Dr. Elinav: I think that of all the different environmental factors that affect us humans and surround us, our stress levels, the medications we take, where we live, and how we conduct our lives, the composition of the diet is probably the most important and most dominant factor which impacts our gut microbes. And this has been shown by us in the Personalized Nutrition Project, but it has been extensively shown by many others. And I think it is safe to say that of all the features that we and others are studying, there's nothing more important and dominant than the composition of our diet.

Dr. Patrick: Let's talk a little bit...dive into that a little bit like, you know, maybe starting with some of the macronutrients. Like how do the composition of our diet including proteins or carbohydrates...complex carbohydrates versus, you know, simple carbohydrates, or even fat and the type of fat, saturated fat versus polyunsaturated fat or monounsaturated fat, how does that affect...or whether we eat a plant-based diet or animal-based diet. How does that affect the composition of our microbiome?

Dr. Elinav: That's a great question, and to be honest, I think that our very young field is only beginning to mechanistically unravel these complex effects. And there are many different types of effects by which micro and macronutrients in our diet could impact our microbes. For example, some of our nutritional inputs could serve as an energy source to microbes, and some microbes would preferentially digest some but not other components of our diets. As you may imagine, there may be a competitive advantage to some microbes over others depending on the diet that they're exposed to. Other impacts could relate to an even more enigmatic part of the microbiome which is bacteria-bacteria communications. And we increasingly know that we have trillions of bacteria in our gut and these form ecosystems or communities in which they are very marked and poorly understood communication channels between different bacteria that determine who would survive, who would flourish, and who would not. And these also in many interesting aspects relate to signals that are obtained from our diet. And a third example of how diet composition could impact our microbes relates to the host, and many of our dietary components are sensed or are absorbed by the host, which changes its behavior in response to these compounds. And the host could be, you know, regarded as a very sophisticated incubator that houses all of these microbes, and by changing its behaviors or its conditions, the host in response to diet could change the relative composition and function of different microbes over others.

Dr. Patrick: There are people, you know, living in, you know, certain parts of, for example, Africa that are...you know, they eat a very, very...like from day to day, the diet's very similar. You know, they're eating lots of complex carbohydrates, for example. I mean, it's a very much...they eat the same meals like almost every day versus someone living in like, you know, in the Western world in the United States, for example, where there's...you know, the diets vary so much from person to person and depending on like processed foods versus, you know, eating whole foods, you know. How stable is the microbiome if, for example, we were to switch diets, so if someone in the Western world was to eat something more like, you know, plantains and these, you know, complex carbohydrates and vice versa?

Dr. Elinav: Yeah. It's an excellent question. And the answer is that it really depends on which resolution you're looking at the microbiome in terms of its stability. So just to give you an example. If you look from a bird's eye view way from up top at an adult person's microbiome, and you're talking about a healthy adult with a relatively stable lifestyle, then the microbiome composition over time in that adult would seem very, very stable. We discovered that even in industrialized nations, people are usually exposed to no more than 40 or 50 components of dietary composition in a routine lifestyle. So the variation in our individual exposure to food is much lesser than you would expect. And if you just, you know, look into the composition and the function of the microbiome from this resolution, you would find that it changes in a very minor manner between the age of three until we get to an old age or if we develop disease or change our lifestyle. However, if you dive deeper into the microbiome, you would find that there are more interesting changes that are, you know, more subtle and characterize our healthy being.

For example, there are studies in Africa looking into rainy or dry seasons, which are characterized by different exposures to different crops and different foods, and you can see that there's a very consistent and very reproducible change that is based on the changes in these seasons and what they represent. If you look even closer as we just discussed, even in the 24-hour cycle, you would find that the microbiome is what we call stably unstable. It is stable but it oscillates throughout a 24-hour cycle in a very reproducible manner, and this relates to a healthy state. Now, when you start adding into it all the perturbations and all the exposures that a human may be experiencing, for example, changes in diet as you highlight, changes in where we live, changes in our health status, in our stress status, in the medications that we eat, all of these environmental signals or cues reflect on our gut microbes in a way that may impact our physiology or risk of developing diseases.

Dr. Patrick: What do you think about, for example, a vegetarian diet versus someone...? It's become quite popular actually in the United States, this carnivore diet where people actually cut out all carbohydrates and they eat only meat. How is that going to impact the microbiome, or do we know?

Dr. Elinav: Yeah. There are very elegant studies early on from kind of birth of the field by researchers such as Jeff Gordon and Fred Bäckhed, which have shown that, you know, if you abruptly change the composition of the diet from one type to another, for example, from a veggie to a carnivore diet, you very reproducibly change in an average...in a population average, you very reproducibly change the composition of the microbe into one which accommodates better the new diet. And this is kind of when you look at a relatively low resolution into the microbiome. However, if you look at a higher resolution, and this I think was one of the exciting discoveries that we came across in the Personalized Nutrition Project, you would find that even within the same diet, people react very differently when you look closely enough. So the answer is a complex one.

You know, in 2015, we've conducted our own kind of mini-trial in which we took a group of healthy human individuals, and we've asked them politely to eat only white rice for a week, then only, you know, a steak for another week while we extensively measured them for their microbiome. And we found indeed that the microbiome changes in a very reproducible manner. Even if the starting configuration is different between people, the direction of the change is very similar when you look at the same bacteria in different people with respect to the response to the same dietary change. But when you look at a more real-life scenario, you would find that people are uniquely responding to dietary components even if they're exposed to the same exact diet, and this is the hallmark of the Personalized Nutrition approach.

Dr. Patrick: What role does microbiome diversity play in, for example, the, you know, metabolic responses to food like postprandial glucose response or, you know, when it comes to our personalized responses to diet?

Dr. Elinav: Well, if you're looking at...or if you're thinking about microbial diversity or the richness of a given microbiome, there are many interesting observations that are trying to relate the loss of diversity to a propensity to develop disease. So, for example, if you look at indigenous populations of humans, hunter-gatherers and so on and so forth, you would find in some studies that the diversity of the microbiome can be tenfold higher than the average diversity that we can see and measure in the same human beings when they live in modern "societies or industrialized societies." And people have tried to link this amazing reduction in diversity to the modern risk of developing diseases such as obesity, type 2 diabetes, fatty liver, and even cancer, and other diseases. However, the causal role implicating the richness per se of the microbiome to these diseases still merits further investigation. So the jury is still out there. Although I must say that in many microbiome-associated diseases, we indeed see a reduction in diversity that characterizes these disease states. Whether the diversity reduction is by itself a risk factor to the development of disease, or whether it just reflects the emergence of dominant disease-causing microbes is an open question that at least to my opinion has not been sufficiently answered yet.