Dr. Patrick: You had a very recent study actually that was very interesting and looked at some of the potential mechanisms behind why people that are starting out overweight or obese go on some sort of dietary program to lose weight, and yet they tend to gain that weight back quite easily. So can we talk a little bit about some of that recent work?

Dr. Elinav: Absolutely. This phenomenon which is medically called recurrent obesity but is more widely known as yo-yo obesity characterizes up to 80% of all obese individuals worldwide. So this is the most common pattern of obesity that we know of yet we have very little clue on what drives it. The pattern is as you suggested, a person who gains weight for any reason and then goes on in one of many different diets that are out there. And most diets are very efficient in reducing weight in the short term because they involve caloric restriction. So that person diets on one of these many diets, loses weight back to his or her original low body weight, but then within 12 months of successfully dieting, 80% of people go on to redevelop obesity or regain all the weight that they've lost and even regain a little bit more than they originally had. And from cycle to cycle of obesity and dieting attempts, we seem to get more and more obese until we gain...we become formally obese. This is exactly the pattern of recurrent or yo-yo obesity.

Now, if we're trying to...or if we're starting to scrape the surface in understanding the molecular mechanism that drives obesity...we know very little about this driving...about this recurrent yo-yo obesity phenomenon. So we tried to study it in mice, and we developed three or four different animal models that recapitulate this recurrent obesity behavior in humans. In other words, for example, we took mice, we put them on an obesogenic diet, we gave them a diet rich in fats and sugar, they gained weight, then we switched them into a low-fat diet. They dieted back to their original level. And then we re-exposed them for a second and a third and a fourth cycle. And what we could see was exactly the same phenomenon that is observed in humans. From cycle to cycle, mice seemed to regain more and more weight even when they started from the exact same weight as never obese mice and were exposed to the same exact diet. This is the exaggerated weight regain that characterizes yo-yo obesity in humans.

Now, in order to try and study and understand what the drivers of these behaviors are, we looked into tens of different parameters that can be measured in mice after they successfully diet to look for something in the mice following a successful diet that could store a bad memory of their previous obesity. And it seems that everything seemed to normalize after a successful diet. All the hormonal and the endocrine and the metabolic features that we could measure totally normalized after a successful diet other than the gut microbiome. When we measure the gut microbiome, it seemed to be persistently disturbed as though the mice were never dieted. It had a configuration which was very similar to the one that we observed during obesity. And when we took this microbiome that never normalized after a successful diet and transferred it into germ-free mice, these mice developed obesity and type 2 diabetes, meaning that this post-dieting microbiome stored a metabolic memory of past obesity that predisposed the mice to an exaggerated weight regain the next time they were exposed to an obesogenic diet. And when we probed even deeper into this memory microbiome, we found that it induced this trait of exaggerated weight regain by altering its ability to degrade dietary compounds which are called isoflavonoids. Normally, we found that isoflavonoids from diet are degraded by the microbiome to compounds which swim into adipose cells and signal to them to release more heat and store less fat when we are exposed to an obesogenic diet. But when these compounds were missing after a successful diet, the adipose cells, the fat cells were no longer given the signal to release heat and not to store fat, and now they were storing more fat and making the mice more obese as compared to non-yo-yo obesity mice. In other words, the microbiome was driving this exaggerated weight regain tendency by changing its metabolism of distinct molecules coming from our diet.

Dr. Patrick: If I remember correctly, some of these distinct molecules were these flavonoids like apigenin, which is high in, for example, parsley and naringenin or naringenin. I don't know how you pronounce it, but it's from grapefruit really essentially. So there's bacteria that are degrading or metabolizing these flavonoids. The obesity is causing a decrease in these types of bacteria. Is that correct?

Dr. Elinav: Exactly. So the bacteria normally...actually generate these flavonoids for more complex flavonoids by chemically modifying them. Once this obesity and then successful dieting occurs, the change in the microbiome that is so persistent means that the microbes are no longer able to generate these compounds, and this leads to a cascade of events that results in more fat accumulation per given diet leading to exaggerated weight regain.

Dr. Patrick: So do you think then that perhaps consuming foods high in some of these compounds like grapefruit and/or supplementation would help with that if your microbiome is not producing those compounds but you need those compounds? Is that correct? Am I understanding that correctly?

Dr. Elinav: It sounds like the microbiome is not producing the compounds if the microbes that are degrading these compounds are expanded in these obesogenic conditions, and therefore there's more degradation of these compounds and less of them that survive this microbial activity. And indeed at least in mice, what we've found was that if we intervened by resupplementing a mice with these now missing metabolites, we could avoid or treat exaggerated weight regain and obesity that it induces. A different approach that we've used in mice and seem to be highly effective is the replacement of this bad memory microbiome with a microbiome that had the ability to generate the right compound. And by fecal microbiome transplantation at least in mice, we could reset the mice to not develop this yo-yo obesity phenotype. So, it seems that by understanding the molecular mechanism that drives obesity in this distinct state, one could intervene through the microbiome or at least in mice and reverse this tendency and therefore treat obesity or ameliorate obesity at least in this context.

Dr. Patrick: Do you have any plans to look in humans, for example, that you could give them a supplement with these flavonoids to see if that...how that affects the metabolic outcome?

Dr. Elinav: It's not only plans, it's an ongoing trial that is aimed at utilizing the many pipelines that we've developed in mice to measure these effects and to measure the possible microbiome impacts on recurrent obesity and to study them in humans. Of course, humans are a much more complex animal than mice, but many of the concepts seem to hold also in humans. So we're studying this and trying to understand what happens in humans, which are the bugs and the molecules that they secrete which may contribute to this bad microbial memory that we have identified in mice, and how we can intervene in humans through different approaches including metabolites supplementation that would reverse or treat recurrent obesity in humans.

Dr. Patrick: That's very exciting. I eagerly wait for the data. You mentioned that people that are...you know, can successfully lose weight by a variety of diets, and a lot of them have to do with caloric restriction, in other words, they're just eating less food, and how, you know, that helps with weight loss. What effect does caloric restriction have on the gut microbiome?

Dr. Elinav: I think that it's very interesting to note that just like the findings that we and many others after us have noted with respect to recurrent obesity and its effect on the microbiome and downstream metabolism, equally interesting studies that recently came out that suggest that caloric restriction may have a peculiar effect on the microbiome that may drive its beneficial effects. There are many studies suggesting that periodic food restrictions such as, you know, those 16:8 diets and many others may have beneficial metabolic effects, although, you know, the jury is still out there. I need to be careful. Some studies have been showing less impressive results. But at least some of the effects may be mediated by the microbiome. Certainly, we see in these studies that caloric restriction or periodic avoidance of food has distinct changes on the microbiome, and these may contribute to different metabolic outcomes that are measured in these studies.