The microbes are limited by low nitrogen levels, a study in mice and other mammals suggests
Humans and other animals may have a way to control the growth of gut microbes: Eat less protein.
That’s because protein contains nitrogen. And, it turns out, the amount of nitrogen in the diet of mice governed the growth of bacteria in the animals’ large intestine, researchers report October 29 in Nature Microbiology. The finding may help researchers learn how to manipulate the types and amounts of people’s gut bacteria, which can contribute to health and disease.
Researchers know that something must limit bacterial growth. “If not, we’d be a few feet deep in E. coli in a couple of days,” says Thomas Schmidt, a microbiologist at the University of Michigan in Ann Arbor not involved in the study.
But so far, scientists have had limited success controlling which microbes inhabit the colon. That may be because researchers were looking at the wrong nutrients, Schmidt says. Most, including Schmidt, have usually considered carbon — found in fiber, starch and sugars, for example — to be the most important nutrient microbes eat, he says. The new study suggests that other nutrients such as nitrogen may be as important, or even more important, for controlling bacterial growth.
Microbial ecologist Aspen Reese of Duke University knew that in most ecosystems, nitrogen, an essential building block of many biological molecules, is a limited resource. “Nitrogen is pretty important and it’s pretty hard to come by,” she says. If the growth of organisms in other ecosystems is limited by the availability of nitrogen, perhaps bacteria in the intestines are also starving for nitrogen, she reasoned.
Reese, currently at Harvard University, and her colleagues started by measuring carbon and nitrogen concentrations in the feces of 30 mammalian species. Herbivores had the highest carbon levels and the lowest nitrogen levels in their feces, the team found. Carbon was also the major nutrient in the feces of carnivores and omnivores, but the meat eaters had more nitrogen than those animals that ate mostly plants.
A study of feces from 30 mammal species (14 shown) suggests that gut microbes have a limited supply of nitrogen. Gut bacteria grown in lab dishes (dotted line) incorporated about four atoms of carbon for every nitrogen, but the feces contained more carbon for each nitrogen. Herbivores had the highest carbon levels and the lowest nitrogen levels. Carbon was also the major nutrient in the feces of carnivores and omnivores, but meat eaters had more nitrogen, which is found in protein, than those animals that ate mostly plants.
The ratio of carbon to nitrogen in feces from selected mammal species
Still, none of the animals’ poop contained as much nitrogen as lab-grown bacteria did, indicating that the microbes can use more nitrogen when they have it. Since gut bacteria incorporate far more carbon than nitrogen, it means the microbes aren’t getting much nitrogen, which could hold back their growth.
Reese’s team also lowered the amount of protein, thereby decreasing nitrogen, in the diets of lab mice. That reduced the numbers of bacteria in the rodents’ feces, the researchers found.
Together, these results suggest that levels of nitrogen in the gut help determine bacterial growth. It’s unclear whether having more or less bacteria is good or bad, but when certain types of microbes take over, it’s generally bad for health.
To track what happens to nitrogen in food, Reese and her colleagues went a step further, and fed mice chow in which the nitrogen was nitrogen-15, a heavier version of the element. The mice absorbed much of the nitrogen in their small intestines where bacteria usually don’t live, leaving little for the bacteria in the colon to eat.
A separate set of experiments revealed how bacteria were getting nitrogen if not directly from food. Some bacteria in the gut (particularly ones belonging to the Bacteroidetes phylum) ate mucus secreted by the mice’s intestines to get nitrogen. In turn, those bacteria converted the mucus into other nitrogen-containing chemicals other gut bacteria could eat. The result suggests that hosts may be able to control which microbes grow in the gut by regulating the amount of nitrogen in mucus. Eating foods with low protein content is one way to do that.
What’s more, antibiotics that lowered the amount of bacteria in the gut led mice to secrete less mucus. The animals seemed to keep the extra nitrogen that wasn’t going to feed gut microbes for themselves, allowing the rodents to grow bigger. That finding could help explain why antibiotics promote growth in farm animals.
People shouldn’t change their diets to consume less protein based on any one study alone, says Katrine Whiteson, a microbiome researcher at the University of California, Irvine. However, she says, “generally eating lots of plants and getting a lot of fiber is likely to be a healthy diet, and that by nature would mean eating less nitrogen.”
A.T. Reese et al. Microbial nitrogen limitation in the mammalian large intestine. Nature Microbiology. Published online October 29, 2018. doi:10.1038/s41564-018-0267-7.