Dr. Patrick: I kind of want to start off, Eran, with the circadian rhythm that the gut microbiome is on and how this can relate to meal timing and metabolic responses. We have talked quite a bit about circadian rhythms on the podcast from, you know, the master circadian clock in our suprachiasmatic nucleus and how light resets that clock and how there's peripheral circadian clocks in other organs such as the liver and how food intake is the major signal that resets that clock. So a few years back, your lab discovered that the bacteria that reside in our gut have their own circadian rhythms. So can you talk...maybe just explain a little bit about this to people?

Dr. Elinav: Absolutely. It's great to be talking to you, Rhonda. We have done a lot of research, I mean, trying to understand better how the composition of diet impacts our gut microbes and through interactions with our microbes mediate metabolic health and metabolic disease. But surprisingly, we stumbled upon a quite major discovery in which not only the composition of diet impacts our gut microbes, but actually, the timing of diet has an independent and very peculiar effect on the composition and on the function of our gut microbes. And through these time-dependent interactions, our gut microbiome can independently impact our metabolic health or our propensity to develop diseases such as obesity and type 2 diabetes.

And basically, the discovery came across a very laborious project in which we tried to characterize the composition and the function of our gut microbes at different time points along the 24-hour cycle. So basically, my students sampled mice or humans each...every four hours of an entire 24-hour cycle, and then we were surprised to find that many of the functions of our microbes change in very consistent manners along the course of a day. Now, this was super surprising to us because, if you think about it, our gut microbes live completely in the dark. So how do they know that it's day or night and change their activity so reproducibly at the exact same hours along a 24-hour cycle? This led to three years of intense research, and the answer was that our microbes sense the timing in which we eat or do not eat and change their activity accordingly. In other words, during the day when humans are awake and eating, the microbes behave in one way, but during the night when we're asleep, they behave in very different manners. And in mice, which are awake at night and sleep during the day, this activity is completely opposite.

Dr. Patrick: So I have a follow-up question for you. You know, there's been a lot of research that has looked at how many genes in our body, and particularly genes that relate to metabolism, are controlled, you know, by a circadian rhythm. And so, for example, you know, there've been quite a few studies now that have shown that people are...if you give them identical foods in the morning versus the evening time, and you look at postprandial glucose response, for example, you'll see that people...you know, their postprandial glucose response is much higher in the evening, people are more insulin sensitive in the morning as well. So, to the bacteria in our gut, is there a role that they play in energy production in perhaps the postprandial glucose response, for example?

Dr. Elinav: Yeah. That was one of the most surprising and intriguing parts of our discovery. Not only did we discover that the timing of our diet impacts the composition and the function of our gut microbes throughout the course of a day, we found that this amazing tangle between our diet and our microbes also signals to the host, to mice in some cases and to humans in other studies which we conducted. And basically, this circadian microbial activity builds into the circadian clock which hallmarks every cell and organ in our body. In other words, the microbial circadian rhythmicity is a critical part that participates in disorderly diurnal behavior of our cells and our organs at different locations in our body. And once we disrupt the circadian microbial activity, for example, by changing the patterns of our diet or by subjecting mice to jet lag behavior, the microbes go crazy and stop behaving in this orderly manner throughout the course of a day, and this directly reflects on how the host behaves in its normal circadian behavior. And we found that once we disrupt the microbes, the host is now susceptible to develop obesity and type 2 diabetes, which is exactly the set of diseases which hallmark humans which feature a chronic disturbance in their wake-sleep patterns such as shift workers that are at a substantial risk of developing obesity and type 2 diabetes. And for many years, we didn't know what was the missing link that caused this risk behavior, and now we think that at least part of the answer lies within the microbes themselves.

Dr. Patrick: Do you think that there's any potential solutions for, for example, shift workers who are awake in the evening hours and eating food? So we've learned a lot about time-restricted eating or time-restricted feeding and how that can potentially positively impact, you know, a shift worker's metabolism if they try to limit their food, for example, into a certain time window, maybe 10 hours, you know, rather than, you know, eating throughout the time that they're awake at night. Do you think that this also has implications for affecting the gut microbiome as well, doing this time-restricted eating if you're a shift worker or even in general?

Dr. Elinav: Absolutely. And what we've discovered at least in mice, and also to some extent, we and others have discovered this to occur in humans, is that the dominant factor that determines the diurnal activity of microbes throughout the course of a day is the timing of our feeding. And when we disrupt the timing of our feeding, for example, by subjecting mice to a shift to our kind of lifestyle or jet lag or even in genetically clock-deficient mice, we disrupt the microbial circadian activity. However, if we take all of these disrupted conditions and now we time-restrict the feeding of these mice to imitate the normal eating behavior in non-disrupted mice, then we can completely restore the microbiome circadian activity and its effect on the metabolic and immune function of the host.

So at least in mice and to some extent in humans, indeed, time-restricted feeding could restore unaltered microbial behaviors across...uh, behavior across a course of a 24-hour cycle. However, you know, if you think about it, this does not really solve the human problem because, if a doctor or a physician or a nurse in a hospital has to go through a night shift and therefore features a disrupted microbiome and a risk of developing obesity and type 2 diabetes because of the disrupted microbiome, you cannot ask a nurse or a physician, you know, to eat after they've been awake for an entire night just so they restore their gut microbiome composition function. So what we're trying to do is to decode the molecular mechanisms by which our microbes communicate with our host cells at different time points throughout the course of a day. And when we understand what goes wrong, what gets disrupted when the circadian rhythm is disturbed, maybe we could develop new interventions that would enable the microbes to now correct the signal to the host and to avoid these risk behaviors and these susceptibility to disease.

Dr. Patrick: If some of these microbes...so they're obviously sensitive to the feeding-fasting period, so food intake versus not eating. What about the composition of the food? Like, does that play a role? Does that matter in addition to, you know, some of these microbe species that are, you know, active on their diurnal circadian rhythm?

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.