Mice colonized with an altered gut bacterium had less fat accumulation in the liver (right) than mice with a normal gut bacterium (left). Image: Devlin lab
Researchers studying the human microbiome—the bacteria that live in our bodies—face a chicken-and-egg problem.
Say they collect data from a group of healthy subjects and a group of diseased subjects, catalog the bacteria and metabolites present in both groups and find significant differences. How can they reconstruct the order of events and distinguish causation from correlation?
“We don’t know which came first,” said Sloan Devlin, assistant professor of biological chemistry and molecular pharmacology at Harvard Medical School. “Did the disease develop and then cause a change in the microbiome? Did a change in the microbiome cause a change in host health or disease state?”
Specifically, the team, from HMS and Brigham and Women’s Hospital, probed how molecules produced by gut bacteria influence metabolism in mice.
The researchers reported July 17 in eLifethat deleting a single gene in a common strain of gut bacteria caused significant changes in metabolism and lowered weight gain in the mice.
“Our work suggests that this particular gene could be a target for future drug development and provides a step toward a fuller understanding of how the microbiome affects metabolism,” said Devlin, senior author of the paper.
The microbiome is known to influence the development of obesity and metabolic diseases such as diabetes, but the specific ways it affects metabolism are harder to decipher. The gut contains so many species of bacteria producing many different kinds of metabolites that untangling their effects poses a significant challenge.
In this study, the researchers used a kind of “genetic scalpel” to remove a particular gene from the microbiome and then investigated the effects of this change on host metabolism.
“It’s important to note that in all our experiments, there were no genetic changes to the mice themselves,” Devlin emphasized. “All the changes in mouse metabolism we observed were caused by a single genetic deletion in the bacteria colonizing the mice.”
Devlin and colleagues focused on bile acids, a group of substances that occur naturally in the human gut. Imbalances in the bile acid pool are thought to contribute to diet-induced obesity.
To find out which specific bile acids cause these effects, the team focused on a class of bacterial enzymes called bile salt hydrolases.
First, the researchers identified a bacterial species with a bile salt hydrolase that metabolizes only certain types of bile salts. Then they generated two strains of bacteria—one with the hydrolase and one without—and introduced them into germ-free mice (mice without any bacteria living in or on their bodies).
They found that mice colonized with the hydrolase-deficient strain had much higher amounts of certain unmetabolized bile salts in their intestine.
They next investigated the effects of altering the levels of specific bile salts on mouse metabolism. They were surprised to find that the mice colonized with the hydrolase-deficient bacteria gained less weight than the mice colonized with the normal bacteria.
They also found the animals had lower levels of fats and cholesterol in the blood and liver than those with the hydrolase, and they had a preference for metabolizing fats rather than carbohydrates for energy.
Genetic analysis revealed that in addition to alterations related to metabolism, there were changes in genes controlling circadian rhythm and immune response. This suggests that bacteria-induced bile acid alterations can cause a broader range of changes in the host, the authors said.
“Our work opens up the possibility for new treatments for metabolic diseases that target the microbiome, specifically, this bile salt hydrolase enzyme,” said Devlin. “However, these are very early days; we’re not there yet.”
This work was supported by an Innovation Award from the Center for Microbiome Informatics and Therapeutics at MIT, a grant from Harvard Digestive Diseases Center (supported by NIH grant 5P30DK034854-32), a Karin Grunebaum Cancer Research Foundation Faculty Research Fellowship (ASD) and a Wellington Postdoctoral Fellowship (LY).
Devlin is a consultant for Kintai Therapeutics, a biotechnology company focused on microbiome metabolites.