Dr. Patrick: I do want to ask you about some of the top lifestyle modifications. And I know that we've been talking a lot about personalized nutrition, so it's challenging to answer that question. But before we get there, just out of my own interest, we've talked a lot about the compounds that are generated in the gut perhaps from, you know, many of the bacteria in the gut and how these compounds can have beneficial effects on human health and also can have detrimental effects on human health. And there's one compound that I've been following for a while and I continue to follow, and it's a compound that is associated with atherosclerosis and heart disease. It's TMAO and it's produced from precursors like L-carnitine or even choline which are found in red meat and eggs respectively. You'll find a lot of conflicting evidence looking at, for example, the observational data, epidemiological studies where you see, you know, people that eat red meat and/or, you know, eggs. If they are healthy and they don't have metabolic disease, they don't have type 2 diabetes or dyslipidemia, they don't have unhealthy lifestyle factors, so, for example, they're active, they don't smoke, they don't excessively drink, they're, you know, not overweight that they actually don't have a higher cardiovascular disease risk or mortality or all-cause mortality as people that are not consuming those types of foods that are high in L- carnitine or choline. But you'll see if people have unhealthy lifestyle factors, they do have an elevated risk. You'll see a lot of conflicting evidence, and it's you're trying to figure out, "What do I eat? What do I not eat?" What role does the microbiome play in the production of the TMAO which is thought to be associated with heart disease? Yeah.

Dr. Elinav: It's a great question based on a great set of stories by Stan Hazen's group, which I think contributed a very important concept to our understanding of how the microbiome cooperates with the human body in generating together compounds which may impact human health. So in this particular case, we're talking about a connection between dietary compounds such as choline and carnitine, which are digested by the microbes into a compound called TMA, which then influxes into the host and is further converted by the host...by the liver of the host into TMAO, and this TMAO swims into the circulation where in some instances, it could impact macrophages that form plaques that are responsible for atherosclerosis and it's potentially devastating health effects, heart disease, brain disease, kidney disease, and more. So from a fundamental microbiome perspective, this is a fine example of a cooperation that exists between dietary cues that are perceived by the microbes and then further modulation by the host that leads to a health outcome.

Now, you're absolutely right that if you look at a health perspective, and now I'm speaking as a physician, you know, you cannot explain atherosclerosis by just one factor. You cannot say that, you know, one type of microbial reaction or one type of food or even one genetic risk factor in a human individual would explain the entire spectrum of this huge and highly variable disease. By definition, these common multifactorial diseases are influenced by a combinatorial collection of risk factors. And I think what this fascinating study has provided was the proof of concept on how mechanistically one could explain the influences of particular types of diet and the microbes on the risk of developing a particular disease in some individuals with other risk factors that contribute to this disease. So I would never expect that every individual that would be exposed to the same levels of carnitine or would feature the same bugs that convert choline into TMA would develop heart disease. It's a combination by many different risk factors.

Coincidentally, we've recently published another study focusing on a peculiar type of obesity that develops after cessation of cigarette smoking, and to make a long story short, we found a similar cooperation between the microbiome and the host in generating compounds that could drive this obesity phenomenon after smoking cessation. So it seems that the concept which we termed the "holobiont" concept, in which you can regard a human as a combined set of microbes and human cells, could contribute to many of the more complex health outcomes that are so concerning to many of us.

Dr. Patrick: Well, with that said...this has been a really interesting conversation, Eran. Thank you so much. We've talked a lot about precision medicine, personalized nutrition, and how people respond differently to foods. So it's a little hard to, you know, come up with a top lifestyle modifications or, you know, to improve gut health. But, you know, in your opinion, are there some low-hanging fruit? We are not there in terms of our precision medicine and personalized nutrition yet. We're beginning to understand a lot more about it, thanks to research from your lab and others. But are there some low-hanging fruit, things that like, you know, maybe perhaps consuming foods that have some of these fermentable fibers or prebiotics like you mentioned or fermented foods that also have probiotics and things like that?

Dr. Elinav: It's a great question and a question that I'm being asked very often. I can tell you that what we've been discovering in our own studies, even, you know, without looking into the personalization aspect, is that some of the behaviors, you know, which your grandmothers would recommend to you are also beneficial in terms of what they do to the microbiome. So, for example, maintaining healthy sleep patterns and avoiding as much as possible erratic sleep weight behavior has very profound effects on our measurement of the microbiome, how it impacts our regulation of weight and the glucose or sugar metabolism or the avoidance of type 2 diabetes, for example. In terms of fiber, you know, in general, I think that the data is quite solid in promoting fiber as a good, you know, family of foods to consume. However, I must say that we and others are engaging very exciting studies, which suggests that even with fibers...not all fibers are created equal. In other words, you know, even fibers are composed of many different chemical formulations that differ from each other in the way that they are consumed by the microbes and impact the human body. So even with fibers and with the generally beneficial effects that have been observed with them, it seems that some fibers are better than others. And we're trying to contribute towards new knowledge that would refine this recommendation in different individuals and with different fibers. You know, smoking seems to be a universally bad behavior for many reasons, but when we measure what it does to the microbiome, we were intrigued to find that many cigarette-related chemicals not only reach the systemic circulation, but they actually penetrate the gut, and they impact the microbiome towards a disturbed composition and function. And this has its own independent effects on, for example, the risk of developing obesity after you start...you attempt to stop smoking. So all of these behaviors, which in many cases we know are probably not good for us, are also not good for us in terms of their effects on the microbiome. Beyond this, I think that we need data, we need knowledge, we need to increasingly learn to harness diet to the individual in order to really optimize the power of the microbiome in impacting human health.

Dr. Patrick: And what about the timing of our food intake? Would you say that's a pretty top...?

Dr. Elinav: I can tell you that in our personalized nutrition machine learning algorithms, which are used to predict a person's dietary responses in a very accurate manner, the timing of our diet and even the timing of our meal last night are part of the features that are used by this unbiased algorithm in order to form its very accurate predictions. In other words, it seems that the timing of our diet is important for many different aspects coming from many different studies by us and by others. What we do with it in addition to, you know, trying to time our diet in a kind of normal and routine manner is still under review or under research.