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   Neuroscience   
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   Gut Bugs Cause Brain Bleeds   
   NEWS   May 18, 2017 | Original Story from the NIH   
       
   Blood Brain Barrier Weakened by Intestinal Gut Bacteria   
       
   A study in mice and humans suggests that bacteria in the gut can influence the   
   structure of the brain’s blood vessels, and may be responsible for producing   
   malformations that can lead to stroke or epilepsy. The research, published in   
   Nature, adds to an    
   emerging picture that connects intestinal microbes and disorders of the   
   nervous system. The study was funded by the National Institute of Neurological   
   Disorders and Stroke (NINDS), a part of the National Institutes of Health.    
      
   Cerebral cavernous malformations (CCMs) are clusters of dilated, thin-walled   
   blood vessels that can lead to seizures or stroke when blood leaks into the   
   surrounding brain tissue. A team of scientists at the University of   
   Pennsylvania investigated the    
   mechanisms that cause CCM lesions to form in genetically engineered mice and   
   discovered an unexpected link to bacteria in the gut. When bacteria were   
   eliminated the number of lesions was greatly diminished.   
      
   "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, Ph.D., program director at NINDS.   
      
   The researchers were studying a well-established mouse model that forms a   
   significant number of CCMs following the injection of a drug to induce gene   
   deletion. However, when the animals were relocated to a new facility, the   
   frequency of lesion formation    
   decreased to almost zero.    
      
   “It was a complete mystery. Suddenly, our normally reliable mouse model was   
   no longer forming the lesions that we expected,” said Mark L. Kahn, M.D.,   
   professor of medicine at the University of Pennsylvania, and senior author of   
   the study. “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 investigating the cause of this sudden variability, Alan Tang, a   
   graduate student in Dr. Kahn’s lab, noticed that the few mice that continued   
   to form lesions had developed bacterial abscesses in their abdomens —   
   infections that most likely    
   arose due to the abdominal drug injections. The abscesses contained   
   Gram-negative bacteria, and when similar bacterial infections were   
   deliberately induced in the CCM model animals, about half of them developed   
   significant CCMs.   
      
   “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 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.”   
      
   The question remained as to how bacteria in the blood could influence blood   
   vessel behavior in the brain. Gram-negative bacteria produce molecules called   
   lipopolysaccharides (LPS) that are potent activators of innate immune   
   signaling. When the mice    
   received injections of LPS alone, they formed numerous large CCMs, similar to   
   those produced by bacterial infection. Conversely, when the LPS receptor,   
   TLR4, was genetically removed from these mice they no longer formed CCM   
   lesions.  The researchers also    
   found that, in humans, genetic mutations causing an increase in TLR4   
   expression were associated with a greater risk of forming CCMs.        
      
   These are MRIs of healthy (left) and a patient with a mutation that increases   
   CCM formation (right). These lesions can cause blood to leak into the tissue.   
   Credit: Kahn Lab   
      
   “We knew that lesion formation could be driven by Gram-negative bacteria in   
   the body through LPS signaling,” said Kahn. “Our next question was whether   
   we could prevent lesions by changing the bacteria in the body.”   
      
   The researchers explored changes to the body’s bacteria (microbiome) in two   
   ways. First, newborn CCM mice were raised in either normal housing or under   
   germ-free conditions. Second, these mice were given a course of antibiotics to   
   “reset” their    
   microbiome. In both the germ-free conditions and following the course of   
   antibiotics, the number of lesions was significantly reduced, indicating that   
   both the quantity and quality of the gut microbiome could affect CCM   
   formation. Finally, a drug that    
   specifically blocks TLR4 also produced a significant decrease in lesion   
   formation. This drug has been tested in clinical trials for the treatment of   
   sepsis, and these findings suggest a therapeutic potential for the drug in the   
   treatment of CCMs,    
   although considerable research remains to be done.    
      
   “These results are especially exciting because they show that we can take   
   findings in the mouse and possibly apply them tothe 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.”     
      
   Kahn and his colleagues plan to continue to study the relationship between the   
   microbiome and CCM formation, particularly as it relates to human disease.   
   Although specific gene mutations have been identified in humans that can cause   
   CCMs to form, the    
   size and number varies widely among patients with the same mutations. The   
   group next aims to test the hypothesis that differences in the patients’   
   microbiomes could explain this variability in lesion number.   
      
   Reference:   
   Tang, A., Choi, J., Kotzin, J., Yang, Y., Hong, C., Hobson, N., Girard, R.,   
   Zeineddine, H., Lightle, R., Moore, T., Cao, Y., Shenkar, R., Chen, M.,   
   Mericko, P., Yang, J., Li, L., Tanes, C., Kobuley, D., Võsa, U., Whitehead,   
   K., Li, D., Franke, L., Hart,    
   B., Schwaninger, M., Henao-Mejia, J., Morrison, L., Kim, H., Awad, I., Zheng,   
   X. and Kahn, M. (2017). Endothelial TLR4 and the microbiome drive cerebral   
   cavernous malformations. Nature, 545(7654), pp.305-310.   
      
   This article has been republished from materials provided by NIH. Note:   
   material may have been edited for length and content. For further information,   
   please contact the cited source.   
      
       
       
       
       
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