Are Your Bacteria Jet-lagged?
By Elizabeth Norton
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.
Microbe shown to regulate its host’s biological clock
April 12, 2013 by Terry Devitt
At a time when scientists are beginning to recognize the pervasive influence of microbes in a legion of plant and animal functions, new research shows a symbiotic bacterium setting the biological clock of its host animal.
The research, published online in the journal mBio, is the first to show that a microbe, in this case a bioluminescent bacterium known as Vibrio fischeri, regulates a daily rhythm of its host, the Hawaiian bobtail squid. The work is important because it hints at a deeper and more extensive biological interplay between host organisms and the microbes that are ubiquitous companions and symbionts to all plants and animals, including humans.
The new study, conducted by a group led by Margaret McFall-Ngai of UW-Madison, reveals that the light generated by the colonizing bacterium triggers a genetic cascade in the cells of the squid light organ, which, in turn, control the daily cycle of biological activity typically synchronized by environmental cues such as sunlight.
"Instead of environmental light, this animal responds and cycles in response to the luminescence from its own light organ," explains McFall-Ngai, a professor of medical microbiology and an authority on the bobtail squid and its luminescing symbiotic bacterium.
Circadian rhythm in humans and other animals is governed by an internal or "biological clock" with a cycle of about 24 hours and seems to be regulated largely by exposure to light and darkness. It is responsible for sleep cycles and other physiological and metabolic functions. Its most visible manifestations in humans occur in things like jet lag and the effects of night work shifts. Disrupting the daily cycle can have serious health consequences, including sleep and immune system disorders, and conditions like seasonal affective disorder.
At the molecular level, circadian rhythm is driven by a set of "clock genes" and their relatives, according to McFall-Ngai.
"This animal has a light-producing system in an organ in the middle of the body," says McFall-Ngai. "The bacteria in the light organ are luminous, and their luminescence affects the expression of a clock gene known as 'cry' in the cells of the light organ that are interacting with these luminous bacteria."
The squid spends its nights foraging near the ocean surface. It uses the light organ as a sort of cloaking device to fool predators lurking below. At daybreak, it expels or vents 90 percent of the glowing bacteria and burrows into the sand where it can safely sleep until nightfall when, with a new crop of bacteria, it resumes its nocturnal foraging.
In the squid, the daily cycling of the cry genes found in the cells of the light organ are triggered by the light from the colonizing luminescent bacteria, making it a neat model to understand the interplay of a symbiont bacterium and the biological functions of its host.
"In humans, the genes expressed in the gut are on a profound circadian rhythm run by the clock genes," notes McFall-Ngai. "Everything in the human gut is on a rhythm. Perhaps the thousands of bacteria there also govern the rhythms of the gut, just as the luminous bacteria partner of the squid sets the rhythms in the light organ.
"In the squid, we have one host and one microbe, and we can manipulate the microbe genetically and the whole system experimentally, which provides much more resolution than can be done in studies of the human gut."
McFall-Ngai and her colleagues assessed the expression of the cry gene with and without bacteria present, and also with mutant bacteria incapable of producing light. Their results showed for the squid's clock genes to be expressed in a rhythm, light from the bacterium is required.
While the study adds insight into the importance of biological rhythms for an animal's well being, the most astonishing insight is that an animal's circadian rhythm and the molecular switches that control it can be governed by a symbiotic microbe. Says McFall-Ngai: "We're beginning to realize that circadian rhythms are really important for health and that microbes are important for everything."
Co-authors of the new study include Elizabeth A.C. Heath-Heckman and Suzanne M. Peyer, also of UW-Madison; Cheryl A. Whistler of the University of New Hampshire; Michael A. Apicella of the University of Iowa; and William E. Goldman of the University of North Carolina, Chapel Hill. The research, published in the (DATE) edition of the journal mBio, was supported by the National Institutes of Health (RO1-RR12294, RO1-AI50661) and the National Science Foundation (IOS 0517007, IOS 0715905).