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Study coauthored by UNM physician links gut bacteria to brain illness found in NM

Copyright © 2017 Albuquerque Journal

Thousands of New Mexicans share a genetic mutation that can cause some people to develop severe brain illnesses, while others with the same defect never show symptoms.

A new study suggests that a type of bacteria that lives in the gut may trigger disease among people with the mutation, which is more common in New Mexico than anywhere else in the world.

The mutation, brought to New Mexico centuries ago by an early Hispanic settler, can lead to an illness called cavernous cranial malformation, or CCM. It can cause bleeding in the brain and lead to strokes and seizures.

A study published this month in the journal Nature offers strong evidence that the microbiome – the trillions of bacteria that live in the intestines – plays a role in triggering the illness.

Dr. Leslie Morrison

“They all have exactly the same gene mutation,” said Dr. Leslie Morrison, a University of New Mexico physician who has treated people with CCM for 25 years. “Something triggers severe problems in some people, while others never develop symptoms. It’s not the mutation itself that changes their severity; it’s something else.”

Morrison said physicians had long suspected that the mutation alone doesn’t cause illness without a “second hit” from some other source. But the microbiome wasn’t on anyone’s suspect list, she said.

“I was surprised, because it wasn’t something we had thought of before,” said Morrison, a coauthor of the study.

The discovery followed a stroke of serendipity at the University of Pennsylvania in Philadelphia, where researchers developed a cohort of genetically altered mice that readily acquired CCM disease.

Researchers there built a new laboratory and moved their mice into it, only to discover that many of the mice developed a resistance to the disease, possibly because of more sterile conditions, said Dr. Alan Tang, a University of Pennsylvania researcher and lead author of the study.

“This confused us for a long time,” he said. Eventually, Tang noticed that a few of the disease-resistant mice developed a bacterial infection and again became vulnerable to CCM disease.

“These mice were no longer resistant to the disease, and in fact, developed a lot of disease,” Tang said. In those mice, a bowel puncture led to infection of Gram-negative bacteria, he said.

“Some developed a bacterial abscess, and these animals were associated with a lot of disease,” Tang said. Researchers took the next step and infected resistant mice with Gram-negative bacteria on purpose, which caused the mice to develop CCM illness, he said.

Gram-negative bacteria release a substance into the bloodstream that prompts a strong immune response in animals, Tang said. That response appears to trigger disease in mice, and possibly in humans, who are genetically susceptible to CCM, he said.

Next, the researchers wanted know if their work with mice had relevance to humans with the CCM mutation, which led them to reach out to Morrison at UNM.

Morrison’s work with CCM patients led her to compile a registry of some 350 New Mexicans who share what is the common Hispanic mutation, ranging from people with severe disease to those with no symptoms.

“Leslie has been gathering large cohorts of CCM patients in New Mexico who all share the same genetic mutation,” Tang said.

Genetic studies performed on patients from Morrison’s registry showed an association between disease severity and a factor that intensifies the response to Gram-negative bacteria, possibly accelerating the formation of CCM malformations in the brain.

For now, there are no cures for the disease, and the only treatment is to surgically remove CCM lesions from the brain. If the research pans out, possible therapies could involve using antibiotics and fecal transplants (bacteriotherapy), Morrison said.

“It’s an avenue of potential treatment,” she said.

The next step involves collecting fecal samples from CCM patients and learning more about the role of the microbiome and bacteria in human disease, but much more work lies ahead.

“We really don’t know enough about the gut microbiome to responsibly recommend any course of action for CCM patients,” Tang said. “Now we need to do fecal sequencing, gathering samples from hundreds of patients, seeing if there’s anything there. That’s where we’re going next.”