microbe that's found a niche found a way to make a living in the gut by consuming something that's common in the diet there so there are these different layers there are human genetic adaptations and there are microbiome adaptations that are cultural and and based on people's geographic location um but you know that there's no escaping the fact that for much of human evolution the vast majority of people that are on this planet had ancestors that were hunter-gatherers foraging consuming huge quantities of plant material just because that's that's what was there and so one of the groups that we study the hodza hunter-gatherers in africa um and i should take a moment just to say that you know um our research and research of many people in our field and other fields rely on study of indigenous communities and it's really important to um think of these communities as um you know our equals they're modern people on the planet they have interesting lifestyles that are informative with regard to certain aspects of human biology but in many cases they also are um you know leading a vulnerable existence and so we really take great care in our research program it's important for people to realize that um you know these populations take partner research because they're wonderful research partners and we need to be mindful of kind of thinking about how um yeah both we talk about them and use our data that has been gained through their generous contribution to our research program the hodza hunter-gatherers it's estimated to consume on the order of 100 to 150 grams of dietary fiber per day and that's in stark contrast to the typical american that consumes about 15 grams so somewhere seven to tenfold decrease in the main nutrient that feeds our gut microbiome in the american diet the hodza are um you know one example there are many different foraging populations but the vast majority of these populations consume huge amounts of dietary fiber because plants are the reliable consistent source that you know if you as a hunter-gatherer go on a hunt usually that hunt is unsuccessful you know i think the data that you know one out of 20 to 30 hunts are successful in landing actually big game for the hodza they have you know birds that they shoot and small animals but quite often um day after day they're relying upon uh berries tubers baobab fruit you know they're relying on the plants in their environment and actually if you um you go to the data and look at what their food preferences are their food preferences are actually meat and honey so they don't eat a high fiber diet because they love fiber they eat a high fiber diet because that's what's available and consistent um for them to survive but you know our brains are wired for caloric density and so if you took out a hodza and put them in a restaurant in the united states they would make the same crappy decisions that we make because we you know all want sugar and fat and calories that's how our brain is wired and protein and fat are essential for brain development as far as we know right so it sounds like the hodza i hope i'm pronouncing that correctly oh you said would prefer to eat meat and honey but they do they happen to consume a lot of plant fiber as a consequence of what's available the um one of the questions i have as it relates um to all of this is it sounds to me like there is no question from the pure vegan all the way to the extreme opposite which would be pure meat diet um that avoiding processed foods is a good idea or heavily processed foods in general and i mean not that you know the occasional consumption is um necessarily bad but whether or not one is thinking about one macronutrient profile or another it sounds like consuming processed foods is just bad for the microbiome can we say that categorically for sure yeah whether you know so you're low carb person you're zero carb person you're extreme vegan no meat whether or not you're all meat organ meat sounds to me as if uh the number one thing maybe even dare i say above chris's uh uh point about plants i'm not gonna challenge chris gardener on nutrition i would be way outside the lane lines to do that but is that avoiding processed foods yeah is paramount yeah and i think that's completely compatible with what christopher was saying he was saying if you put prioritize getting a huge amount of whole plant-based food with a lot of fiber first you're not going to have room for eating a lot of processed food so so it's kind of the same as avoiding processed food so i think that those are exactly the same rule and i think that you're exactly right we can break down you know there's a lot of data of why different components of processed food are so bad for us and so bad for our microbiome and i can talk about a few examples of that but the flip side of this is this mechanism of you know and again thinking about the spectrum of a plant-based diet versus a meat-based diet um you know there's a lot of data to tell us that a meat or ketogenic or high fat diet may have big benefits in terms of short-term metabolic health that's typically how people think about that diet um there's also a lot of heart disease that's linked with that as well there's good literature for that which is something to for people to look at and be aware of the plant-based diet if you're eating a bunch of complex um you know fibers that feed your gut microbiota your gut microbiota produces these substances called short-chain fatty acids things like butyrate and it's known that these short-chain fatty acids play really essential components both in terms of fueling colonocytes enforcing the barrier keeping inflammation low regulating the immune system regulating metabolism and so you know a lot of people think of dietary fiber as this inert substance it passes through makes us feel full maybe for a little bit but we get hungry afterwards right away if you're eating a lot of fiber that's feeding your gut microbiota your gut microbiota is just producing this vast array of fermentation end products that then get absorbed into our bloodstream and have all of these tremendous cascading effects that appear to be largely beneficial on our biology and so to think about that paradigm of simple carbs versus complex carbs in the case of simple carbs you end up with high blood sugar you know something that will spike your insulin and you know have all kinds of weird metabolic effects in the case of complex carbohydrates you'll end up with very low blood sugar because most of those have low glycemic index and a bunch of short-chain fatty acids that are having regulatory rules so so just to round out that topic i think there is a reason to think that you know maybe not appropriate for absolutely everyone out there but i think the vast majority of people particularly given the statistics of what we know people eat in the united states and industrialized countries most people would reap tremendous health benefits from eating more whole plant-based dietary fiber now process foods i think is this other dimension we have all of these weird chemicals artificial sweeteners weird fats um you know a lot of refined simple nutrients the simple nutrients we've talked about But we know that, for instance, artificial sweeteners can have a massive negative impact on the gut microbiome and can lead us towards metabolic syndrome. Actually, there's been beautiful work out of the Weizmann Institute on this. And then emulsifiers, these compounds that are put in processed foods to help them maintain shelf stability so things don't separate.

And so, you know, all the moisture content is retained appropriately. Many of these are known to disrupt the mucus layer. And as soon as you start disrupting that barrier, that can lead you in the direction of inflammation. And in animal models, we know that can lead towards metabolic syndrome as well.

So there's components of processed food that are, when studied in isolation, known to have a direct negative impact on gut biology and the microbiota. The mention of artificial sweeteners is interesting. I confess it's a third rail on social media. Talking about artificial sweeteners, there are two camps, it seems, or at least two camps.

One that, say, artificial sweeteners are not detrimental at all. Another that says they're very detrimental, mainly based on the mouse studies. And then there are people in the middle that are, I put myself in that category. I drink the occasional diet soda.

I don't consume them in large volume. But I'm sort of in the middle there. However, and so I just throw that out there because I know immediately people are jumping on that. But I will just mention there's some recent data out of Diego Bordes' lab at Duke University that the neurons that live in the gut mucosa, these neural pod cells, can actually distinguish between artificial and true sugar versus artificial sweeteners.

They send different patterns of neural signals up to the brain. And the brain circuitry seems strongly impacted. So I think as the data emerge, we're hearing more and more of these artificial sweeteners either are problematic or at least are signaling different events in the gut. I do want to make sure that we distinguish artificial sweeteners from non-caloric plant-based sweeteners.

And this is based on the mistake that I've made over and over again on the podcast, where I'll just kind of lump artificial sweeteners into one big category. And then I'll mention stevia. So what about plant-based sweeteners that are not artificial? They weren't manufactured in a laboratory like saccharin or sucralose or aspartame.

Do we know anything about plant-based non-caloric sweeteners or low-caloric sweeteners? Very little. You know, a lot of those have a lot more bang for the buck. They're incredibly sweet.

So it takes a really small amount for them to trigger a huge amount of sweetness. And so it's depending upon the mechanism of action by which these sweeteners that are not sugar are impacting our biology, it may be that those are actually, you know, less negative or more healthy than the ones that are artificial, just because it requires less of them in the food for us to perceive that sweet taste. It may also be that because they're, you know, I don't think that everything that's natural is better necessarily than things that are artificial. But it may be that because of, you know, kind of evolutionary exposure to these compounds in our diet.

Historically, there are, I think, traditional populations that use these, for instance, to sweeten, you know, sweeten different foods that our bodies just kind of know how to deal with those compounds better than the ones that are synthetic. But I think that, you know, the studies still need to be done. Do you actively avoid artificial sweeteners, sucralose, aspartame, saccharin? You personally?

Yeah, you know, so I do. I avoid them, but I'm not, you know, so I work closely with my wife, Erica, as you know, we do, we run the lab together and we, you know, wrote this book, The Good Gut, where we kind of document our journey in changing our lifestyle, dietary habits, choices we make based on the research as we've gotten to know it and got microbiota over the past 15 years. And, you know, I think that one of the lessons that we've learned is that just doing things in moderation makes it a lot easier and doing things slowly makes it a lot easier. And so there are very few rules that I have that are hard and fast.

I'm a pretty flexible eater. I don't believe that having an artificial, you know, having a Diet Coke will, you know, somehow cascade into some terrible disease or something like that. I try to avoid them. I don't really like the flavor of them.

I'm super sensitive to the nuances of the flavor, even with the, you know, stevia and magra sites from monk fruit and stuff like that. I just really, the off flavors are really hard for me to deal with. But so, but I also, in this journey of changing our diet, like when we started off in microbiome research, I was in the habit of, you know, in the afternoons having a sweet, a muffin or a cookie or something like that. And when we started to realize that, you know, we should be eating less sweets and eating more dietary fiber, this was an incredibly difficult change for me to make.

I was just wired to kind of crave, you know, this classic scientist, scientists love this pastry in the afternoon coffee. In the old days, it used to be a cigarette too, right? When I started my training, a lot of people still smoke and it was only during my postdoctoral training that they eliminate smoking on campuses and productivity took a trough for a while until these people developed other tools to focus their attention. Exactly, exactly.

So there is this kind of like need. And then once you have an ingrained behavior and maybe things that are addictive, it becomes incredibly difficult to break that habit. And, and so I would say, you know, gradually over the course of like, you know, five or more years, we have, you know, migrated our diet away from sweet foods to things that are less sweet. And it's, you know, it's been a journey.

It's been a slow process, but we've gotten to the point now where we've just retrained our palates. And it's amazing how this happens now, where I'll have something that, you know, is something that I would have used to have like daily and it's unpalatable. I like, I just can't deal with the sweetness of it. And, and so I avoid, I certainly avoid artificial sweeteners, but I also avoid just sweet things in general that have sugar in them just because they now, they, you know, it was originally I was making, I was trying to be disciplined and trying to change my diet, but now they just don't taste good to me.

Likewise, I completely lost my appetite for sugar at the turn of the last year. And I don't know how to explain it, but the way I, you know, I don't have a mechanistic explanation. I just, I say, I like sweet people. I don't like sweet food anymore.

I just don't, I have not lost my appetite for fatty foods. I love cheese and a certain, certain meats for me. I blame my Argentine lineage is, uh, I gravitate towards it. But in any case, um, avoiding processed foods, probably avoiding sugars, emulsifiers, these kinds of things.

And for people listening or watching, we're not setting up strict guidelines. We're just, um, bouncing around the, uh, the carnival that is the microbiome and nutrition because I think that these, we hear this everywhere, eat this, don't eat that, or this is best for microbiome or worse for microbiome, but I'm hearing fiber again and again. So we're going to come back to fiber, but I want to make sure that we, um, close the hatch on this issue of fasting and cleansing. It sounds like I don't have to try and flush all the current microbiota out of there first.

Is that correct? Yeah, you know, it's a very good question. And I don't mean to suggest that those things are known to be terrible, or I would just say like this, you know, the studies haven't been done. And to me, wiping out this microbial community, um, unless it's done with like some sort of, unless it's done in an informed way and we don't really have the information for how that would be done.

It just seems like, um, you know, playing the lottery a little bit. And so, so I think, you know, I don't want to say that those, it may be that when the study is done, those are shown to be amazing, but I just don't think we have the data to know that yet. So it's somewhat of an arbitrary thing. Um, if somebody, you know, out there, it feels way better when they do this and are not experiencing problems with it, then maybe it's the right thing for them.

But I certainly can't, can't say that it's something great to do. I can't imagine a future where, um, as the microbiome gets incorporated into this, you know, emerging paradigm of precision health, you go into a clinic, somebody types your microbiome and says, oh, there's this huge, massive misconfiguration. You have all these, um, engrafted bacteria that live, that are residents in your gut microbiome that are sending out molecules that are not good for your health. It would be good if we do a mass reprogramming of it.

The way that we do that is we flush your gut and we actually give a light antibiotic treatment to try to kill everything that's there. And then we repopulate with this other consortium of microbes that we've studied and know are healthy, know are compatible with your human genome and can be reinforced with a diet that we know is good for you. We'll install those microbes. We'll help you along in the diet to know, so you know how to nourish those microbes.

And that will be the way that we'll reconfigure your gut microbiome. So, you know, I can't imagine a future where that sort of flushing or cleansing is part of something for repopulating the gut. But right now it seems a little half-baked to me. Great.

I'd love to talk about fiber and fermented foods because you and Chris had a really, what I think is a really interesting, exciting paper at the end of last year about comparing, um, the inflammatory markers of people who ate a certain amount of fiber or a certain amount of these fermented foods, this study is amazing for several reasons, but, um, almost as amazing is how diverse the interpretation of the study was in the media. If ever there was a study that was, um, kind of hijacked by different priority schemes out there, um, it's this study. So you performed the study with Chris and your postdocs and graduate students and staff. What are the major conclusions and what sorts of directives, if any, emerge from this study?

And I'll just preface this again by saying, if I wasn't clear, some news report said, ah, this means fiber is not important. And then others said, this means fermented foods and fiber are important. And others said fermented foods are the thing and the only thing it was all over the place. And, um, one of the reasons for doing this podcast at all is so that we can go straight to the people who perform the work and even though I'm not, certainly not an expert in microbiome, give you the opportunity to share with me and me to ask the kinds of questions that have zero agenda.

I do like sauerkraut. I do drink the occasional, uh, uh, kombucha. Um, I do like low sugar, not so sweet forms of fermented foods. So I'd be delighted that fermented foods are good for me, but I have no stake in the fermented food industry.

Yeah, absolutely. Yeah, yeah, great. Um, yeah, wonderful. And an important note there is the one you pointed out that this is an incredible collaboration with Christopher Gardner's lab and, um, you know, a bunch of people, um, Erica Sonnenberg helped lead the study and then, and then tons of, like you were saying, postdoc staff and, um, other people at Stanford and then wonderful participants that, um, were part of the study.

So a huge team effort. Um, let me take, before I dive into that study, let me take a step back because I think the reason that we did this study and kind of, um, Christopher's group and our group has started to, um, pursue this line of, of looking at dietary interventions and how they impact our microbiome, how they impact, um, human biology goes back to this, um, kind of epiphany that we had while studying the gut microbiome. Because I think when we started studying it at Stanford, we were thinking about it as this kind of newly appreciated aspect of our biology, almost like, um, finding an organ that we didn't know was there and starting to think about like all the drug targets that were there. Can we go in with small molecule drugs and think of ways to manipulate this community to ameliorate disease?

And, um, this is largely the mindset of Western medicine and largely born out of the era of infectious disease. Um, you wait for an infection to start a bacterial infection, you treat with antibiotics and, you know, that's the way medicine is practiced. And that's become less successful over time as we moved into this era of inflammatory Western diseases. And, um, you know, with the exception of the current pandemic, that's, you know, sweeping the world, um, you know, largely moved out of the era of infectious diseases, at least infectious bacterial diseases, that this paradigm of waiting for diseases to appear and come into the clinic, um, is not really very effective in the context of inflammatory Western diseases, autoimmune diseases, metabolic syndrome, heart diseases and inflammatory disease, you know, the list goes on and on.

And, um, and so we started to think a lot about like, how can we get out in front of this? How can we think about like preventative ways of dealing with this crisis of metabolic and inflammatory diseases? And this tremendous, beautiful body of literature started to come forward in the field about 10 years ago that showed that the gut microbiome is absolutely critical to modulating our immune status. So if you change the microbiome, you can fundamentally change how the immune system operates.

And we know that the immune system is at the basis of a lot of these diseases, inflammatory chronic diseases. And so it brought up this possibility that maybe the fact that we're not nourishing this community well enough, maybe the fact that it's deteriorated over time, um, due to all of the things that go along with an industrialized lifestyle, antibiotics and so forth. Um, maybe we have a microbiome right now in the industrialized world that is setting our immune system at a set point, simmering inflammation that's driving us towards these inflammatory diseases. And wouldn't it be wonderful if we could figure out how to, um, uh, use diet specifically, but just kind of learn the rules of how to reconfigure both the composition and function of our gut microbiome so that inflammation was different in our bodies so that each one of us was less likely to go on and develop an inflammatory disease, leading to better, you know, longevity and health, um, over the course of our life.

And, um, so we, we were, you know, setting this in actually in mouse models and realizing that, um, you know, we really needed to start doing human studies. We needed to, um, start studying microbiome in humans. And because we were studying diet, we knew that this was something we could go in and do right away. We didn't have to apply for FDA approval for a drug before we could do a human study.

We could just start doing human dietary interventions, longitudinally monitoring the immune system and the microbiome and starting to put the pieces together of what is it in diet that can change our microbiome in a healthy way, help us to find what a healthy microbiome is and monitor the immune system in great detail. And so there were really two critical components of this. In addition to our microbiome expertise, one was Christopher Gardner's group. Uh, we wanted to do these human studies, but we're absolutely terrified of humans.

We work with mice. Humans are terrifying. Um, in many ways. They house themselves.

You don't have to pay for their housing. That's true. Yeah, sadly, just for that portion of the population, the, um, so, so Christopher's group were, they were our masters of working with human populations. And then the other wonderful thing that we have at Stanford is this human immune monitoring center, um, run by Mark Davis and Holdenmaker.

They started this beautiful center for allowing people to do immunology in humans, critical element, because a lot of the mouse studies don't translate well to humans. So if you can do the studies in humans, uh, similar to how we were thinking about the microbiome, you learn something that you know is relevant to humans. And so having that immune profiling capability where we can monitor, you know, hundreds to thousands of different parameters in the immune system longitudinally in people from a blood draw, and not just know if CRP goes up or if interleukin-6 goes up or down, but to be able to see all these facets of the immune system change in concert as we're changing the microbiome with diet was really a key component of this. And so our flagship study supported by wonderful donors, um, so this actually isn't funded by typical foundations and national institutes of health.

It was funded by, um, philanthropy. We wanted to understand if we put people on a high fiber diet, um, how would that affect their microbiome and immune system? And if we put them on a high fermented food diet, a diet rich in live microbes and all the metabolites that are present from fermentation foods, how would that change microbiome and immune system? Could you give us some examples of what those diets look like?

And were you changing their basal diet or were you just adding things on top of what they were already eating? So, uh, it's hard to change people's diets. It's very hard to trust that they actually do it and they're not sneaking and, uh, totally. Yeah.

And so, so we, um, and you know, we started the center for human microbiome studies at Stanford for doing a lot of these studies and a portion of the studies we do focus on supplements, probiotics, uh, microbes delivered in pill form, prebiotics, which are purified forms of fiber. And in those cases, we actually can have placebo groups, um, because you know, it's, it's more like a drug study and, um, we don't change people's diets so we can just administer this on top of what they're doing. So in a way they're a lot more controlled, but it's not food. When you start doing food studies, you can't do a placebo group because people know what they're eating.

And the other problem is that, um, it's really hard to just change one thing because as soon as you start adding something, people usually eliminate something else. So the idea was to basically give these people simple instructions for, in the case of the high fiber diet, just increasing plant-based fiber. So can you eat more whole grains, more legumes, more vegetables, nuts, get the fiber up in the range of, you know, from 15 to 20 grams per day up to over 40 grams per day. So can you kind of double or more the amount of fiber that you eat per day, knowing that that would have a tremendous impact on a lot of other facets of their diet.

They eat less, um, uh, meat, animal-based protein, um, less animal-based fats as a product of this. Um, you know, I will say that getting back to the, you know, Christopher's rule for a healthy diet, um, a lot of the macronutrient changes that we saw in their diet were consistent with, um, healthy changes in diet, less saturated fat, less animal-based protein, more plant-based protein. So a lot of changes that are known to be beneficial kind of came in concert with just telling people to eat a high fiber diet, high plant-based fiber diet. Um, the people that were eating the high fermented food, uh, diet, um, they were instructed to basically eat, um, you know, foods that you could buy at a grocery store that were naturally fermented and contain live microbes.

And so this, you know, largely consisted of yogurt, uh, kefir, uh, sauerkraut, kimchi, um, you know some fermented vegetables um kind of brine fermented vegetables pickles things like that but but they do you know one of the things that i think is a pitfall in choosing fermented foods is you know you can go down the canned food aisle and there's this huge section of pickles and jars that are canned um those are not fermented foods those are cucumbers that they put in acetic acid and vinegar to reconstitute that fermented flavor but there's no live microbes involved in that and even sauerkrauts in the canned food aisle even if they were naturally fermented quite often they're not quite often they're just brine um in vinegar but even if they are naturally fermented all the microbes are killed prior to canning or during the process of canning and so if you want so what we use for the study and if you want to have live fermented foods that contain microbes you need to buy those out of the um the refrigerated section essentially and i'm really glad you pointed this out because you can find sauerkraut on the non-fermented non-refrigerated shelf that is indeed non-fermented um a lot of fermented foods that are available in the u.s um can be high in sugar um so was there any instruction as to you know getting people to make sure that they were consuming yogurts that weren't loaded with sugar or did you let them just select for the stuff in the cold the cold section that is fermented no it's a super important point we instructed people to eat non-sweetened yogurts um the you know it's i think a huge pitfall in this area is you can have yogurt loaded with bacteria kind of the base of what's healthy and then a ton of like artificial flavoring and sugar loaded on top of that manufacturers put a ton of sugar in after the fact to kind of mask the sour taste of fermented foods which is hard for some people to become accustomed to when we were switching to more fermented foods our daughters were young at that point we would take you know plain yogurt which they didn't like just kind of neat um we would mix in like a little maple syrup or honey um just a little bit and gradually we reduced that over time to the point where um their palate adjusted now they just really like plain um yogurt but it is you know i think getting used to that sour flavor is difficult but people really should try to stay away from those um fermented foods that are loaded with sugar and that's what we instructed people in the study and beer was not included right the number of people had asked when i did a brief thing on social media about the study and hopefully i got it right i think i did um but people just ask about beer i'm not a drinker so um for me beer has no appeal anyway um but uh beer is fermented correct um but were they instructed to avoid beer or to drink beer just to go with their normal dietary habits but that did not count as a fermented food and kombucha was it was and kombucha can have small amounts of alcohol in it um but uh you know um we yeah kombucha actually was one of the major things that people drank during their consumed during the fermented food phase and um that you know the deal with um with uh beer is that there may be beneficial properties of the microbial communities and naturally fermented beer but most of the beer that we buy again is canned and filtered and there's no live microbes there so very different than if you you know siphon it off of your home brew and drink it probably than if you buy it in the store i just i will get to the results of the study in just one moment but i want to say a lot of people shy away from the high quality fermented foods because they can be quite costly um i'll just refer people to a resource in tim ferris's book the four-hour chef he actually gives an excellent recipe for making your own sauerkraut which basically um involves cabbage and water and salt but you have to do it properly because you can grow some um not necessarily a lethal but some somewhat dangerous factory if you don't scrape off the top layer properly but he gives beautiful instructions for how to do this in vats we started doing this at home now actually we got which is ceramic that you can make large amounts of truly fermented sauerkraut just from cabbage water and salt if you're willing to follow the protocol and if you're interested in science that protocol looks a lot like what you'll do for most of your graduate career so maybe some sequencing too so anyway just refer people to a source that's very low cost compared to buying the high quality fermented foods even kombuchas for somebody you know it's like five dollars a bottle or you know only this much and if you consume liquids the way i consume them that's kind of that's uh just the start so um and but you know if you can get your hands on a scoby kombucha is another one that's super simple you can grow your own you can just make your own and it's super easy to do i make it i constantly have a batch of kombucha going at home and it's just you know it's a scoby semiotic community of bacteria yeast that you you know you brew tea you add sugar to it and you put the scoby in and you wait a week or two depending on the temperature and you then you just you know move the scoby over to a new batch and you're all you know what the scoby was in is kombucha it's wonderful i love it i would love it if members of the audience would um start to make their own kombucha i've been having so much fun i don't do it but um you know uh it's done in our home um i don't go anywhere near the food production it's for everyone's benefit um so how much fermented food and then uh were they consuming and because you mentioned the number of grams approximately of fiber and uh but was it in servings ounces um how many times a day early day late day right yeah so um the we had a wonderful dietitian instructing people for this and her name is delia perlman and she really was a key and is the key for many of our studies for getting people to eat differently and um you know the general instructions were for people to eat as much fermented foods as possible more is better and the reason is that with this initial study we really wanted to maximize our chance of seeing a signal if there was something biological going on with the idea that if we you know the dose was excessive and not easily achievable by a lot of people in the end we can go back and say okay this is the point at which we lose the biological signal um but people um during the height of the intervention phase the intervention phase was six weeks um during the height of that we're up over six servings on average per day of fermented food so kind of two servings at each meal and the you know ounces or weight or size it really depended on what the fermented food was and we just told them to stick to what was a recommended dose on the package that they were they were buying you know for kombucha would be like a six to eight ounce glass um sauerkraut like a half cup or something like that and same with yogurt great so what what were the results yeah so the results um astounded us in a way but then thinking more deeply and it'll be evident even after i explained it in the context of this conversation likely why we saw the results we saw um the results were astounding because um our hypothesis going into this was that the high fiber diet was going to give the massive signal we know that this is the big deficiency in the western diet um we uh all the mouse studies have told us that high fiber really leads to a much healthier microbiota can lead to positive changes in the immune system and in fact even when we had a limited you know we had wonderful donor support but still limited amount of money when we started the study um my lab was really very eager to do the high fiber um part of this really well and christopher kind of had to twist our arms to do the fermented food side of it and we thought it was kind of quirky and neat like live microbes should be exciting like let's try it so we put that in and it turns out that we were very thankful that he twisted our arms because it was that um high fermented food arm that really gave us a big signal even though our hypothesis was that the high fiber was going to lead to more short-chain fatty acids produced in the gut more diverse microbiota um less inflammation in the immune system we didn't see that across the cohort we actually saw a very to the dietary fiber and i'll come back to what those responses were the big signal really was in the fermented food group we saw all the things that you would hope to see in a western microbiota and western human we saw this increase in microbiota diversity over the course of the six weeks while they were consuming the fermented foods um and we can't always say that um higher diversity is better when it comes to our microbial communities we know there are cases for instance bacterial vaginosis where higher diversity is actually indicative of a disease state um but we um know in the context of the gut and for people living in the industrialized world higher diversity is generally better um we know that there's a spectrum of diversity people with higher diversity generally are healthier if you can push your diversity higher you're in better shape and so we saw that increase in diversity and then the major question is what happened to the immune system as these people were increasing their gut microbiota diversity through the fermented foods um we so we did the um this massive immune profiling and we see you know a couple dozen immune markers inflammatory markers decrease over the course of the study so we multiple we measure these at multiple time points throughout the course of the study and there's kind of a set wise reduction in things like interleukin 6 and um you know interleukin 12 a variety of kind of famous inflammatory mediators um and then even if you go into the immune cells and you start looking at their signaling cascades we see that those signaling cascades are less activated at the end of the study compared to the beginning of the study indicating an attenuation of inflammation so so kind of exactly what we would hypothesize would lead to less propensity for inflammatory disease over time that's a huge extension of a very short study so the complete protocol i think was 14 to 17 weeks or something like that the actual intervention phase consisted of a four-week ramp and then a six-week maintenance period so the intervention itself was 10 weeks but there were six weeks of really kind of hardcore high levels of fiber or fermented foods yeah and i'm glad you mentioned the ramp because my experience with um fermented foods is that you it can be beneficial to give the system an opportunity to acclimate i mean if you consume a giant bowl of sauerkraut um it's not gonna be the worst day and night of your life but you'll you'll know you did so we'll just leave it at that and so you want to kind of acclimate to it um i'm at the point now where people some people might think this is first after i um exercise i've been sweating a lot i like the saltiness of the i actually drink the uh the liquid that the sauerkraut has been um stewing in and i get i'd like to think that i consume some uh fermentation that way it's salty that's kind of a post-training replenishment but if i had done that um six months ago straight off i think it would have been pretty rough on my system i started taking little bits of it and then adding it each day totally and so both with the fermented foods and the fiber it's well known that this kind of gradual ramping is a really important way of mitigating um bloating and other kind of digestive discomfort that can happen when your microbiome reconfigures and starts fermenting more and changing community members so um you should take that ramp at your own pace if something seems to be going wrong just kind of level off stay there you know we did this in a very delicate way to get people up to the high dose the um brian question just a um a tangent here for a second um that was actually one of the products that we um had people use in the fermented food phase there's actually a product called gut shots which is just the brine from that they've marketed um we actually are now studying it in the lab i just actually before this came from a lab meeting where a gi fellow in my lab is actually putting gut shots sterilized gut microbes or the fermented um fermentation microbes removed or present into mice and looking at changes in their mucosal immune system so we're studying this in detail now because this is it's a rich source of lactate and a bunch of other interesting metabolites i love that my weird behavior is uh inadvertently being studied uh at stanford medicine um i want to mention something about the gut shots um those are sold as a drink those also just for certain listeners different budgets they can be very expensive if you really think about some of them are exceedingly expensive but what i described before with making your own um kombuchas it's not quite brining but the um homemade sauerkraut on protocol is out there as i mentioned in tim's book the four hour chef and you get a lot of the brining from from that an almost endless amount uh a cautionary note i once went into the refrigerator and saw something similar to gut shot it wasn't got shot and i drank the whole 12 ounce bottle and realized that it was 24 servings and that's where i got my initial um experience with what it is to not do a ramp up phase i do not recommend doing that some of these it's very potent it seems and you can consume you know even half an ounce or an ounce yeah they're i mean very potent from the standpoint of fermentation but also very salty so you know there's a lot of effects yeah don't do what i do um at least not at the outset and um uh but so that is a inexperienced warning so they did this as i recall there was a swap condition or there was a halt condition so you did controls right it wasn't just comparing groups you had individuals um who were initially in one group or the other um move to a different group well so we stop and then return yeah we actually just did a stop and follow them during a washout phase and i the ideal situation for um dietary interventions like this are to do um crossover studies as you're suggesting we've um recently completed a ketogenic versus mediterranean diet intervention not yet but christopher's been tweeting a lot of these data and there's a paper in revision right now so if you go to christopher erdner's um twitter feed you'll be able to find him reporting some of the early results of the study give us a snippet of was there a superior just give us a you don't have to tell us which one but um was there a superior condition of either mediterranean versus ketogenic so um so the metabolic effects of these um it's a beautiful study i should let his group comment on that the microbiota data we actually are just generating now so the study that he's his group has put together from this is largely independent of the microbiota data and now we're doing a more in-depth analysis and i'll have more to say about that in the future but we'll return to that but it's a super exciting study because it is one of these where people eat a certain way and what's really beautiful about this is we even got food delivered for part of the um intervention so we had complete control over what they at least had available to eat um and in the second phase they um they um make the food on their own and then we cross over and do the same thing and so that's really like the um if you have a good enough budget the right way to do a study like this for this we didn't have the um the time or money to do a crossover but we did do a washout phase where people we didn't make them stop eating whatever if they were enjoying it but we monitored and there was some recidivism where there was a decrease of fiber from into food and we could see for instance diversity start to plateau in reverse in many of these people so there does appear to be like a need for maintenance of the intervention to maintain the perceived health benefits that we were measuring great uh we will provide a link to the study in the caption and thank you for that very clear and thorough description um from the best one of the investigators involved in the study that it's great to go direct to the source um anecdotally were there improvements in mood in um resistance to colson infection um during the course of the study and this is uh kind of a prelude to where i'm headed next which is there is a tremendous amount of interest in the so-called gut-brain axis but also i want to make sure that we talk about how these microbes and the conditions they're establishing in the gut are creating positive or negative health effects i mean actually basically how signals get out of the gut um so did people i certainly notice that when i'm eating more fermented foods or there's probiotics and drinks i consume so forth that i feel quote-unquote air quotes completely i feel better um i wish there was an objective measure of feeling better um but i seem to think more clearly sleep better mood etc and i know i'm not alone in that um and people anytime i've taken harsh antibiotics i feel worse but then again i'm usually taking them because i'm feeling bad about something else right i don't think i'm just because so do people say they were feeling better um in any way and so what do you observe and again we're highlighting these as data yeah totally um you know we um as as part of this effort um to look at how dietary interventions affect our our health and well-being and so forth the microbiome immune system um we uh interact with a lot of people who have like read our book or you know kind of have become microbiome enthusiasts and have implemented a lot of these changes in their personal life and i hear the same thing that you're saying andrew that you know tons of people say they have more energy they think more clearly they sleep better their family is nicer to each other like a number of crazy things and it's really hard to uncouple like is this because you know these people take in charge now what they're eating just feel better in general for being in control of kind of what they're doing or is there this cascading um set of effects that are actually you know impacting or you know kind of emanating from the gut brain axis and so we actually implemented a bunch of questionnaires and even a cognitive test to try to get at some of this and i should say you know that the list of this goes on and there are people who claim that their complexion improves and that they're you know allergies and there's probably all sorts of ripple effects if you can affect your inflammation you we know that you can affect your cognition we know that you can affect your you know your skin and inflammation that's occurring on your skin so so i really think that there is a basis for a lot of those anecdotes it may just be hard to see in a short study and in a small you know a small cohort of people over a short period of time but we didn't really see significant things associated with cognition and moods and you know all of the things that that we were testing for which um yeah there could be a variety of explanations for that but you know we also have a standardized um uh stool measure that people use and there was um you know kind of less constipation better bowel movements over the course of both of these interventions so it did seem like bowel habits improved which um a lot of times can lead to better moods but that we weren't able to measure that the classic psychoanalysts would have a field day with that um what sorts of interesting things did you observe in the fiber group because it's clear that that group um yielded some unexpected findings in both directions that you think you expected to see you didn't see as to the same amplitude as you did in the fermented food group but i'm guessing you also saw some very interesting things in the fiber group totally yeah so um so we started looking at the data in more detail when we didn't see the cohort wide response. And one of the things we observed is that in measuring all these immune parameters, there appeared to be three different groups of kind of immune responses that we were seeing. One group that got overall less inflammatory and then two other groups that kind of had a mixed result, partly more inflammatory, partly less inflammatory in all these markers that we were looking at. And when we started digging into like what aspects of the, you know, biology of those people dictated or predicted which group they fell into, the really interesting part is the people with the highest diversity got microbiomes to start the study were the ones that were most likely to have the decreases in inflammation.

And so, you know, data seemed to be telling us that if you start off with a diverse microbiota, maybe 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. And thinking back to that experiment that we talked about before with a multi-generational loss of fiber fermenting microbes in mice that were fed a Western diet, it may be that many of us in the industrialized world have a microbiome that's so depleted now 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. And this has actually been observed by other groups, beautiful study out of University of Minnesota, looking at immigrants coming to the United States.

And, you know, within nine months, but certainly over the course of years, immigrants that come here lose a lot of the diversity in their gut microbiome, but a lot of the fiber degrading capacity in their gut microbiome too. So it could be that over time, this becomes a one-way street and it's hard for us to recover the microbes that actually can degrade the fiber. And I think that this probably intersects with sanitation in our environment and the fact that we don't have access to new microbes that might help us degrade the fiber, that we actually, you know, have lost these microbes and they're in some ways irrecoverable without deliberate reintroduction of fiber degrading microbes. I can recall from childhood, there were kids that would eat dirt and snails, and so it just sounds totally disgusting, but, you know, kids covered with mud and, you know, maybe not so much anymore.

And certainly during the pandemic, there's been a lot more use of these hand sanitizers that prior to that, people seem pretty spooked about, but then obviously that they prioritize them. So do you, while you have children, do you encourage them to, when they were young, do you encourage them to interact with pets and dirt and stuff in the environment, provided that stuff wasn't immediately toxic? Exactly. So this is really, you know, it's a continual cost-benefit analysis, I think.

I will say that, you know, with the pandemic now and certainly just with infectious diseases in general, it's really important to be aware of, you know, the possibility for compromising your health through the spread of germs. And so that is just, you know, hand-washing is important and we have to be careful with, you know, the spread of germs. But I do think that, you know, the sanitization of our environment has gone overboard with, you know, various things being impregnated with antibiotics, you know, shopping carts and things like that and toothbrushes and, you know, it's like antibiotics and, you know, things for killing microbes are everywhere. And when we were raising, you know, when our daughters were young and we were making these decisions, the calculations that we would make were really, one, how likely are they to encounter a disease-causing microbe?

If we've been out, you know, on a hike or in our garden, you know, just kind of working in the dirt or whatever, maybe it's not as important to wash your hands before you have lunch, even if there's a little bit of dirt on them. If they've been in a public playground where maybe there's other kids with germs or maybe even chemicals like pesticides and herbicides that are being used, maybe it's more important than to wash your hands. You know, certainly if you've been in the grocery store or on the subway, probably a good idea to wash your hands. But I think you really need to think about kind of the context of it.

And exposure to microbes from the environment is likely an important part of educating our immune system and keeping the proper balance in our immune system. And it's just a matter of figuring out the right way to do that safely. And it may be that the fermented food result we saw is a way of tapping into the same pathways, kind of an environmental exposure to microbes that's safe. Interesting.

I'd like to touch on how signals get from the gut to the rest of the body. And we probably don't have time to go into all the systems that benefit from having a diverse microbiome or healthy microbiome, but we talked about the immune system. There's active signaling and transport from the gut all along its length, as far as I know, into the bloodstream and other organs and tissues. So for the immune system, it seems straightforward to reduce the amount or number of inflammatory cytokines like IL-6 and so forth, but maybe increase the anti-inflammatory cytokines like IL-10 and others.

But we know there's a brain axis of neurons that literally talk in both directions between brain and gut. But let's say I'm eating my fermented foods, I'm doing all the right things, and my gut is diverse, and I have all the goodies at all the right places. How is it that the fact that those microbiota are thriving is conveyed to the rest of the body? Because they're in there doing their thing, and I don't know that they have a mind, but they're probably not thinking of taking care of me, Andrew, but I feel better, or I might get sick less often or combat any illness more quickly.

How is that actually happening? I mean, is it that the microbiota stay restricted to the gut, but the signaling molecules are all downstream, in a downstream way, or are making good or bad things happen? Or is there some sort of direct recognition at the body level, or are there cells in the body that are responding to, ah, the gut microbiome is healthy, and therefore I can make more of the good stuff and less of the bad stuff, so to speak? Yeah, great.

You're right, it's super complex. There's a huge array of ways that our body perceives both the microbes and the molecules that they produce in our gut, and the molecules they produce are, of course, a product of what microbes are there, and then what they receive as kind of metabolic inputs, what we're eating, and what other microbes are present in the environment, providing molecules to them. So, you know, it's this complex matrix, but we, you know, probably the simplest place to start is just the immune system. We have an immune system that, you know, the vast majority of immune cells in our body are located in our gut, just because there's such a dense population of microbes there that have, you know, we consider them beneficial microbes, but they're only beneficial if they're in the right spot in the gut.

As soon as they mislocalize, we know that they can become opportunistic pathogens, and so the immune system really playing an important role to keep them in place is essential for the system not moving into a disease space. The immune system has a variety of ways of monitoring what microbes are there. There are actually specialized structures in the gut, known as pyres patches, that actually take up microbes. They actually allow microbes to transit into this population of immune cells in a very controlled way, so that that set of immune cells becomes educated as to what microbes are just on the other side of the barrier.

Wow. So kind of like a border patrol. Exactly. Yeah.

So they bring them in, they, you know, fingerprint them, and then, you know, have kind of this, you know, set of responses ready to go if needed. Amazing. There are other cells known as dendritic cells, special types that actually send long arms, these processes, out into the lumen of the gut and do the same thing, take up microbes, bring them back in and sample them. In addition to these direct sampling mechanisms, the cells that line the gut have a huge array of receptors, specialized proteins that perceive patterns that the molecular patterns that the microbes make.

So things like endotoxin, lipopolysaccharide, just the cell wall of the bacteria, we have specialized receptors that recognize those. If those signals become too profound or if they're perceived in the wrong place, that can stimulate an inflammatory response. So there's all these ways of kind of monitoring the membership and where it is and how close it is. But then there's this whole other set of ways of perceiving metabolic activity and what's happening in the gut.

You mentioned before this direct, you know, these cell types that express taste receptors in the gut and have ways of sampling dietary components. They're the same types of analogous cells in our gut that are perceiving metabolites produced by the microbiota so that our bodies can perceive what sort of metabolic activity is going on. And then, you know, in addition to that, there's this tremendous, tremendously important enteric nervous system that's sending signals back to the brain, dictating things like motility. Do I get rid of what's in here?

Do I move it along quickly? What actually is happening? Do I need to interact with immune cells? So there's this really complex array of interactions between the different cell types.

And then a lot of the cells that are in the gut perceiving all of these signals, a lot of the immune cells can actually get up and leave. They can, you know, get into the blood cycle through and then home to other regions of the mucosal surfaces so that mucosal surfaces are educated broadly against what's passing through our gut. So there's a variety of ways of cells communicating. And then a lot of the molecules that the microbiota makes can actually make their way into the bloodstream directly.

And so, you know, the array of molecules is still being defined. We're trying to figure out what all these chemicals are. We mentioned the short-chain fatty acids, but those are just the tip of the iceberg. They're really interesting compounds like, you know, indole derivatives and phenols and, you know, derived from amino acids, metabolized by gut microbes, taken up into the bloodstream.

And then we further metabolize these. They become kind of co-microbe host metabolites. And then they can go on and bind to different receptors throughout our body, anywhere our bloodstream has access to, and start to trigger signaling cascades. Is it known whether or not any of those molecules are small enough to cross the blood-brain barrier?

Because the hypothesis and the current thinking is that neurotransmitters manufactured in the gut and signaling along the gut-brain axis, literally neurons talking back and forth electrically from brain to gut and gut-brain, is what regulates things like mood or at least in animal models. And so there are some emerging human studies improvement of symptoms in autism spectrum disorders, maybe even ADHD. What I'm basically saying here is there's some evidence emerging that improving the gut microbiome can improve outcomes in psychiatric and developmental disorders. But what you're telling me is that the microbiota themselves are manufacturing chemicals that can make it into the bloodstream.

And therefore, I'm asking if those chemicals can move from the bloodstream into the brain directly, it may not be a gut-brain axis via neurons. It actually could just be seepage of serotonin into the brain or cetylpoline into the brain, for that matter. Totally, yeah. And, you know, the biology of most of these molecules is not well understood, but certainly in, like, cerebral spinal fluid that's been analyzed, you can perceive these microbial metabolites.

So they are there. That's the answer. Some of them are getting across the barrier. But the really interesting thing is I think a lot of these molecules are, if they're experienced at high enough doses are toxic or have toxic properties, we know that a lot of these metabolites, when they make their way into the bloodstream, eventually are excreted through the kidneys and urine.

So actually, we can monitor the metabolism that's going on in your gut by actually looking at the metabolites that are present in your urine, because many of those originated in your gut from your gut microbes. But people with kidney disease, whose kidney's filtering process is not functioning properly, actually build up high levels of many of these metabolites into the bloodstream. And that can lead to more of these molecules making it across the blood-brain barrier. And in fact, some of the transporters in the kidney that are responsible for shuttling these molecules out into urine are also found at the blood-brain barrier for shuttling the molecules back into the bloodstream if they do get across.

And we know that mental fog is one of the big symptoms of kidney disease, potentially because a lot of these metabolites accumulate in blood and then make their way across the blood-brain barrier into the central nervous system. Amazing. I'm glad you mentioned mental fog. A few years back, there were some reports, some scientific reports, and as a consequence in the media, that excessive intake of pill-formed probiotics to create mental fog.

I don't know if that ever took hold. And it raises a general question about pill-formed probiotics. I took them for a few years just thinking that would be good for my gut microbiome, and I switched to the fermented food thing, largely as a consequence of the work that you and Chris published. But what's the thought about probiotics for the typical person that's not recovering from a round of antibiotics or that has been prescribed to them?

I've heard that the species of microbiota that they proliferate might not be the species that we want to proliferate, but I've also heard that maybe that doesn't matter. So what's your general stance? They can be quite expensive. I know I've been talking about expense a lot today, but I always want to take into account that people are showing up to the table with a variety of budgets.

And probiotics are one of the more expensive supplements out there. You can quickly get into several hundreds of dollars per month if you're getting the quote-unquote best quality ones. And if they're actually causing brain fog, then I'm not sure I want to use them. No, completely.

And there's a ton of snake oil out there. I mean, there's just people know that they, you know, I think that many of these companies are aware that they can prey off of people's fears and get a lot of money from them with absolutely no data to back up their probiotics doing anything. So I think the first thing to say is buyer beware because it's a supplement market. It's largely unregulated.

And that means that 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, over the counter, just kind of off the shelf probiotics, surveyed what's in there based on sequencing and shown that they, what is in there does not match what's on the label. And that's true of many supplements and unfortunately supplement companies. This is something we get into on the podcast a lot.

There are reputable brands and they go through a lot of work to get things right. And there are many that just, for whatever reason, it just doesn't match what's listed. Exactly. And so 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 just very well known and, you know, it's, you know, their reputations are on the line. So they probably invest a little bit more in quality control than maybe some of the other lesser known names. But, you know, there's a huge range of data on probiotics.

And I think, you know, the thing that we kind of recommend is, you know, try to find good products and then experiment for yourself and see if you can find something that works for you. I know people who have experienced, you know, constipation and, you know, can't, don't want to change their diet and have found a probiotic that helps them with that. If you can find that right next, great. You know, that's wonderful.

I would say that the data right now is not overwhelmingly positive for what probiotics do to the gut microbiota. So there have been some studies looking at the impact of probiotics on recovery after antibiotic treatment. And it appears to slow down the recovery of the mucosal microbiota and some other studies that have where the big signal isn't seen, as you might hope, with a probiotic that's supposed to treat different disease. There have been meta analysis that do suggest in certain instances recovery from antibiotics that there, even though it may cause your microbiota to recover more slowly, that it may actually prevent diarrheal disease recovery from viral diarrheas.

Probiotics may help, but because there's such a huge range of products and because each person is their own little caper 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 that I've heard is try to find a study that supports in, you know, a really well-designed study. And this is very hard for people who aren't scientists to evaluate. But, you know, if you're experiencing a medical problem or want to consult a doctor, you know, that might be helpful.

But finding a study where a specific probiotic has successfully done whatever it is you're looking for and then sticking with that probiotic is really the best recipe as a place to start in this space, I think. And what about prebiotics? Is there a number of reasons why I can imagine that prebiotics would be beneficial? Which essentially, you're pushing the fiber system, which we talked a lot about today.

Yeah, yeah, absolutely. You know, the studies that have been done on prebiotics, it's really kind of a 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 that are in the gut.

And so it's really hard to replicate with purified fiber what you get, for instance, at a salad bar in terms of the array of complex carbohydrates that you would be exposing your microbiota to. And I think the kind of broad view of this in the field is that consuming a broad... variety of plants and all the diverse fiber that comes with that is probably better in fostering diversity in your microbiota than purified fibers. Now, there are, again, a lot of people who benefit from purified fibers, either for GI motility or for other aspects of GI health problems that they've been experiencing.

Again, I think it's a type of thing where you have to try to find the thing that's right for you. But there also are studies that suggest that if you layer rapidly fermentable fibers on top of a Western diet, you actually can result in weird metabolism happening in your liver because you have this incredibly rapid fermentation fiber along with a lot of fat coming into the system. At least that's the theory. And in a mouse study that was published a few years ago, they actually see the subset of the mice develop hepatocelular carcinoma when they're a high dose prebiotic liver cancer on top of a Western diet.

So whether that's representative of human biology, we don't know. But purified fibers are definitely very different, both in terms of the diversity of structures, but also in terms of how rapidly they're fermented in the gut. Because if you are eating plants, the complex structures there 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 this big burst of fermentation that can happen if you eat something that is highly soluble and easily accessed by the microbes.

Interesting. So I guess it's fair to come back to this idea. I'm trying to avoid processed foods, the highly palatable foods that are sometimes super highly palatable foods. They're now called that are packed with hidden sugars and mulchipers.

It sounds like some fiber is good. And despite the outcome of the study, you identified that if you have the appropriate microbiota, then you will back around and one will respond even better to the fiber, maybe a longer ramp up phase for those folks. And then the fermented foods. There's no reason why you can't do both.

And as we talked about before, a lot of fermented foods have fiber. So you can build two birds with one stone. Totally. And it could be that the diversity increase that we saw in the high fermented food group could be something that would aid the high fiber group.

And so now we're planning another study coming up where we're doing high fiber, high fermented food, and then fiber plus fermented food, just to see if there's a synergistic effect there. Great. I want to enroll. Seriously.

Although I guess I'm biased because I sort of know where you're trying to... Well, is it blood draws that you use to measure the inflammatory? Exactly. So you've covered a tremendous amount of information and I'm incredibly grateful.

This was an area of biology that despite having learned a lot about through papers and going to talks and reading articles and media has remained somewhat mysterious to me until today. You've given us a very vivid picture of how this system works. Where can people find out more about the work that you're doing? We can certainly provide links.

And you and your wife who co-run your lab, you have a book on this topic. So could you tell us about the book where we can learn more about the Sonnenberg lab and the work that you're doing? Maybe people even try to enroll in some of these studies. Yeah, fantastic.

Yeah. It'd be great if we could get people to enroll where I was looking for willing participants. Yeah. So Eric and my wife and I wrote a book called The Good Gut.

And that really was a response to how we were changing our lives in response to being in the field, being very familiar with the research, seeing a lot of our friends that weren't studying about microbiome but were very well informed. Many of them scientists were not doing the same things we were doing. And it was very clear that it was just the lack of information funneling out of the field to other people. And so we wanted to make that accessible to people who are not microbiome scientists.

There's also a really interesting story. We were at a conference site that just has scientific conferences all summer long, week after week after week, different fields. And so it's people that work there that are just dealing with these new groups coming in week after week. And the week we were there for a microbiome conference, people that work in the dining commons came up to us and they said, what group is this?

This is weird. And we're like, what's weird? And they said, we can't keep the salad bar stocked. And it was very clear that nobody was doing what we were doing until we'd go to a microbiome conference.

And then everybody was doing the same stuff that we were doing. And so anyway, we wrote this book to talk about our personal journey and kind of the science in the field. And yeah, just to lay a foundation for people if they want to start thinking about these changes. And then, you know, in terms of kind of connecting with our research, certainly there's the Center for Human Microbiome Studies at Stanford, which is kind of our home base for doing a lot of these dietary interventions.

We list the studies there, give more information on what we're doing. And then we have a lab website too, that people can go to and read more about our research. Yeah, but we're always looking for participants for our studies. Great.

Well, we will provide links to all of those sources. And I just want to say thank you so much for sharing with us your knowledge, for the incredible work that you and Erica, your wife and Chris do and are continuing to do. I think this is an area that when I started my training, I heard a little bit about microbiota. And I always just thought those are people that work on infectious disease and like all the bad stuff.

So it's interesting and really important that people realize that we're carrying all this vital cargo and we need to take care of the cargo so it can take care of us. So thank you so much for your time and for the work you do. And I hope we can do it again. Thanks, Andrew.

This was a great conversation. Terrific. Thank you for joining me today for my discussion with Dr. Justin Sonnenberg, all about the gut microbiome and how to optimize your gut microbiome for health.

Please check out the Sonnenberg Lab webpage. That's Sonnenberg, spelled S-O-N-N-E-N-B-U-R-G-L-A-B. .stanford.edu. That's Sonnenberg Lab.stanford.edu.

They often recruit for studies exploring how different aspects of nutrition impact the gut microbiome, much as we discussed during today's episode. Please also check out the book that he and his wife, Dr. Erica Sonnenberg, wrote called The Good Gut. It's readily available on all the usual sites, such as Amazon and so forth.

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