Dr. Patrick: Speaking about the diversity and how it changes...the question is how it changes throughout the lifespan. So you mentioned, you know, a few minutes ago about the microbiome being pretty stable, generally speaking, at...you know, after the age of about three. This is a two-part question. One would be, you know, what factors...? Like it seems as though during early development, it would be very important, you know, if you're shaping the overall general stability of the gut microbiome in the first three years of life, what impact, you know, for example, feeding your infant and young child, you know, breast milk, which has things like human milk oligosaccharides and a variety of factors that have been shown to be very important for the gut microbiome in shaping it, and then also, you know, what foods you do feed your child or antibiotic use or factors like that. Do you think that parents should be focused somewhat on the health of their young growing child's, you know, gut microbiome in those first three years of life, or exposing them to, for example, you know, soil and other, you know, bacterial exposures that they're getting from their environment?

Dr. Elinav: I think that the data we have certainly points toward that direction. So there's lots of data emerging in animal models and also quite a lot of data emerging in humans that suggest that the critical window of opportunity in the first three years of a human's life is the window in which we shape our adult configuration of the microbiome. And this window of opportunity is also a window of risk is one in which, you know, the microbiome can be influenced both by our parents and our immediate surroundings but also by what we eat, what we're exposed to, and the amount of environment that our microbes sense. And this kind of brings a little bit of a paradox because we as humans were raised in the last two centuries to be afraid of microbes and of infections, which justifiably were the leading cause of death in humans for millions of years. We now are slowly realizing that by overly protecting our children from exposure to these microbes that surround us in, you know, every material that surrounds a young child may predispose to an underdevelopment of their microbiome. In other words, by subjecting kids to an overly sterile condition, we may be harming them by not allowing their microbiome to shape in a diverse enough manner that would train our immune system and would impact our healthy metabolism in a way that would result in health in years to come, especially in mice but also to some extent in humans, it was shown that early-life exposure to antibiotics, for example, could save lives in many cases, but the price that we may pay is an increased risk for diseases such as asthma, these are elegant studies that were performed by my friend and colleague, Brett Finlay, and to obesity in later life and other diseases. So, you know, the proof of causality especially in human patients is very hard to achieve, but it seems that the majority of evidence from the decade and a half of microbiome research certainly points to that possibility and to that direction.

Dr. Patrick: I remember...my son is now four, but, you know, when I was, you know, a really new mother, I remember coming across a study where early life exposure within the first year to dirt like, you know, dirt and, you know, obviously the bacteria that are in the dirt, it seemed to be protective against later development of asthma was a big one. I think there was, you know, an autoimmune type of, you know, response. As you mentioned, you know, we... This hygiene, you know, obsession that we have in the industrialized nations, you know, which, you know, there's a good rationale behind that, but, you know, we all live in these buildings, and, you know, not many people have, you know, any dirt or trees or just, you know, sand, and so you really in some cases have to make an effort to go out and expose your young child, you know, let them play in the dirt, let them get dirty. And so I definitely tried to do that as much as possible when my son was...during early development.

Dr. Elinav: I totally agree. And this is supported, for example, by epidemiological evidence of some of the autoimmune or other inflammatory diseases being much less prevalent in kind of, you know, "dirtier countries" or countries in which the prevalence of exposure at early life to environmental infection is higher as compared to cleaner "countries," which suffer from a marked increase in these autoimmune or other inflammatory diseases. There are very elegant studies by my colleague, Martin Blaser, from NYU showing in mice and I think also in humans that this overly...these distinct depletion or changes on the development of the microbiome could impact on the susceptibility to develop diseases such as inflammatory bowel disease in later life. So this link certainly has been suggested and to some extent has been demonstrated to probably occur. A formal proof of causality in diseases, which may take many years and even decades to develop, is very hard to achieve in humans. So there too I think that the supporting evidence is very robust, but in order to get a completely, you know, finalized proof, you know, it will take more time.

Dr. Patrick: The question I have is like is there...? We're talking a lot about the environment, how that's shaping the gut microbiome, and it just sort of came to my mind like, you know, there are some women, for example, that, you know, have IBD, irritable disease, or something for whatever reason, you know, whatever the causal factor is. Is there a genetic component or something that can still influence the microbiome composition let's say that woman has a child? And, you know, like is there some sort of transgenerational effect of microbiome? Like what if, you know, this woman had a lot...? Maybe she's got IBD because she had serial exposures to antibiotics combined with, you know, poor meal timing or, you know, who knows what the combination of environmental factors could have been to influence her microbiome. Does the mother's microbiome affect the child's microbiome? Is there any evidence of that?

Dr. Elinav: Well, I would divide my answer into two parts. First of all, every child is born sterile to the best of our knowledge and acquires his or her microbiome during the neonatal period from his or her immediate surrounding, which mainly consists of their parents who are very close to them. So in addition to many other environmental factors, it seems that a child's microbiome is very much influenced by that of their parents, and especially their mother in cases in which the mother, you know, takes more care of a baby than the father. With that said, the question you're raising is a fundamental question in the microbiome field, which if I were to rephrase would ask whether the microbiome is shaped by our genes or by our environment. And this remained an open question for many years until we conducted an ambitious study in which we took 500 healthy individuals, and we comprehensively profiled their microbiome and assessed as much as we could many of the environmental factors that influenced them including their dietary habits and so on and so forth. And we sequenced their genes, so we characterized their human genome. So for the first time, we could directly compare the influence of our human genome and our environment on the composition and the function of the microbiome and also to compare the potential contribution of the microbiome and the human genes on different human traits. And the answer was an intriguing answer. What we found was that most of the effect shaping our microbiome comes from the environment. Only 1.9% of the variability in the human microbiome could be explained by differences in the human genes, while close to 99% of the variability in the human microbiome was explainable by factors coming from people's environment. That doesn't mean that the 1.9% of the genes is not exceedingly important. There could be some genes there that are exceedingly and dramatically important in generating a healthy microbiome. It just tells you that the weight of the effect is mainly coming from the environment, and this is very encouraging because the environment in contrast to our human genes could be modulated. So if a microbiome changes for any reason to a configuration which favors disease, we could hopefully find ways by which we modify the environment that is sent by the microbiome in order to reverse it back into a healthy configuration.

The second revelation from this study was equally interesting to us, and what we found was that some human traits were only impacted by the human genes. So, for example, if you look at human height, it is not affected by the microbes whatsoever. So almost all of the explanations for differences in human height came from the human genes and not from the microbes. However, when we looked at a number of metabolic parameters such as weight, waste to heat ratio, cholesterol levels, and many other metabolic features, we found that the microbes...the microbiome and the human genes had independent and very substantial effects on these traits. In other words, the microbiome in the human body or the human genomic system participate in the determination of our healthy metabolism and our risk of developing metabolic disease.