Why do some love to exercise? It might be their microbiome.

Some mice are more inclined to run on an exercise wheel than their less active counterparts. That’s because, according to a recent study, these mice carry microbes in their guts that send signals to their brains boosting their desire to exercise. Could the same be true for humans?

It’s long been known that regular exercise is good for health and decreases the risk of many diseases. Yet more than 80 percent of adults don’t manage the recommended 150-minutes per week even though lack of physical activity causes between 6 and 10 percent of premature deaths, coronary heart disease, type 2 diabetes, breast cancer, and colon cancer globally. In fact, sedentary lifestyle is estimated to be the fourth leading cause of death worldwide.

But the factors that motivate some to exercise more than others are not well understood. Exercise affects the gut microbiome, but how microbiome directly affects exercise behavior is not clear. There have been hints that the two are linked. A study published in 2019 found that after the Boston Marathon, runners had more of a particular bacterial species in their stool than sedentary volunteers; these microbes could trigger better athletic performance when transplanted into mice. Building on such studies, new research published in the journal Nature, shows that at least in mice, some species of gut-dwelling bacteria can drive the production of dopamine, the feel-good neurotransmitter, to reward exercising for a longer duration.

A large surge in dopamine is just one of many neurochemical changes that happen both in human and mouse brains after exercise.

"The study shows pretty conclusively that in mice, the desire to exercise is influenced by the microbiome," says Anthony Komaroff, a professor of medicine at Harvard Medical School "[This study] provides a mechanistic explanation as to how the microbiome could influence the appetite of the animals to exercise."

Why don’t people want to exercise?

Christoph Thaiss, a microbiologist at the University of Pennsylvania, who led the new study wanted to know what prevents most people from wanting to exercise. Since it's not easy to do experiments in humans, his team gathered eight types of genetically diverse mice.

"We took a very unbiased look by studying mice, because there is a lot of natural variability among how much mice exercise," says Thaiss.

Some of this variability in motivation or ability to do hard exercise is related to genetics. For example, Theodore Garland, Jr., an evolution biologist at the University of California Irvine, wanted to understand how complex traits—like marathon running—evolve at multiple levels of organization, ranging from behavior to DNA. He has shown in an ongoing experiment launched in 1993 that a strain of super-runner mice—bred over more than one hundred generations—evolved specific changes in their DNA and ran over three times longer than average. These mice also have different microbiomes than their less active counterparts.

To test whether eliminating the gut microbiome would affect the motivation to exercise Garland gave the athletic mice antibiotics. It drastically and irreversibly reduced the voluntary exercise behavior of super runners. The mice with depleted gut bacteria ran about 21 percent less every day, even though they continued to eat well and were otherwise unaffected.

"The gut microbiome is obviously one of the factors that can influence ability to run and exercise," says Garland, but his study did not directly explain how gut bacteria could affect motivation for physical activity.

Thaiss’ new study in Nature explored the connection between the gut and brain of mice. Thaiss’ team measured how long 199 untrained mice would voluntarily run on exercise wheels and how long they could sustain a particular speed. Not knowing what specific factors might explain their desire to exercise, the scientists also collected 10,500 other data points such as the complete genome sequences for all 199 mice, gut bacterial species, and metabolites present in the bloodstream of each mouse. This resulted in nearly 2.1 million total data points.

"It's an insane amount of data," says Matthew Raymond Olm, a computational microbiologist at Stanford University.

Rather than trying to understand the effect of variables one by one, the scientists used a machine learning approach in which they plugged all the data into a computer program and let it identify the most critical factors that explained the endurance of high performing mice.

"This study is a really great example of big data working well to home in on something important and fundamental about the microbiome," says Olm.

What Thaiss found surprised him because genetics accounted for only a small portion of the performance differences between mice, whereas differences in gut bacterial populations appeared to be substantially more important.

"We do see a certain heritability of exercise performance," says Thaiss. "But it's just relatively small."

To confirm that gut microbes were indeed responsible for the observed difference, the researchers eliminated the gut bacteria of mice by giving broad spectrum antibiotics. This reduced the running endurance of high performing mice by about half. Conversely, when scientists transplanted the microbiome from a top performing mouse, it boosted the exercise capacity of the recipient mouse.

In a years-long scientific investigation in a dozen laboratories in the United States and Germany, Thaiss’ team identified two bacterial species Eubacterium rectale and Coprococcus eutactus, which were responsible for boosting the motivation to exercise in high-performing mice.

Molecules that motivate mice to move

The researchers then traced the exercise boosting effect to small molecules called metabolites produced by these specific gut bacteria. A class of specific metabolites known as fatty acid amides stimulated the sensory nerves embedded in the walls of the gut, which are connected to the brain via the spine. The nerves release a neurotransmitter called dopamine, which then activates the motivation-controlling region in the brain called the striatum. Dopamine-sparked activity in the striatum enhances the desire for exercise by providing a feeling of reward.

Unlike normal mice, the dopamine levels in the striatum of microbiome-depleted mice did not rise after exercise. When scientists gave mice a dopamine blocking drug, it suppressed their desire to exercise. Conversely, activating dopamine signaling by using a different drug, restored the capacity to exercise in microbiome-depleted mice.

"This is really an exceptional study," says Francesca Ronchi, a microbiologist at Charité hospital in Berlin, Germany. Not only did the authors collect a large quantity of data, used many controls, and identified the potentially responsible bacteria, they also managed to find out the exact mechanism that can explain the ability of some mice to exercise extensively, said Ronchi.

"This study in animals raises the question whether humans who love to exercise and humans who avoid exercise are being influenced by their microbiomes," says Komaroff.

But the new study cannot yet directly draw conclusions for humans, warns Thaiss.

However, similar pathways are active in humans. The bacterial species identified in the gut flora that drive exercise capacity in mice are also present in the human microbiome. Similarly, the fatty acid amides found to drive exercise performance in mice and trigger the gut brain pathway that drives motivation for exercise are also found in the human gut.

"Does this mean that the pathway will look one to one the same? We don't know," says Thaiss. "There are many differences between mice and human physiology. But we're embarking on a human study that will answer this question."