WITH MORE MICROBES than cells in our body, bacteria and other invisible “guests” influence our metabolism, immune system, and even our behavior.

Now, researchers studying mice have worked out how bacteria in the mammalian gut can signal the brain to regulate an animal’s appetite and body temperature—and it involves the same molecular pathway the immune system uses to detect bacterial pathogens.

Over the past 20 years, researchers have uncovered connections between the human gut and the rest of the body. They have linked certain intestinal microbes to conditions such as depression, multiple sclerosis, and immune system disorders; they have also documented nervous system connections between the gut and the brain. But researchers have been hard pressed to understand exactly how gut microbes—or the molecules they make—influence the brain.

When certain gut bacteria infiltrate the rest of the body, our immune system picks up on them by sensing fragments of their cell walls, known as muropeptides. Our molecular detectors for these muropeptides, proteins called Nod2, coat the surfaces of cells involved in the body’s first line of defense.

Researchers started with genetically engineered mice: Some were designed to lack Nod2, and others were engineered to produce a fluorescent tag that marked wherever the molecular detector was made. The first evidence that muropeptides influence appetite came from the mice without Nod2. Compared with regular mice, these rodents gained extra weight as they aged. That suggested that the muropeptides may provide a “full” signal to the brain that is absent in Nod2-free mice. Because food can stimulate microbes in the gut, eating likely induces the release of muropeptides.

Next, they fed other mice slightly radioactive muropeptides. Four hours later, they checked to see where the muropeptides traveled in the rodents’ bodies. By monitoring for radioactivity, they found that the muropeptides had traveled to the brain. Together, the experiments reveal Nod2 is indeed produced in the mouse brain, and that muropeptides can get there within hours of reaching the gut.

The experiments also showed radioactive muropeptides build up more in female mouse brains than in male brains, and have stronger effects on females. Older female mice lacking Nod2 in the brain ate more per meal than mice that had not been genetically modified. They also maintained a higher body temperature and tended to spend less time building nests to stay warm—indicating that Nod2 might have other physiological roles.

There were other downsides of disrupting this gut-brain communication pathway: Female mice without a normal complement of Nod2 tended to develop diabetes and did not live as long as typical mice. And mice given antibiotics to kill off their gut bacteria had similar problems; researchers think this is because muropeptides never got into the brain to help regulate appetite and body temperature. 

Unclear is whether Nod2’s role in the brain, or its immune function, came first. “The same molecule that alerts our immune system that something is wrong could be used by our nervous system as a signal to regulate key survival processes” such as eating and temperature control. By Manny Palomar, PhD (EV Mail October 10-16, 2022 issue)