With more microbes than cells in our body, it’s not surprising that 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 ping 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.
“It’s quite an important finding,” says Antoine Adamantidis, a neuroscientist at the University of Bern who was not involved with the work. “Our life depends on food intake, and this is one more [thing] that bacteria can [influence].”
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. Ilana Gabanyi, a neuroimmunologist at the Pasteur Institute, wanted to know whether these molecular detectors also exist in the brain’s nerve cells.
Gabanyi and colleagues 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, Gabanyi says, 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, she adds.
Next, she and colleagues 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, Gabanyi and her colleagues report today in Science.
“I had no idea that these [fragments] make it into the brain,” says Christine McDonald, a molecular biologist who studies the body’s bacterial sensors at the Cleveland Clinic.
The experiments also showed radioactive muropeptides build up more in female mouse brains than in male brains, and have stronger effects on females, Gabanyi says. 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.
Together, the new experiments identify a direct mechanism by which bacteria can control the brain, says Livia Hecke Morais, a neurobiologist at the California Institute of Technology. Until now, demonstrations of such direct connections “have been lacking,” adds Margaret McFall-Ngai, a developmental biologist at the Carnegie Institution for Science.
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, says Juan Escobar, an evolutionary biologist studying gut microbes at the Vidarium Nutrition, Health, and Wellness Research Center who was not involved with the work.
Based on the findings in the older, female mice, Gabanyi and her colleagues speculate that the muropeptide control system gains importance as hormone-driven regulation of appetite and body temperature declines with age. Similar hormonal changes in women entering menopause are associated with weight gain and hot flashes, making researchers wonder whether the muropeptide-Nod2 system could provide a nonhormonal target for treating those problems. If this system also exists in humans, “there’s a lot of potential [for treatment],” Morais says.
Still other scientists stressed that the findings were in mice—and therefore need much further study. But McFall-Ngai notes that in squid, Nod2 also senses bacterial cell wall fragments and helps controls the animal’s development. So she is convinced this communication system is an ancient one, likely to be found in all vertebrates.
Science, 14 April 2022