Druglike molecules produced by gut bacteria can affect gut, immune health

November 23, 2017
Credit: CC0 Public Domain

Stanford researchers found that manipulating the gut microbe Clostridium sporogenes changed levels of molecules in the bloodstreams of mice and, in turn, affected their health.

Here's some food for thought: When you lick your Thanksgiving plate clean this week, you're not just feeding yourself; you're also providing meals to the trillions of that live in your gut.

And if your dinner includes turkey, a notoriously rich source of the amino acid tryptophan, the gut bacterium Clostridium sporogenes will have the job of breaking down that tryptophan. Then the molecules that are produced by the microbe will flow into your bloodstream in the same way a prescription drug might, interacting with your immune system and changing the biology of the intestines.

Stanford University School of Medicine researchers have used to demonstrate how gut bugs could be bioengineered to produce possibly therapeutic changes in the body.

A paper describing their efforts was published online Nov. 22 in Nature. Justin Sonnenburg, PhD, associate professor of microbiology and immunology, and Michael Fischbach, PhD, associate professor of bioengineering, share senior authorship. The lead author is Dylan Dodd, MD, PhD, instructor in pathology.

When the researchers blocked the ability of C. sporogenes to break down tryptophan in mice, levels of certain molecules in their bloodstreams changed. Moreover, the researchers saw physiological changes to the mice's immune systems and intestines.

"This is a vivid example of not only how the microbiome is affecting things all over your body, but of how we can leverage that to improve health," said Sonnenburg, using a term for the collection of microbes living on or inside an animal, or in a particular part.

Improving health from the inside

Over the past 15 years, researchers have shown that the composition of a person's gut microbiome can alter their risk for all sorts of health problems, from diabetes and heart disease to allergies and depression. One reason these tiny microbes have such an outsized effect: They can produce molecules known as metabolites that enter the bloodstream and circulate throughout the body. Pinning down exactly which molecules are produced by which bacteria, however, and how to alter their levels to change health, has been challenging.

Previous studies have shown that just a few bacteria, including C. sporogenes, can break down tryptophan and produce the metabolite known as indolepropionic acid. Studies have also hinted that IPA helps fortify the intestinal wall, letting fewer molecules leak through.

In the new work, the researchers first detailed exactly how C. sporogenes produces IPA from tryptophan. They identified a handful of other compounds also produced in the process—12 metabolites in total, nine of which can accumulate in the blood and three of which are produced only by bacteria. Then, the researchers pinpointed for the first time the genes that C. sporogenes requires for the breakdown of tryptophan and metabolism of the resulting molecules. A gene called fldC, they showed, is required for the production of IPA.

Next, the team gave germ-free mice either wild-type C. sporogenes—with the ability to produce IPA—or a version of the bacteria that lacked fldC. In mice that received the wild-type bacteria, levels of IPA in the bloodstream were around 80 micromolar; in mice that received the engineered version of the bacteria, IPA was undetectable.

Finally, they looked at how altering the levels of IPA affected the mice. Mice with undetectable IPA, they found, had higher levels of immune cells, including neutrophils, classical monocytes and memory T cells. This suggested activation of two branches of the immune system—the innate and adaptive immune system. In addition, the mice with the engineered version of C. sporogenes had more permeable intestines, a defect which is often seen in gut diseases, including .

Targeting microbes

If the results hold true in humans, said Sonnenburg, it could point toward a new paradigm for treating some diseases: rather than give a compound, such as IPA, physicians may one day be able to tweak levels of bacteria to affect levels of metabolites. For instance, it might be possible to treat inflammatory bowel disease by boosting levels of C. sporogenes and ensuring patients eat enough tryptophan.

"This gives us a specific example of how we can target individual microbes and pathways in the gut to change a person's health," Dodd said. "And this is just one example of hundreds or thousands that are likely out there."

The group next plans to study C. sporogenes and IPA levels in mice with more complex gut microbiomes—rather than germ-free mice—and begin tracking down other metabolites produced by the that may have health effects.

"While providing a stunning example of how a single gut microbe, and a single gene within that microbe, can impact host health, IPA is just the tip of the iceberg," said Fischbach, "The possibility to positively impact human health through microbiome-produced chemicals is tremendous, and we are poised to take big strides and make this a reality."

Other Stanford authors are Matthew Spitzer, PhD, a former graduate student; graduate students William Van Treuren and Bryan Merrill; postdoctoral scholar Andrew Hryckowian, PhD; life science researcher Steven Higginbottom, PhD; Gary Nolan, PhD, professor of microbiology and immunology; adjunct faculty member Anthony Le; and Tina Cowan, PhD, professor of pathology.

Explore further: Mice fed tryptophan develop immune cells that foster a tolerant gut

More information: A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites, Nature (2017). nature.com/articles/doi:10.1038/nature24661

Related Stories

Mice fed tryptophan develop immune cells that foster a tolerant gut

August 3, 2017
Immune cells patrol the gut to ensure that harmful microbes hidden in the food we eat don't sneak into the body. Cells that are capable of triggering inflammation are balanced by cells that promote tolerance, protecting the ...

Black tea may help with weight loss, too

October 3, 2017
UCLA researchers have demonstrated for the first time that black tea may promote weight loss and other health benefits by changing bacteria in the gut. In a study of mice, the scientists showed that black tea alters energy ...

Gut microbes contribute to age-associated inflammation, mouse study finds

April 12, 2017
Inflammation increases with age and is a strong risk factor for death in the elderly, but the underlying cause has not been clear. A study published April 12 in Cell Host & Microbe reveals that gut microbes are one of the ...

Natural compound coupled with specific gut microbes may prevent severe flu

August 3, 2017
Microbes that live in the gut don't just digest food. They also have far-reaching effects on the immune system. Now, a new study shows that a particular gut microbe can prevent severe flu infections in mice, likely by breaking ...

From mice, clues to microbiome's influence on metabolic disease

February 17, 2017
The community of microorganisms that resides in the gut, known as the microbiome, has been shown to work in tandem with the genes of a host organism to regulate insulin secretion, a key variable in the onset of the metabolic ...

Recommended for you

Exposure to larger air particles linked to increased risk of asthma in children

December 15, 2017
Researchers at The Johns Hopkins University report statistical evidence that children exposed to airborne coarse particulate matter—a mix of dust, sand and non-exhaust tailpipe emissions, such as tire rubber—are more ...

Bioengineers imagine the future of vaccines and immunotherapy

December 14, 2017
In the not-too-distant future, nanoparticles delivered to a cancer patient's immune cells might teach the cells to destroy tumors. A flu vaccine might look and feel like applying a small, round Band-Aid to your skin.

Immune cells turn back time to achieve memory

December 13, 2017
Memory T cells earn their name by embodying the memory of the immune system - they help the body remember what infections or vaccines someone has been exposed to. But to become memory T cells, the cells go backwards in time, ...

Steroid study sheds light on long term side effects of medicines

December 13, 2017
Fresh insights into key hormones found in commonly prescribed medicines have been discovered, providing further understanding of the medicines' side effects.

The immune cells that help tumors instead of destroying them

December 12, 2017
Lung cancer is the leading cause of cancer-associated deaths. One of the most promising ways to treat it is by immunotherapy, a strategy that turns the patient's immune system against the tumor. In the past twenty years, ...

Cancer gene plays key role in cystic fibrosis lung infections

December 12, 2017
PTEN is best known as a tumor suppressor, a type of protein that protects cells from growing uncontrollably and becoming cancerous. But according to a new study from Columbia University Medical Center (CUMC), PTEN has a second, ...

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.