Research in mice paves way to teasing out cause and effect between gut microbes and disease

December 6, 2017, Harvard Medical School
Credit: CC0 Public Domain

Clearing a major hurdle in the field of microbiome research, Harvard Medical School scientists have designed and successfully used a method to tease out cause-and-effect relationships between gut bacteria and disease.

Reporting Dec. 6 in Nature, the team says the approach could propel research beyond mere microbiome- associations and elucidate true cause-effect relationships.

The experiments, conducted in , also identify a previously unknown gut microbe that tames intestinal inflammation and protects against severe colitis. The researchers say the finding makes a strong case for testing the newly identified gut bacterium as a probiotic therapy in people with , a constellation of conditions marked by chronic inflammation of the intestines and estimated to affect up to 1.3 million people in the United States, according to the Centers for Disease Control and Prevention.

The approach uses a sort of "microbial triangulation." It mimics the principles of classic maritime navigation or, in more modern terms, tracking the location of a mobile phone by verifying data from multiple sources—but instead of stars or cell phone towers, the researchers are homing in on intestinal bugs. Based on the method of elimination, the technique involves the gradual narrowing down of to identify specific microbes that modulate the risk for specific diseases. In the current study, researchers adapted the principles to identify beneficial, protective bacteria.

"Our approach can help scientists find the proverbial needles in a 'haystack' of thousands of microbes that are currently thought to modulate health," said investigator Dennis Kasper, professor of microbiology and immunobiology at Harvard Medical School. "If the field is to move past associations—the Achilles' heel in microbiome research—we need a system that reliably teases out causative relationships between and disease. We believe our method achieves that," added Kasper, who is also the Harvard Medical School William Ellery Channing Professor of Medicine at Brigham and Women's Hospital.

Over the last decade, study after study has identified thousands of commensal microbes—those residing innocently in our bodies—and catalogued observations of possible links between groups of microbes and the presence or absence of a panoply of diseases, including diabetes, multiple sclerosis and inflammatory bowel disease. Yet, scientists don't know whether and how the presence of specific microbes—or fluctuations in their numbers—affects health. It remains unclear whether certain microbes are innocent bystanders, mere markers of disease, or whether they are active agents, causing harm or providing protection against certain ailments.

The holy grail of this work would be not to merely define whether a microbe fuels or minimizes the risk for a given disease but to discover microbes and microbial molecules that can be used therapeutically.

"The ultimate goal is to clarify the mechanisms of disease and then identify bacterial molecules that can be used to treat, reverse or prevent it," said study lead author Neeraj Surana, Harvard Medical School instructor in pediatrics and an infectious disease specialist at Boston Children's Hospital.

Old-fashioned detective work

For their study, Kasper and Surana compared the gut microbiomes of several groups of mice that harbored different populations of .

The researchers started out with two groups of mice. One group had been bred with human gut microbiomes—housing intestinal bacteria normally found in human intestines. The other group had been bred to harbor normal mouse microbiomes. When researchers gave the animals a chemical compound that triggered , or colitis, mice that harbored human intestinal microbes were protected from the effects of the disease. Mice whose guts harbored typical mouse bacteria, however, developed severe symptoms.

Next, the researchers housed all mice in the same living space. Sharing living space for as briefly as one day led to noticeable changes in how the animals responded to disease. Mice that had been originally protected from colitis started showing more serious signs of it, while colitis-prone mice grew increasingly resistant to the effects of the condition and developed milder symptoms—a proof-of-principle finding which shows that exchange of intestinal bacteria through shared living space can lead to changes in the animals' ability to cope with the disease.

The needle in the haystack

The disease-modulating microbe would be lurking amid the hundreds of bacterial species present in all mice. But given that each mouse group harbored between 700 and 1,100 bacterial species in their guts, how could scientists identify the one that truly mattered in colitis? The team began by analyzing the intestinal makeup of each one of the mouse groups, comparing their microbial profiles before and after they shared a living space. To "triangulate" the suspect's identity, scientists looked for microbes that were either scarce or abundant, tracking with colitis severity. In other words, the numbers of the causative microbe would either go up or down with disease severity, the scientists reasoned. Only one such microbial group fit the profile—a bacterial family known as Lachnospiraceae, commonly found in human intestines as well as the guts of other mammals.

To pinpoint the one organism within the Lachnospiraceae family that regulates response to colitis, the researchers isolated one bacterial species and gave it to colitis-prone mice. To compare its effects against other microbes, they also gave the animals organisms from different bacterial families. The only bacterium that protected colitis-prone animals from the ravages of the disease was a never-before-described microbe that the researchers had isolated from the guts of mice seeded with human feces, the animals that had harbored human microbiomes. The microbe was notably absent from mice with mouse microbiomes. Because of its immune-protective properties, Kasper and Surana christened the newly identified organism Clostridium immunis.

The isolation of the disease-modifying microbe makes a powerful case for testing it as therapy in people with inflammatory bowel disease, the researchers said.

Taken together, the team said, the experiments show that a model of winnowing the list of possible microbial suspects down to the level of individual species is not only feasible but critical in unmasking specific disease-modulating .

Explore further: Exercise changes gut microbial composition independent of diet, team reports

More information: Moving beyond microbiome-wide associations to causal microbe identification, Nature (2017). nature.com/articles/doi:10.1038/nature25019

Related Stories

Exercise changes gut microbial composition independent of diet, team reports

December 4, 2017
Two studies - one in mice and the other in human subjects - offer the first definitive evidence that exercise alone can change the composition of microbes in the gut. The studies were designed to isolate exercise-induced ...

Changes in bacterial mix linked to antibiotics increase risk for inflammatory bowel disease

November 27, 2017
Exposure to antibiotics in mothers may increase risk for inflammatory bowel diseases in their offspring. This is the finding of a study in mice led by researchers from NYU School of Medicine and published Nov. 27 in the journal ...

Smoking may cause inflammatory bowel disease

October 31, 2017
A new study shows a direct effect of cigarette smoke on intestinal inflammation for the first time. Researchers in South Korea report that exposing mice to cigarette smoke results in colitis, an inflammation of the colon ...

Intestinal fungi may aid in relief of inflammatory disease

June 23, 2016
Fungi that live in a healthy gut may be as important for good health as beneficial intestinal bacteria, according to new research conducted at Weill Cornell Medicine.

Recommended for you

New inflammation inhibitor discovered

November 16, 2018
A multidisciplinary team of researchers led from Karolinska Institutet in Sweden have developed an anti-inflammatory drug molecule with a new mechanism of action. By inhibiting a certain protein, the researchers were able ...

Gut hormone and brown fat interact to tell the brain it's time to stop eating

November 15, 2018
Researchers from Germany and Finland have shown that so-called "brown fat" interacts with the gut hormone secretin in mice to relay nutritional signals about fullness to the brain during a meal. The study, appearing November ...

Brain, muscle cells found lurking in kidney organoids grown in lab

November 15, 2018
Scientists hoping to develop better treatments for kidney disease have turned their attention to growing clusters of kidney cells in the lab. One day, so-called organoids—grown from human stem cells—may help repair damaged ...

How the Tasmanian devil inspired researchers to create 'safe cell' therapies

November 15, 2018
A contagious facial cancer that has ravaged Tasmanian devils in southern Australia isn't the first place one would look to find the key to advancing cell therapies in humans.

Researchers discover important connection between cells in the liver

November 15, 2018
University of Minnesota Medical School researchers have made a discovery which could lead to a new way of thinking about how disease pathogenesis in the liver is regulated, which is important for understanding the condition ...

Precision neuroengineering enables reproduction of complex brain-like functions in vitro

November 14, 2018
One of the most important and surprising traits of the brain is its ability to dynamically reconfigure the connections to process and respond properly to stimuli. Researchers from Tohoku University (Sendai, Japan) and the ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.