Bacteria in the gut microbiome drive the formation of cerebral cavernous malformations (CCMs), clusters of dilated, thin-walled blood vessels in the brain that can cause stroke and seizures, according to new research published in Nature.
The team's research suggests that altering the microbiome in CCM patients may be an effective therapy for this cerebrovascular disease. CCM disease, which occurs in about one in 100 to 200 people, can present in two forms. One is sporadic, accounting for 80 percent of cases, and is most frequent in older individuals. The remaining 20 percent are familial, inherited cases.
In 2016, the lab discovered the molecular mechanism in endothelial cells that underlies the formation of CCMs. In the current Nature study, the team discovered that this molecular pathway is activated by TLR4, a receptor for the bacterial molecule lipopolysaccharide (LPS). Activation of TLR4 on brain endothelial cells by LPS vastly accelerated CCM formation. Conversely, if TLR4 was removed from endothelial cells genetically, or if the mice were treated with drugs that block TLR4 function, CCM formation is prevented.
Since TLR4 primarily responds to LPS from Gram-negative bacteria, the student in the lab, proposed that bacteria from the animal's gut microbiome may drive CCM formation. To test this theory, the student examined CCM formation in mice that were housed under germ-free conditions or treated with antibiotics to reduce the number of bacteria living in the gut. In both cases, CCM formation was dramatically reduced, demonstrating a key role for bacteria in the pathology of CCM disease.
The team next sought evidence that bacterial LPS-TLR4 signaling might also support CCM formation in human patients. They studied several hundred patients who carry an identical mutation in one CCM gene but display a widely variable disease course.
"Some of these patients experience severe stroke by the age of two and others have no symptoms over their lifetime," senior author said. "What makes the disease outcome so variable?"
They discovered that genetic variations that raise the amount of TLR4 that is produced are associated with higher numbers of CCM lesions, suggesting that the key role for LPS-TLR4 signaling identified in mice is also present in humans.
These studies identify an unexpected, direct link between the microbiome and a common cerebrovascular disease. "This suggests that treatments designed to block TLR4 signaling or alter the microbiome may be used to treat this disease," senior author said.
https://www.pennmedicine.org/news/news-releases/2017/may/penn-study-finds-relationship-between-common-brain-disease-and-gut-microbiome
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature22075.html
Relationship between common brain disease and gut microbiome identified!
- 3,582 views
- Added
Edited
Latest News
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Role of fat in rare neurolo…
By newseditor
Posted 23 Apr
How protein synthesis in de…
By newseditor
Posted 22 Apr
Atlas of mRNA variants in d…
By newseditor
Posted 22 Apr
Other Top Stories
Fourth wheat gene key to flowering and climate adaptation identified
Read more
Mechanism of TNT toxicity in plants
Read more
A new cyanogenic metabolite in Arabidopsis required for inducible p…
Read more
How cancer drug Taxol protects the plants against the pathogen
Read more
Detoxification of host plant's chemical by the larvae
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Exploiting pancreatic cance…
By newseditor
Posted 23 Apr
Structure of antiviral drug…
By newseditor
Posted 23 Apr
Type-I-interferon-responsiv…
By newseditor
Posted 23 Apr
Selenium, diabetes, and the…
By newseditor
Posted 23 Apr
Long-term neuropsychologica…
By newseditor
Posted 23 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar