Summary

Mice intestinal immune systems sync with gut microbe activity to provide scheduled protection against contaminated food, a new study suggests

Using scanning electron microscopy, scientists spotted segmented filamentous bacteria (green) attached to a mouse’s intestinal lining. This attachment typically occurs during the night (right) – when mice eat and are exposed to foodborne pathogens – and triggers timed production of antimicrobials. Credit: J.F. Brooks et al./Cell 2021

Immunity against foodborne bacteria may be linked to certain times of the day.

Most animals are programmed to eat according to the 24-hour day-night cycle. That means eating mostly during the day for humans, and mostly at night for mice. Microbes in the gut help digest food, and synchronize their activity with the host’s internal body clock.

Now, researchers have shown that some gut bacteria can anticipate when mice eat and activate the rodents’ intestinal immune systems. As darkness falls and mice begin to feed, these microbes attach to the gut lining – potentially to siphon off nutrients. This attachment triggers the production of antimicrobial proteins that ward off infection from contaminated food, Howard Hughes Medical Institute’s (HHMI) Investigator Lora Hooper, HHMI Hanna Gray Fellow John Brooks, and colleagues report July 28, 2021, in the journal Cell.

“It suggests that the time of day at which you eat determines your susceptibility to foodborne pathogens,” says Brooks, a microbiologist at the University of Texas Southwestern Medical Center.

To Ali Keshavarzian, a gastroenterologist at Rush University Medical Center in Chicago who wasn’t involved in the research, the study “opens up a new avenue to understand why some people exposed to foodborne bacteria get sick and others don’t.” But he cautions that “although mice studies help us understand an awful lot, we cannot extrapolate it to humans.”

Nearly all animals have a 24-hour circadian clock that’s tuned to the rising and setting of the sun. It regulates when they eat, sleep, and remain active. Mice, for instance, sleep – and fast – during the day and forage at night. Scientists have wondered how the mouse immune system responds to this daily periodicity of food, and foodborne germs.

Scientists detect higher levels of antimicrobial protein REG3G (green) at night (right), when mice feed, compared to daylight hours (left). Credit: J.F. Brooks et al./Cell 2021

Brooks and his colleagues first tracked the production of an antimicrobial protein called REG3G that’s secreted by the mouse small intestine. In a laboratory experiment, the researchers saw the protein levels oscillate over a 24-hour cycle, peaking when the lights went off and falling when the lights were on. But in germ-free mice that lacked gut microbes, the protein levels stayed low.

Those findings suggested that gut microbes play a role in dialing up production of antimicrobial proteins. The researchers took a close look at the animals’ small intestines to figure out which microbes might be involved.

Electron microscopy images revealed a key suspect: wispy strands of segmented filamentous bacteria tightly attached to the gut lining. Follow-up experiments confirmed that bacterial attachment peaked at night, and that this attachment upped antimicrobial protein levels.  

“They’re microbial timekeepers, sensing when the mouse is eating,” says Hooper, a professor of immunology also at UT Southwestern. The microbes somehow sense nightfall, and the onset of the animal’s natural feeding schedule, and then communicate with the mouse’s gut immune system.

The communication channel operates like this: when the bacteria attach to the small intestine, they stimulate immune cells that help protect and repair the gut lining. These cells then switch on a signaling protein called STAT3, which drives the secretion of antimicrobial proteins like REG3G.

In mice, cranking out bacteria-fighting antimicrobials at night is a way to “save energy by producing expensive immune molecules only when you need them,” Hooper explains. “That’s the rationale for almost all circadian biology,” she adds.

How susceptible different kinds of foodborne pathogens are to this scheduled antimicrobial protection remains to be seen. And scientists don’t yet know what the study’s outcomes mean for humans, who harbor segmented filamentous bacteria along with other microbes that attach to the gut.

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Citation

John F. Brooks et al. “The microbiota coordinates diurnal rhythms in innate immunity with the circadian clock.” Cell. Published online July 28, 2021. doi: 10.1016/j.cell.2021.07.001

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