Justin and Erica Sonnenburg
The Gut Connection

One of the most talked about areas in science right now is the link between our gut and our overall health. Your gut's microbiota contains tens of trillions of bacteria, profoundly influencing your metabolism and immune system. The potential of exploring these new areas, combined with new sets of technology, has created a wave of excitement in the general public.

Husband and wife, Justin and Erica Sonnenburg, who work out of the Stanford University School of Medicine’s Department of Microbiology and Immunology, are now shining a light on this thriving province of scientific research.
Having just written a revealing book entitled ‘The Good Gut’, Justin and Erica tell us why the Western diet has been so damaging and whether it can even explain shifts in our mental wellbeing.

I want to give our readers an overview of this fascinating and ever-growing field of science. It seems as though there are startling discoveries being made in relation to the gut-brain connection and yet we’re only just breaching this new field – one of the facts that impressed me the most in my research leading up to this interview was that our gut makes up 2/3 of our immune system. How did you begin your interest in this field?

JUSTIN SONNENBURG: I think we both got interested in this because of curiosity. I didn’t come in with any grand vision of how significant this thing would become, to be completely honest.

ERICA SONNENBURG: We started working in this area around 12 years ago, so it was pretty early days for the field – there was no realisation of the impact it would have.

JUSTIN SONNENBURG: It was mostly curiosity. Over the course of the past decade, this concept of plasticity that you mentioned has become really apparent. This has happened at the same time that we’re realising this microbial community is incredibly fundamental to all aspects of our health. We also realised that, in the Western world, this community is degraded and deteriorated to the point that it is likely impacting our health in many negative ways; predisposing us to many problems that we as Westerners experience. So, the possibility of leveraging this plasticity to nurture back the community and our health is really a powerful idea.

Let’s talk about the Western paradigm in terms of the gut. In the book, you talk about this thing called ‘the mass extinction event’. I’d love you to delve into that a little bit. You talk about the diversity of bacteria that have lived in our bodies throughout human history but have now died off, somewhat. How wayward have we gone?

ERICA SONNENBURG: I think in the past year especially, but for the past 3 or 4 years we’ve started to realise how the gut of Westerners is likely very different from that of our ancient ancestors. Over the past year, there has been a few studies where they have looked at the microbiota of individuals that lived hunter-gatherer lifestyles – how our ancestors lived for around 150 thousand years of human existence. There are people today who still live this lifestyle of getting all their food from hunting and gathering. If you look at these hunter-gatherers on 3 different continents of the world right now, all of them have a microbiota that not only looks different to ours in the west, but one of the major features that distinguishes their microbiota from ours is the fact that they just have way more microbial species living in their gut than we do.

In the book we use this analogy of a jar of jelly beans. If you look at the hunter-gatherers, their jelly bean jar – if each jelly bean represents a different species of microbe – is just way more flavourful and colourful than ours here in the Western world. So, this is really the beginning evidence that over our history something in our modern lifestyle has resulted in the loss of probably hundreds of bacterial species that have been with humans for most of our existence on the planet.

JUSTIN SONNENBURG: I think the element of diversity is very clear; looking at these different traditional groups of humans, you can see that they have groups of bacteria that we lack by living in an industrialised society. That really suggests that there were specific phylogenetic groups, closely related groups of bacteria, that we co-evolved with. Undoubtedly, these groups are fundamental in certain functions and interactions that our bodies are supposed to be carrying out, and we’ve just lost them. We don’t have them anymore. The question is how important they are.

There’s another interesting follow-up to this, which is, ‘how did we lose these?’. Everything that’s specific to industrialised society, ranging from diet to medical practices to lifestyle, is in play. But Erica has done a really interesting experiment in mice, modelling this loss of diversity over the course of generations, that gives some insight into this.

“We realised that in the Western world this community is degraded and deteriorated to the point that it is likely impacting our health in many negative ways; predisposing us to many problems that we as Westerners experience.”

Justin Sonnenburg

We interview quite a few scientists and I’m always interested to know, while we’re talking about this, do you feel somewhat dismayed? We talk about how smart we are and how clean we’ve become and how we’ve become a really “affluent” society. But, the more we pursue this notion that we’re becoming this extraordinary species, we lose the insight that we’re actually doing more harm to ourselves. You are telling me that we’ve lost so much diversity in the gut and how important that is, and so now we have to scramble to find the solution to getting back to the most basic way we were – the hunter-gatherer way.

JUSTIN SONNENBURG: Yeah, I think that’s a beautiful insight you have into it there. On the one hand, it’s really remarkable how we’ve been able to virtually eliminate infectious disease as a cause of mortality in the Western world, and that’s not totally unrelated to what we’re talking about; the use of antibiotics has been wonderful for getting rid of really bad bacteria, but it’s obviously at a cost.

I think we’re marvellously clever and incredibly ignorant all at the same time. Biology is just incredibly complicated, and this is the perfect example of how we stumbled onto something just over the past 10 years that we realise is absolutely fundamental to our health yet is something we have been neglecting in our decisions over the past century and a half.

ERICA SONNENBURG: I think that was part of the influence for writing this book; general scientists like us don’t write books for the public, but we felt like there was a real urgency for this message. Our research in the field is suggesting that there’s this huge downside to antibiotics that a lot of people don’t realise and there’s a huge downside to a processed food diet that a lot of people don’t realise. We just wanted to make sure that information was available so people understand that, while antibiotics are important and we should take them when they’re needed, we’re harming the community that’s living inside of us. We need to be conscious of that and also try to negate some of the damage.

JUSTIN SONNENBURG: On the concept of ‘dismay’, I think, ‘dismay’, yes, but also ‘hopeful’. This gets back to the idea of plasticity, I’m dismayed because there seems to be a connection between the deteriorated microbiota, our diet, and all Western diseases just shooting up. The projections are just terrible for so many of these diseases, like obesity and autoimmune diseases. So, ‘dismayed’ from the standpoint of the future looking so bleak for these projections. Dealing with a system that is so intrenched. Pharmaceutical companies and what they’re focused on, food giants making this food, lobbying efforts, and the way that governments are set up. It’s just becoming an incredibly difficult problem to attack and change. It will be slow – it requires a movement from people. That’s where it gets back to the book; people really need to make this a top priority. I think, ‘hopeful’ because this community is plastic and we’re able to help nurse back a healthy microbiota over time with the right diet and lifestyle choices.

I want to get into stress. You said that bacteria fights pathogens, helps blood group development, digests food, produces energy, produces hormones, and many other things. It seems like a very sensitive little eco-system in our guts. I’m really fascinated by stress, we talk about it a lot in society. I’m interested to know what studies have been done, or what your studies inform you about how stress effects our microbiota.

JUSTIN SONNENBURG: There have been studies about this. There have been animal models, mice, who have been put in stressful situations and the idea is to potentially induce something like IBS (irritable bowel syndrome). There appears to be an impact of stress on the microbiota, there also appears to be an impact of the microbiota on stress levels. Certain strains of mice are intrinsically more stressed-out than other strains of mice. By doing a microbiota-swap experiment you can somewhat change their anxiety level.

So, it really appears to be a two-way street and it totally makes sense. If we change gut motility or any aspect of the environment of the gut, those changes, whether they’re how rapidly food is moving through or hormonal signals, they translate into biochemical differences that relate to each species and what they’re doing. Without a doubt, stress on the host’s side relates to physiological and hormonal changes that will translate into microbiota differences. Of course, these bacteria in our gut are like little drug factories; they’re making all of these interesting little molecules that we absorb and circulate through our blood. It’s not well understood how those molecules interact with our nervous system, but it’s clear that they do in different ways. This is going to be one of those areas that will explode over the coming decade. The likelihood that microbes influence our moods and behaviour on a day-to-day is significant. I think everybody in the field would be shocked if they found it had only a minor affect.

“The over-use of antibiotics has been wonderful for getting rid of really bad bacteria, but it’s obviously at a cost.”

Justin Sonnenburg

JUSTIN SONNENBURG: I think that’s true. Another great scientist at UCSF, named Michael Fischbach, has studied the small molecule that these microbes make. He makes the argument that we all learn that drugs are something that are discovered by pharmaceutical companies who do rigorous testing and are approved by the FDA and eventually we take them in pill form. But, in reality, these bacteria have figured out an end-run around the whole system; they’ve been co-evolving with us, optimising these drug-like chemicals that they’re delivering to us to stimulate various chemicals that are advantageous to them. There’s without a doubt a huge pharmaceutical potential just in studying these gut microbes. There are many other ways that they’re hard-wired into our microbiology, so I think he [Fischbach] is exactly right; it’s a revolution in biomedicine that really eclipses anything we’ve seen in recent history.

This is kind of a hard question to answer, but I’m really fascinated to know where this is all heading. There are so many places that science is only just able to peek underneath and start questioning – we don’t even have the whole set of questions yet. What are some of the questions that you would like to answer over the next few decades?

ERICA SONNENBURG: Like you said, there are a lot of potential questions that we could address with the microbiota. I think it would be nice to see mechanistic studies. I guess what we’re not really missing at the moment is a lot of correlative studies, so there’s all this microbiota enumeration – you look at a disease like autism, and we know that the microbiota in autistic children is different from that of children who don’t have autism. But, what we’re really missing is the ‘why’ or what that really means; is it just a side-effect of having autism? Is there something about autistic children’s microbiota that’s contributing to their disease and their symptoms, and if that’s the case what can we do about it?

The nice thing about the microbiota is, because it lives in our gut which is in essence on the exterior of our bodies, since humans are basically a tube, it makes it a much more drug-able target than, say, pills that need to get inside our body and inside our cells. Smart microbes that can deliver therapeutics exactly as we design them, that’s how the field would go, ideally. But, I think there are a lot more mechanistic studies that need to be done to hammer out what these thousands of microbes are doing in our gut on a molecular level.

JUSTIN SONNENBURG: I think Erica is exactly right; understanding the mechanisms and causal relationships will be where this field is heading. There’s a possibility that the microbiota underlies a lot of Western disease, and we can actually change what we’re doing now to take more care. If we consider that a large amount of our microbiota is involved in our health, 80 or 90% of that can be taken care of without any personalised mechanistic understanding. That would be the big thing for the next 3-4 years. We’re all existing in the modern world in this simmering state that’s predisposing us to all these terrible diseases, and we need to understand which species is delivering which molecule.

I’m not a scientist, but do you think we need to understand it to this depth, do we need to understand the complexities that will take so many years to uncover and potentially reveal a whole other set of problems and open up a whole new pandoras box? I’m reminded of an interview we did with a neuroscientist who said, “I think it’s good advice to look at nature first; it had millions of years figuring out what’s needed to survive.” Do we just leave it as it is? You talk about the hunter-gatherer diet, isn’t it just as easy as that?

ERICA SONNENBERG: I think that you’re right for the majority of people; just by repairing our diet and being more mindful of our lifestyle choices we can get rid of a lot of diseases without any more understanding of the microbiota. But where this research is heading and where it could help people is in cases where, because of genetic predisposition or a need to take a huge amount of antibiotics to fight off a serious infection, there will be people for which diet or probiotics alone cannot repair their gut. Those individuals will benefit from microbiota research.

JUSTIN SONNENBERG: Let me give you an example of how a fundamental understanding could make a difference for a certain group of people, and I think this is exactly in line with what Erica was just talking about. There’s this group of bacteria – categorised as a single group of species but probably broader than that – called oxalobacter formigenes. They degrade dietary oxalates and there’s some indication that if you don’t have oxalobacter you build-up excessive oxalates and are more likely to develop kidney stones. So, this is one of those groups of bacteria that most Westerners appear to have lost and traditional populations haven’t. So you can imagine a simple experiment where you type somebody’s microbiota who’s having kidney stone problems, and if they don’t have oxalobacter you supplement that bacteria back in. All the details there aren’t perfectly ironed out, this is still very speculative, but there is a body of literature out there that connects oxalobacter to kidney stone formation. It’s this kind of fine-tuning that would be a real benefit for the understanding of microbiota.

“Certain strains of mice are intrinsically more stressed-out than other strains of mice. By doing a microbiota-swap experiment you can somewhat change their anxiety level.”

Justin Sonnenburg

Globally, we’re just eating the wrong foods. What I’m also interested in is this relationship with pharmaceutical companies, and I include the food companies because, from the research I’ve done, it’s drugs. Food is so over-processed and full of chemicals and we collude with it; we sit with it, we eat with it, we have a relationship with it day-to-day. So, as two scientists working in this area, how do we view this relationship now that it’s so entrenched in our society?

JUSTIN SONNENBURG: This is one of the major problems. One of the analogies we use when talking to people is: if you imagine Western disease as a large tree that’s growing at a rapid rate, the processed food companies are essentially fertiliser for that tree and the pharmaceutical companies are just figuring out ways to trim some of the limbs – they’re just treating symptoms. Nobody is thinking about how to tear the roots out and knock the tree down. I think you’re exactly right, the system is incredibly entrenched. Actually, I was just at Andrew Weil’s conference and talking with him and others, we were all saying that this seems like such an immovable force. I think it was agreed by everyone that it just takes a critical mass, it takes the population to really understand the problem and demand a change and start voting for different people. It’s got to come from the masses.

ERICA SONNENBURG: I think the education aspect is really what’s critical. If you look at hunter-gatherers in Tanzania, they have a diet that’s composed of mostly tubers that they forage and are very high in fibre, and berries, but they also hunt for meat and honey. If you ask them what their favourite foods to eat are, it’s meat and honey – fat and sugar. They just don’t eat a lot of fat and sugar because they don’t have access to it, but if you put them in our society they would be at MacDonald’s just as frequently as we are. So, it’s clear that our brain is wired to want fat and sugar because throughout our evolution those things were high-calorie but low abundance foods. Part of this processed food problem is it’s really tapping into the most basic wants our brains have. We just need to educate people about the fact that our brains are craving fat and sugar when what our bodies need is high-fibre diets.

Let’s talk about the high-fibre diet. From the research that I’ve done on you guys, I can see you often hint towards a high-fibre diet. I read a long feature about you in The New York Times Magazine and you talk about the way that you feed your family, but you say that none of it is for sure, there’s not enough conclusive evidence to guarantee that a high-fibre diet is the perfect diet. Yet, the surrounding evidence seems to suggest that it is conclusive. Are you guys scared of starting a fad or a fashion diet, or is it really not conclusive?

JUSTIN SONNENBURG: You’ll have to wait for the cookbook… Haha. No, I’m just kidding. I think what we’re hedging on is just microbiota mediating the affect of fibre being healthy. So I think there’s no doubt about it that we should all be eating more fibre. If you go to the Harvard School of Public Health webpage, the Mayo Health Clinic webpage, the FDA, all of these places are saying that we should be eating more fibre, so that’s definitive. The question is whether the microbiota is actually mediating the affect. For instance, are the short-chain fatty acids that the microbiota produces and are fermenting the fibre actually mediators of a lot of the beneficial affects?

There are a lot of arrows pointing in that direction, but that’s the part that the field really needs to hammer out. The other part of this that is really difficult to de-convolute is all of the other health components in plants that are consumed when people eat high-fibre diets. We’re actually doing a study at the moment at Stanford where we compare a high-fibre plant-based diet against a high-fibre purified-fibre diet and look at the effects on health and the microbiota. There are still some areas of this that need to be hashed out in terms of mechanism.

You only recently discovered that you could sequence the microbiota, how has technology shaped the field you’re in and how will technology shape the future of it?

ERICA SONNENBURG: I think the technology of our field has been everything. We’ve known for over a hundred years that there’s a community of microbes living in our gut, but we didn’t have the tools needed to study this community. It was really the sequencing technology, developed initially for the human genome, that really blew the field wide open; one of the issues when dealing with these microbes in our gut and studying them is that our gut is an anaerobic environment (there’s no oxygen there) so it makes it extremely difficult to study these microbes in the lab; as soon as they’re exposed to oxygen they die. But the DNA stays there, so this sequencing technology really allowed us to peer into the gut in a way that scientists just couldn’t do before. So, in many ways, we feel very fortunate to be studying the microbes at a time where this technology is available to us.

JUSTIN SONNENBURG: There’s still a long way for technology to go. If you look at the sequencing technology, it’s wonderful. So, this is great if you have an academic lab at Stanford and you’re conducting studies, but if you’re trying to conduct field research in Bangladesh or if you want to engage the public and have a simple device to allow them to monitor their microbiota on a daily basis, the technology really isn’t there for that. I think a lot of us are starting to think about devices that can be something you could plug into your iPhone or even something that could go into a clinic would be a big advance – a doctor could monitor a patient on a day-to-day basis with a semi-expensive machine that could just get data quickly. We simply don’t have the devices right now.

“We’ve discovered that there’s this class of chemicals in the mother’s milk that is there, not for the baby to digest, but for the microbiota to digest. The mother actually laces her milk with a kind of dietary fibre that’s a class of molecules you can’t find anywhere else on the planet. They’re not even present in cow’s milk.”

Justin Sonnenburg

I met some incredible people working in the field of technology, there’s a lot of investment going on. You must see that happening?

JUSTIN SONNENBURG: Especially here in Silicon Valley; there’s a huge number of venture capitalist firms that are interested in this and they’ve been around since we came to Stanford 7 years ago. It’s interesting to see where these companies place their bets, because it’s not exactly intuitive from researchers point of view.

One of the most awesome things I heard when delving into this was on a documentary I saw in Australia, by a TV show called Catalyst. They did a 2-part series on the gut. It really made me rethink the whole parameters of the gut and the way we live. They said something to the effect of, “We don’t host the microbiota, the microbiota host us.”

JUSTIN SONNENBURG: Yeah, I love that. Another quote that is widely circulated in our field is, “Humans are elaborate culturing vessels that have evolved to propagate and pass on these micro-organisms.”

It goes back to that earlier point about how sophisticated we as humans believe ourselves to be and how, the more we look into it, we are just a large organism – part of this big web of diversity and microbiota and bacteria, etc.

JUSTIN SONNENBURG: I think the baby formula industry is a great example of this. Mother’s milk, which is such an important product of millennia of evolution and optimised nutrition, we’ve discovered that there’s this class of chemicals in the mother’s milk that is there, not for the baby to digest, but for the microbiota to digest. The mother actually laces her milk with a kind of dietary fibre that’s a class of molecules you can’t find anywhere else on the planet. They’re not even present in cow’s milk, they’re very specific to species. So, it’s very clear that these chemicals are in there to help recruit and nurture the assembly of the microbiota as the baby is born into the world.