Your genome is the same right now as it was yesterday, last week, last year, or the day you were born. But your microbiomes—the combined genes of all the trillions of microbes that share your body—have shifted since the sun came up this morning. And they will change again before the next sunrise.
Christoph Thaiss from the Weizmann Institute of Science has discovered that the communities of microbes in out guts vary on a daily cycle. Some species rise to the fore during daylight hours and recede into the background at night, while others show the opposite pattern.
These cycles are a lot like our own body clocks, or circadian rhythms. Over a 24 hour period, the levels of many molecules in our body rise and fall in predictable fashion. These rhythms affect everything from our body temperature to our brain activity to how well we respond to medicine. But these clocks tick by themselves. You can reset them by exposing yourself to light at different times of day (which is what we do when we cross time zones and get jetlag), but they are still self-sustaining.
Our microbiome clock is not. The microbes aren’t waxing and waning of their own accord. Their world is completely dark. There’s no way for them to tell what time of the day it is, except for clues provided by us. The most important of these clues is food. Thanks to our own rhythms, we eat at regular times of the day, and it’s these feeding patterns that drive the cycles in our microbiome. Diet is the gear that synchronises the ticks of our clocks with those of our microbes.
Thaiss first discovered these cycles by studying mice. He found that 15 percent of the bacterial species in their guts (representing 60 percent of the total microbes) varied in abundance over the day. But mutant mice that lack their own circadian clocks showed no such cycles. Instead of peaks and troughs, Thaiss found flat lines.
This difference was caused by food. Normal mice are nocturnal animals, and prefer to eat when it’s dark. But the clock-less mice don’t know when they’re meant to feed. “They eat like a buffet, throughout the 24 hour cycle,” says Eran Elinav who led the study. “They eat roughly the same amount, but the on-off timing is lost.” And since the flow of nutrients into their guts never changed, neither did their microbes. If Thaiss fed them on a strict schedule, he restored the usual rise and fall of their microbes.
The same cycles exist in humans, with one major and telling difference: the timing. A rodent’s microbes tend to switch on genes for growing, burning energy, and repairing DNA at night. During the day, they switch to maintenance mode, by activating genes for getting rid of toxins and sensing the environment. Our microbes do the opposite: metabolism and growth during the day, and maintenance at night. And this makes perfect sense! We are creatures of daylight, while mice are nocturnal. We flood our microbes with food while the sun shines and starve them when night falls; mice do the reverse. Our lifestyles are mirror images, and so are the cycles of our gut microbes.
And what if those cycles are disrupted? To find out, Thaiss jetlagged his mice. He shifted the lights-on time in their cages forward by eight hours, kept them like that for three days, and then shifted them back. This went on for four weeks. It was as if the mice were repeatedly flying back and forth from the UK and the west coast of the USA.
Predictably, at the end of this fake travel, the mice started eating at random times of the day. Their gut microbes stopped cycling normally, and the proportions of different species also shifted. In turn, these changes affected the mice, which developed signs of burgeoning health problems. If they ate a high fat diet, they put on more weight than mice with normal rhythms, even though they ate the same amount of food. They also had more problems controlling their blood sugar.
Thaiss confirmed that the ‘jetlagged’ microbes were responsible, by transplanting them into germ-free mice that lack their own microbiomes. The recipient rodents also started putting on weight. So jetlag, by disrupting a mouse’s regular feeding habits, can change the community of microbes in its gut. These distorted communities can then affect the health of their host, by influencing how they process their food.
Does the same apply to humans? To find out, the team analysed the gut microbes of two volunteers, before and after a flight from the USA to Israel. Sure enough, crossing the time zones changed the make-up of their microbiomes. In particular, they had a higher proportion of Firmicutes—a major group of gut bacteria, whose overabundance has been linked to obesity. Two weeks later, when the volunteers had recovered from their trip, their microbes had also reverted to their usual cycles.
When the team transplanted these human communities into germ-free mice, the rodents that got the jetlagged microbes put on weight, while those that got the normalised ones did not.
A lot of this is unsurprising. Dozens of studies have shown that what we eat can quickly affect the make-up of our microbiome. And if circadian disruptions make us eat at weird times of the day, our microbes would react accordingly. “But this paper is very important, because no one has ever proven that all of these logical things actually happen,” says Elizabeth Heath-Heckman from the University of California, Berkeley. “Hopefully, this paper will change how people view circadian disruption in humans, and get other researchers to looks towards the microbiome in determining how things like jetlag promote disease states.”
Elinav says that the health implications of the study are still unclear—a necessary caveat, especially given the fashionable tendency to ascribe everything to the microbiome. Many studies have shown that people who work variable shifts, or who suffer from disturbed sleep or repeated jet lag, are more prone to various health problems, including obesity, diabetes, and even some types of cancer. This study suggests that microbes (or rather, diet via microbes) might be involved in some of these connections. But how big a role do they play, compared to other possible factors? No one knows.
With just two human volunteers, “one really does need to be cautious not to over-interpret the implications for people,” says Mimi Shirasu-Hiza from Columbia University. Still, “this is really beautiful, thorough work, and I have to admit that I’ll definitely think twice about having that piece of cake for dessert when I’m jet-lagged!”
“The fact that alterations in scheduled feeding in the [mutant] mouse brought rhythm back to the microbiome gives us evidence to support controlled feeding in night-workers and jet lag situations,” says Jack Gilbert from the University of Chicago. “That might influence how bad we feel, or maybe even weight gain.” But Elinav cautions that this might not be feasible for people who live in a chronic state of disrupted clocks. “I’m not sure the future lies in changing their eating habits,” he says. “We eat when we’re awake.”
“There are factors besides travel and work schedules that can disrupt circadian rhythms,” adds Heath-Heckman. “Some mental disorders such as schizophrenia and Alzheimer’s disease are linked to alterations in circadian rhythms, and so advances in this field may help patients with such diseases as well.”
The study also has implications for scientists who study the microbiome. Many groups have compared the microbiomes of different people—say, lean versus obese, or old versus young—by using samples that were collected at a single point in time. But those samples might not be representative since this study, and several others, have shown that a single person’s microbiome can change dramatically over the course of a day. “Maybe, we should time our collection of the microbiome to a certain point of the day,” says Elinav.
Reference: Thaiss, Zeevi, Levy, Zilberman-Schapira, Suez, Tengeler, Abramson, Katz, Korem, Zmora, Kuperman, Biton, Gilad, Hamelin, Shapior, Halpern, Segal & Elinav. 2014. Transkingdom Control of Microbiota Diurnal Oscillations Promotes Metabolic Homeostasis. Cell http://dx.doi.org/10.1016/j.cell.2014.09.048
PS: I am writing this post having flown back from a microbiome conference. I am jetlagged, and eating a bowl of cereal at 4 in the morning. Paging Alanis…
More on circadian rhythms: