Interview Summary

My impression is that this field of work on the microbiome is just exploding. It seems like every day something new comes out, something exciting, some kind of major breakthrough. It’s wonderful to have a leading scientist like you to join us to help explain this. Let me begin with this question. I recently read something very interesting in the article that discussed your work, namely that you’ve hypothesized, and this is a quote from this article, “Humans may merely be elaborate vessels “designed for the propagation of bacterial colonies.” Now that’s pretty interesting. Tell us more if you would?

Yes, absolutely. I should note that this is an idea that has been propagated, just as microbes are propagated over time. I did say that, but I’m now attributing it to the great scientists that came before me. I will say that the microbes in our gut have been for a long time a curiosity. For hundreds of years we’ve known that they live there. Over time we’ve learned that they’re affected by what we eat. We know that they’re involved in digestion and gut health. But what is really phenomenal is, as you alluded to in the introduction just the ability of these microbes to impact so many dimensions of our health. Everything from our immune system, to metabolism, to things like moods, behavior, and neurodegeneration. When you start to think about microbes getting passed from generation to generation – because as a new baby is born, their gut is sterile in the womb, and then they’re rapidly colonized when they come to this world largely by microbes from their mother and other adults around them – you start to realize that these microbes may actually be the ones calling the shots and dictating aspects of our biology to promote their growth through evolutionary time. It does change the way you think about this relationship in some ways.

One might jump to the conclusion that microbes are a bad thing, and you’d like to have fewer of them. That’s in fact what antibiotics do, they get rid of them. But we need more rather than less, and it sounds like the shrinking diversity of the microbiome is really a problem. How do our diet and lifestyles damage the vitality of the human microbiome? I’m imagining this is a ‘let me count the ways question,’ but what are the leading concerns in your mind?

Yes, completely. I think you’re right in that it’s very hard to single out one particular factor, because as populations become more industrialized and embrace all of the technologies and medical practices that go along with the industrialized lifestyle, we have so many factors that can impact our microbiome. Certainly, diet is a major factor, and we can come back to this. But we know that most of the microbes in our gut reside at the far reaches of our digestive tract – at the very end of the line down in our colon in our large intestine. That means that if we’re eating simple nutrients, like most of the things in a western diet – sugars, starch, fat, protein – a lot of those things get digested and absorbed in our small intestine, which leaves nothing remaining for the microbiota. It’s really complex carbohydrates and dietary fiber, that serve as the major fuel for the microbiota because we can’t digest those complex carbohydrates. The western diet has greatly reduced dietary fiber content, which has left a lot of our gut microbes starving. But there are other aspects of diet, certainly artificial sweeteners, emulsifiers, and probably the high fat content of the western diet are not great for our microbiome. Then beyond diet, antibiotics as you mentioned known to be great for fighting infectious diseases, but not so great for maintaining all of the friendly microbes that we harbor in our body. A variety of other factors like C-sections, baby formula, the incredible sanitation in our environment, again, a lot of these things are a trade-off because we have reaped a lot of benefits from a lot of the lifestyle medical practices technologies. But at the same time, we’ve implemented these in the absence of understanding the importance of our gut commensals, and the other commensals on our body for our health. Now we really need to start thinking about do we need to restore diversity to this community? Certainly, we need to start thinking about taking care of the community more diligently.

You mentioned in some detail how diet affects the gut, but how does it happen in the reverse? Is there a reciprocal relationship going on?

Yes, it’s a great question, and there are some papers that have been published looking at how gut microbes can affect food choice in model organisms like fruit flies and other organisms that are studied in the lab. We know that microbes in the gut as they metabolize things are producing a lot of interesting chemicals, little metabolites that get absorbed into our bloodstream can circulate through our body. Certainly, some of them cross the blood-brain barrier and can interact with our central nervous system. Now, whether some of those molecules can actually impact our food choice, I think is an interesting topic, we don’t know a lot about that. You can imagine a microbe that’s really good at, for instance, degrading pectin and it might grow very well. We know there are many microbes that grow well when we, for instance, eat an apple. If that microbe happens to produce a molecule just by chance that then can go in and increase our craving for an apple, that microbe has hit the jackpot for proliferating, it can guide our actions to choose an apple and then it actually profits from the pectin that comes in when we eat the apple. While this would be a very rare quirky event to happen, when you think about the trillions of microbes that exist in every person and have existed in every person across the planet throughout time. It’s possible that things like this have happened, and it’s a matter of us as scientists trying to track down those stories.

There’s at least some optimism that there could be virtuous cycles that gets set up rather than these destructive cycles potentially. Help us place this in some sort of a context. You talked about a myriad of dietary things that could affect the microbiome, and probably other things out there in the world too. How serious is the impact?

Yes, and this brings up kind of the question of what is a healthy microbiome? Has lifestyle impact that our microbiome? What would be ideal would be to have a time machine to go back, and actually survey what the microbiome looked like thousands of years ago before industrialization, and maybe even going back greater than 10,000 years to what our gut microbiome looked like when we were hunter-gatherers even before we started farming. Just to get a sense of what are the microbes that humans harbored over long periods of time during our evolution with the idea that perhaps our human genome was shaped over evolutionary time in some way by these microbes, that we have adapted our human biology to deal with the specific set of microbiome features or species. We don’t have a time machine, but there have been groups that have surveyed paleo feces for instance – the fossilized stool from humans from 1 to 2000 years ago. These data indicate that the microbiome has changed drastically. As we have industrialized, we have totally departed from this more ancestral microbiome. The other way that we can gain insight into this is by looking at modern humans that live lifestyles similar to our ancestors. Hunter-gatherer populations and rural agriculturalists, and we’ve done a lot of work studying the Hadza hunter-gatherers of Tanzania looking at their gut microbiome. That exactly supports what the paleo feces have told us. That there were features in the microbiome from before industrialization that have changed drastically. We’ve lost species, they’ve gone extinct. Hunter-gatherers and many rural populations still harbor these microbes. We expect that there’s probably around 500 to 1000 different species of bacteria in an individual’s gut microbiome. We’ve lost hundreds of these species over the course of industrialization. Then, the flip side of that is hundreds of other species have come in and replaced them. We’ve actually had this kind of wholesale change in configuration in our gut microbiome, and what this means to our biology, we’re trying to figure out right now, but it is a really marked change.

I have to say I admire the breadth of your work all the way from basic laboratory studies to in the field studies with hunter-gatherers. I could see how your big picture view of this is really pretty unique. Let’s talk about how the gut communicates with the brain, and does the health of the microbiome affect things like eating regulation? We’ve talked about that a little bit already, but also things like mental health.

I just want to start by saying that this is a field of research that is in very early days still, we have a lot of work to do to really figure out the connections. You can imagine then the gut microbiome composed of hundreds of species, and then trillions of cells and changing over time within an individual, and different between individuals, and then secreting thousands of chemicals that go into the bloodstream. Then put on top of that the complexity of the central nervous system and brain, and then try to map the interactions between the microbiome and the central nervous system is exceedingly complex.

I think that one of the really important things to note here is that if you look at a lot of the anxiety, and depression, Alzheimer’s disease, neurodegeneration in general at this center of a lot of these diseases much like other diseases of the industrialized world lies inflammation. The immune system actually becoming too inflammatory, and that leading to, you know, in some cases autoimmune diseases, but in other cases Alzheimer’s disease, and/or anxiety and depression. One of the things that our lab is focused on is really trying to understand how when you change the gut microbiome, how does the immune system change? How does the inflammatory status change of the system? Because we really think that this is the key mediator of many of the things that have gone wrong including things like diabetes and metabolic syndrome.

We’re now at the point of understanding that certainly if you go into an animal model and you change the gut microbiome in a major way like industrialization has changed the microbiome of people living in the United States, you completely change how the immune system functions. You can really change how an individual would react to a respiratory infection, how well they would respond to an immunotherapy if they were battling cancer, you can just completely change immune system functionality. In trying to understand this better we’ve started to do dietary interventions in people to see if we change the gut microbiome in beneficial ways with diet, can we make the immune system less inflammatory? We’ve done this so far in healthy adults, and now we’re really interested in extending this into all sorts of populations that are suffering from different inflammatory diseases, including things like anxiety, and depression, and neurodegenerative diseases. We’ll have more information about this. There’s some beautiful fundamental research out there that shows unequivocally that the gut microbiome is regulating behaviors, and cognition, and fundamental aspects of what happens in our brain. But a lot of this has been done in animal models, and it’s very hard to extend to humans in a detailed way.

I can’t wait to see these studies, they’re just absolutely fascinating and so important. You know, something occurred to me as I was thinking about this, and this may be outside the area of work that you’re focused on, but there’s a lot of interest out there in the world and the impact of endocrine disrupting chemicals, or things that leach from plastics and things known as forever chemicals, and their impacts on a whole host of things like cancers, and obesity, diabetes and more. Is there any reason to worry about the microbiome in this context?

Yes, completely. I think everything that we come in contact with, particularly things that we ingest, but even things that are absorbed through our skin or we inhale, the microbes that live in and on us are just incredibly sensitive detectors of everything going on in the environment. I mean, their survival depends upon it. One of the, in fact, key features of one of the first species from the gut microbiome to have its genome sequenced, Bacteroides thetaiotaomicron this is a bacterial species that was sequenced in the lab of Jeffrey Gordon, it was published in 2003. One of the key interesting features of that genome was the expansion of environmental sensors that were encoded by that genome. It was very clear that this bacterium was living in a dynamic environment, and having to sense and respond to minute to minute variations in the chemical cues that were coming in. That means that when you start to change those chemical cues, you start to change the function of the microbiome because those sensors that those bacterial encode are wired into their function and how they behave. This is again, hypothesis, but I think your question is a a great one because there are these realms of inquiry where we are just right at the beginning of understanding that major things that are going on in our environment could be impacting this really essential component of our biology. And we really have no specific idea of how the perturbations may cascade through our microbiome and our biology. A lot to look at there, but I have no doubt that those chemicals are having an impact on this community filled with environmental sensors.

It’s going to be so interesting to see that work take shape. It would be great if community of people working on the microbiome could come together with the people in interested in the impact of these forever chemicals on health so that a full picture of their impact can get painted. So what do you think are the most pressing scientific questions that need to get addressed?

I think that we’re still really searching for the definition of a healthy microbiome. And this is something that dates back to a wonderful project that was started by the National Institutes of Health, the Human Microbiome Project. That was an effort from sequencing centers that had sequenced the human genome to turn these sequencing technologies to this uncharted aspect of our human biology, our microbiome. One of the goals of that sequencing project was to determine what a healthy gut microbiome is. And our assumption at the time was, well, we should sequence a bunch of healthy Americans, and kind of look at what’s common between them. We now understand that the healthy American most likely harbors a microbiome that is not really optimal for health, it’s actually probably a microbiome that’s predisposing us to a number of inflammatory conditions.

Our human genome probably dictates whether you as a person will get an autoimmune disease, or cancer or you know, a different inflammatory disease. But it’s really a microbiome that appears to be pro-inflammatory, and so that doesn’t mean that it’s terrible and that we need to scrap the whole thing. But it means that it probably can be improved. A big part of that improvement probably can come through feeding it better food and getting better functionality out of the microbes we have. But it also probably means that we need to bring back certain functions or certain species that we’ve lost over the course of industrialization, to bring back some of that biodiversity.

You know, I think of the microbiome as similar to this complex rainforest, just hundreds of species interacting in this really dynamic way, and as you start to degrade that ecosystem it’s really hard to maintain its full functionality. You start to lose functions, and it starts to operate suboptimally. And so thinking about ways to bring back the health and biodiversity of this ecosystem, I think is super important. One of the key things that we have to do as a field, and I want to just reflect back on the work that we’re doing with hunter-gatherers and implications for what might be a healthy microbiome. It is not at all clear that all of the microbes that we’ve lost are healthy and need to be reinstalled in our gut. I think that we’ve probably lost species that we, you know, just as soon not have. But mapping which ones are health-promoting, and in which context, because you know, what’s health-promoting for one person may not necessarily be health promoting for someone else that’s going through something very different in their life in a different life phase. So we need to understand all that complexity, and really crystallize how can we optimize a microbiome for an individual in a given context.

This sounds like a really complex problem, and it is, but I think that one of the really exciting things that’s happening in the field right now is this combination of what we call omics data, the ability to measure so many different aspects of the microbiome at one time so we can get a really detailed picture. Then all the great computational approaches for bringing all that data together, using things like machine learning and artificial intelligence on big data sets to really distill out meaningful signals that give us a better idea of some of these complex questions. It is a complex thing to go after, but I think it’s not out of reach and that’s I think the big frontier for the gut microbiome.

Well, speaking of the big frontier, let’s end with a big picture question. What can be done to make things better? You mentioned improving diet would be one thing, but how do you look at those big picture questions?

One of the incredible things about the gut microbiome and its relationship to its human host, is this like feedback system. For instance, if you are in a slightly inflammatory state, it can be hard to get out of that inflammatory state because the inflammation is reinforcing microbes that are then reinforcing the inflammation. You end up with these feedback loops that are very hard to break, so even if you were to do something like a fecal transplant in some instances of inflammation where you try to reinstall healthy microbes, those may not engraft and take up residence because the host inflammation will get rid of the good microbes and select in the microbes that feed the inflammation. There are these feedback loops that are very hard to break, and we know the gut microbiome is very resilient, so you can perturb it and it will by and large return to a starting state, not exactly what the starting state was, but there is this great resilience and recalcitrant to change over short time periods. This is why industrialization has been so powerful because it’s happened over multiple generations across an entire population, and it’s driven our microbiome in one direction.

I think if we want to bring back a more diverse healthy microbiome, it requires changes in our habits, changes in what we eat day after day for years on end to really change the species that are in our microbiome and what those species are doing. We got a little bit of insight into this, but I’ll finish with one specific example. One of the dietary interventions that we did, we compared a high fiber diet, so this is eating things like legumes, whole grains, vegetables, fruits, thinking that that would be kind of optimal food for a healthy gut microbiome. We compared that diet with a high fermented food diet, so another cohort of individuals, we gave kombucha, kefir, yogurt, kimchi sauerkraut, food with living microbes in it that had been transformed by fermentation. Basically, so these were just healthy adults we let them eat those foods, they ramped up on the foods for four weeks, and then for six weeks they maintained high levels of those foods. We actually saw that the high fiber diet had very different effects on individuals depending upon their starting microbiome. If you had a very diverse microbiome to start with, you actually improved your inflammatory status, you got less inflammatory over the course of the intervention. But if you start with a low diversity microbiome, the high fiber diet doesn’t do much for you. The fermented foods actually had a really amazing effect, they increased microbiome diversity and they also decreased over two dozen inflammatory markers that we were able to survey through these great technologies that give us comprehensive immune profiling. We really saw a signature of exactly what we’d want to see to counter the industrialized deterioration of the gut microbiome with the fermented food diet, increased microbiome diversity, decreased inflammation, and this was just over the course of a 6 to 10 week intervention. We’re really curious to pursue these findings in more detail, and see if now we can go into diseases that are pro-inflammatory, and counter those diseases to actually treat them in some way with the fermented food diet.

If I were to tell people what to do to counter all the negative impact of industrialization on our microbiome, I would say consume some fermented foods every day, and then start to integrate dietary fiber. As you eat the fermented foods, you’ll increase your microbiome diversity. And our hope is that will allow you to harness the benefit of the high fiber diet as your microbiome diversity increases.