Malformed blood vessels in the brain can lead to stroke or epilepsy.
A new preclinical trial suggests that gut bacteria may be involved with the formation of blood vessels in the brain. These latest findings add to numerous evidence that intestinal microbiome influences conditions that affect the nervous system.
Cerebral cavernous malformations (CCMs) are dilated, thin-walled blood vessels that can cause a seizure or stroke when the vessels leak into the brain. The authors of the study published by Nature investigated the cause of CCM lesions in mice.
They discovered that when certain gut bacteria were eliminated, the number of lesions lessened.
"This study is exciting because it shows that changes within the body can affect the progression of a disorder caused by a genetic mutation,” said Jim I. Koenig, PhD, program director at the National Institute of Neurological Disease and Stroke.
The investigators examined a mouse model that develops a large portion of CCMs after the injection of a drug that sparks gene deletion. Interestingly, when the mice were relocated, lesion formation decreased to nearly zero, according to the study.
“It was a complete mystery. Suddenly, our normally reliable mouse model was no longer forming the lesions that we expected,” said senior study author Mark L. Kahn, MD. “What’s interesting is that this variability in lesion formation is also seen in humans, where patients with the same genetic mutation often have dramatically different disease courses.”
While exploring this occurrence, the authors discovered that the mice that continued to develop CCM lesions had bacterial abscesses in their abdomens, likely due to abdominal injections. The abscesses contained Gram-negative bacteria.
When similar bacterial infections were introduced to the mice, approximately 50% developed CCMs, according to the study.
“The mice that formed CCMs also had abscesses in their spleens, which meant that the bacteria had entered the bloodstream from the initial abscess site,” said researcher Alan Tang. “This suggested a connection between the spread of a specific type of bacteria through the bloodstream and the formation of these blood vascular lesions in the brain.”
It was still unclear how bacteria in the blood would affect blood vessels in the brain.
Gram-negative bacteria produces lipopolysaccharides (LPS), which activate innate immune signaling. When mice received LPS injections, they developed significant amounts of CCMs, which was similar to those developed by the infection, according to the study.
Then, the LPS receptor, TLR4, was genetically removed from mice. The authors discovered that the mice no longer developed CCM lesions.
In humans, a link between mutations that increase TLR4 expression was linked to a higher risk of forming CCMs, according to the study.
“We knew that lesion formation could be driven by Gram-negative bacteria in the body through LPS signaling,” Dr Kahn said. “Our next question was whether we could prevent lesions by changing the bacteria in the body.”
The authors then studied the body’s microbiome. In this approach, newborn mice models of CCM were raised in normal conditions or in a germ-free environment. The mice were then given antibiotics to reset their microbiome.
In mice exposed to the germ-free environment and after antibiotics, the authors found that the number of lesions were reduced. This suggests that the quantity and quality of the gut microbiome may affect CCM development, according to the study.
Additionally, the authors discovered that a TLR4 inhibitor decreased CCM lesion formation. The drug has been studied in clinical trials of sepsis. While these findings suggest it could also treat CCM, further research is necessary.
The authors plan to study the link between microbiome and CCM in humans. Gene mutations have been implicated in CCM formation in humans, but the size and number varies among patients with the same mutations, suggesting that other factors may be involved. They plan to determine whether differences in gut microbiomes could explain the variability of lesions, according to the study.
“These results are especially exciting because they show that we can take findings in the mouse and possibly apply them at the human patient population,” said Koenig. “The drug used to block TLR4 has already been tested in patients for other conditions, and it may show therapeutic potential in the treatment of CCMs, although considerable research still remains to be done.”