Life on Earth is intimately connected to the natural cycles of light and dark that make up a 24-hour day. For plants, animals, and even bacteria, these circadian rhythms control many biological functions. Humans can overrule their body clocks, but at a price: People whose circadian rhythms are regularly disrupted—by frequent jet lag or shift work, for example—are more vulnerable to diabetes, obesity, cardiovascular disease, and cancer. There are various theories to explain these associations, and researchers now have a new player to consider: the bacteria that live in the digestive tract. According to a study in mice and a small group of human volunteers, the internal clocks of these gut microbes sync up with the clocks of their hosts. When our circadian rhythms get out of whack, so do those of our bacteria.
The last several years have seen an explosion of interest in the constellation of bacteria that call the gut home, and these microbes appear to play a role in everything from immunity to metabolism to mood. But although disrupted bacteria are observed in many of the same diseases that arise from skewed circadian rhythms, the precise link isn’t fully understood. Eran Elinav, an immunologist and microbiome specialist at the Weizmann Institute of Science in Rehovot, Israel, wondered whether the microbes’ own circadian rhythms were a missing piece of the puzzle.
To test the theory, he and his colleagues analyzed bacteria in fecal samples from lab mice kept in normal 12-hour cycles of light and darkness. Samples were taken every 6 hours for two 24-hour cycles. Up to 60% of the microbes consisted of various bacterial types that fluctuated, in both their total number and their prevalence relative to each other, throughout the day and night. During the dark phase (when mice, being nocturnal, are most active), the bacteria were busy digesting nutrients, repairing their DNA, and growing, as evidenced by the various bacterial gene activity documented from fecal samples taken at different time points. During the light phase, microbes went about ongoing "housekeeping" processes, such as detoxifying, sensing the chemicals around them, and building the flagella, or tails, that help the microbes move.
In mice with a mutation that disables the inner clock, the gut bacteria didn’t exhibit the same fluctuations, in either population or activity, in response to light and dark—suggesting that the animal's clock somehow controls that of the bacteria. When bacteria from these "clockless" mice were transplanted into healthy animals living in normal light-dark conditions, the microbes began to show normal rhythms within a week.
The findings, reported online yesterday in Cell, came as a surprise, Elinav says. Previous studies have shown that many bacteria do have light-responsive circadian clocks—cyanobacteria, for example, which get their energy from photosynthesis. But microbes deep in the bowels of—well, the bowels—spend all their time in the dark. How did they know what time of day it was? Some signal must pass from the host to the bacteria.
One major difference between normal mice and clock-disabled ones was the time at which the animals ate, the researchers observed. Normal mice eat at night, while they're active; the clockless mice ate almost continuously. So could the timing of meals be the signal? When the researchers altered the animals' eating patterns by feeding normal mice only during the light cycle (a mouse's night), the numbers, types, and activity of the bacteria shifted as well. The researchers also found that mice whose light-dark cycles were disrupted gained weight and developed physiological changes linked to diabetes, such as insulin resistance. Because humans with irregular sleeping patterns also tend to eat more at night, the researchers suspect that these eating habits contribute to disease specifically by disrupting the gut microbes.
Bacteria are likely not the whole story; irregular sleeping and eating can contribute to disease through other routes, such as excess stress hormone and insulin production. Even so, "this is a compelling study," says microbiologist Rob Knight of the University of Colorado, Boulder. Knight says some of the strongest evidence for a bacterial role in circadian-linked diseases lies in the final phase of the study, when the research team analyzed fecal samples from two people on a normal schedule and two more who had recently flown from the United States to Israel. Analyzing the samples before, during, and after the bouts of jet lag, they found fluctuations in bacteria similar to what they saw in the mice. The jet-lagged participants showed an increase in a type of bacteria known to be more prevalent in people with obesity and diabetes; levels of these microbes dropped back to normal once the travelers adjusted to the new time zone.
Most convincing of all, Knight believes, is that when samples of gut bacteria from the jet-lagged humans were transplanted into healthy mice, the animals gained weight, showed increased blood sugar, and had a higher body fat content compared with animals given the bacteria of participants before their flight.
So can we ward off the ill effects of jet lag by being more careful about how or when we eat? At this point, "it's an educated guess," Elinav says.