Can gut microbes regulate appetite and body temperature? | Science

With more microbes than cells in our bodies, it’s no surprise that bacteria and other invisible “guests” affect our metabolism, immune system, and even our behavior. Now, researchers studying mice have worked out how bacteria in the mammalian gut can pressure the brain to regulate an animal’s appetite and body temperature — involving the same molecular pathway that the immune system uses to detect bacterial pathogens.

“It’s a very important discovery,” says Antoine Adamantis, a neuroscientist at the University of Bern, who was not involved in this work. Our lives depend on eating, and that’s another matter [thing] Bacteria can [influence]. “

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

When certain gut bacteria infiltrate the rest of the body, our immune system picks up on them by sensing parts of their cell walls, known as muropeptides. Our molecular reagents for these moropeptides, proteins called Nod2, coat the surfaces of cells involved in the body’s first line of defense. Ilana Gabbani, a neuroimmunologist at the Pasteur Institute, wanted to know if these molecular reagents are also present in neurons in the brain.

Gabbani and colleagues started with genetically modified mice: some were engineered not to contain Nod2, and others were engineered to produce a fluorescent tag that identifies where the molecular reagent is made. The first evidence that morphopeptides affect appetite came from mice without Nod2. Compared to normal mice, these rodents gained additional weight with age. This suggests, says Gabbani, that morphopeptides may provide a “whole” brain signal that is absent in Nod2-null mice. She adds that because food can stimulate the microbes in the gut, it is likely that eating food will trigger the release of morphopeptides.

Next, she and her colleagues fed the other mice a little more radioactive peptides. Four hours later, they examined to see where the morphopeptides traveled in the rodents’ bodies. By monitoring the radioactivity, they found that the morphopeptides were transported to the brain. Together, the experiments revealed that Nod2 is actually produced in the mouse brain, and morphopeptides can get there. Within hours of reaching the gutGabbani and her colleagues today in Science.

“I had no idea about this [fragments] “You make it to the brain,” says Kristin MacDonald, a molecular biologist who studies bacterial body sensors at the Cleveland Clinic.

The experiments also showed that the radiopeptides accumulated more in the brains of female mice than in the brains of males, and had stronger effects on females, says Gabbani. Older mice lacking in the brain Nod2 eat more at each meal than mice that were not genetically modified. They also maintained a higher body temperature and tended to spend less time building nests to stay warm–suggesting that Nod2 may have other physiological roles.

There were other downsides to disruption of the gut-brain communication pathway: female mice without a natural supplement of Nod2 tended to develop diabetes and did not live as long as typical mice. Mice that were given antibiotics to kill gut bacteria also had similar problems. Researchers believe this is because morphopeptides never entered the brain to help regulate appetite and body temperature.

Together, the new experiments identify a direct mechanism by which the bacteria can control the brain, says Livia Heck-Morais, a neurobiologist at Caltech. So far, Margaret McFall-Ngai, a developmental biologist at the Carnegie Institution for Science, adds, “there has been a lack of manifestations of such direct links.”

It is unclear whether Nod2’s role in the brain, or its immune function, comes first. “The same molecule that alerts our immune system that something is wrong can 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 who studies the gut microbiome at Vidarium Nutrition. Not involved in the work.

Based on findings from older female mice, Gabbani and colleagues predicted that the morphopeptide control system gains importance as hormone-driven appetite regulation declines as body temperature decreases with age. Similar hormonal changes in women entering menopause are associated with weight gain and hot flashes, causing researchers to wonder if the muropeptide-Nod2 system could provide a non-hormonal target for treating these problems. If this system also exists in humans, “there is a lot of potential [for treatment]Morris says.

Still, other scientists stressed that the results were in mice – and therefore need further study. But McFall-Ngai notes that in squid, Nod2 also senses bacterial cell wall fragments and helps control animal growth. So she is convinced that this communication system is ancient, and is likely to be found in all vertebrates.

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