Gut microbiota influences blood-brain barrier permeability

Uptake of the substance Raclopride in the brain of germ-free versus conventional mice.
Credit: Miklos Toth

A new study in mice, conducted by researchers at Sweden's Karolinska Institutet together with colleagues in Singapore and the United States, shows that our natural gut-residing microbes can influence the integrity of the blood-brain barrier, which protects the brain from harmful substances in the blood. According to the authors, the findings provide experimental evidence that our indigenous microbes contribute to the mechanism that closes the blood-brain barrier before birth. The results also support previous observations that gut microbiota can impact brain development and function.

The blood-brain barrier is a highly selective barrier that prevents unwanted molecules and cells from entering the brain from the bloodstream. In the current study, being published in the journal Science Translational Medicine, the international interdisciplinary research team demonstrates that the transport of molecules across the blood-brain barrier can be modulated by gut microbes -- which therefore play an important role in the protection of the brain.

The investigators reached this conclusion by comparing the integrity and development of the blood-brain barrier between two groups of mice: the first group was raised in an environment where they were exposed to normal bacteria, and the second (called germ-free mice) was kept in a sterile environment without any bacteria.

"We showed that the presence of the maternal gut microbiota during late pregnancy blocked the passage of labeled antibodies from the circulation into the brain parenchyma of the growing fetus," says first author Dr. Viorica Braniste at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet. "In contrast, in age-matched fetuses from germ-free mothers, these labeled antibodies easily crossed the blood-brain barrier and was detected within the brain parenchyma."

The team also showed that the increased 'leakiness' of the blood-brain barrier, observed in germ-free mice from early life, was maintained into adulthood. Interestingly, this 'leakiness' could be abrogated if the mice were exposed to fecal transplantation of normal gut microbes. 

The precise molecular mechanisms remain to be identified. However, the team was able to show that so-called tight junction proteins, which are known to be important for the blood-brain barrier permeability, did undergo structural changes and had altered levels of expression in the absence of bacteria.

According to the researchers, the findings provide experimental evidence that alterations of our indigenous microbiota may have far-reaching consequences for the blood-brain barrier function throughout life.

"These findings further underscore the importance of the maternal microbes during early life and that our bacteria are an integrated component of our body physiology," says Professor Sven Pettersson, the principal investigator at the Department of Microbiology, Tumor and Cell Biology. "Given that the microbiome composition and diversity change over time, it is tempting to speculate that the blood-brain barrier integrity also may fluctuate depending on the microbiome. This knowledge may be used to develop new ways for opening the blood-brain-barrier to increase the efficacy of the brain cancer drugs and for the design of treatment regimes that strengthens the integrity of the blood-brain barrier."

Source: Karolinska Institutet

Gene discovered that reduces risk of stroke

Lab microscope (stock image). The discovery of a gene that protects people against one of the major causes of stroke could lead to new treatments and prevention strategies for the disease.
Credit: © 18percentgrey / Fotolia

Scientists have discovered a gene that protects people against one of the major causes of stroke in young and middle-aged adults and could hold the key to new treatments.

Researchers from Royal Holloway, University of London, together with an international team from across the United States and Europe, have found that people with a specific variant of a gene, known as PHACTR1, are at reduced risk of suffering cervical artery dissection, which is caused by a tear in an artery that leads to the brain.

The new discovery, published in the journal Nature Genetics, could lead to new treatments and prevention strategies for the disease, which is a major cause of stroke in young adults. The same gene variant has also been identified as a protector against migraines and affects the risk of heart attack.

Professor Pankaj Sharma, from the School of Biological Sciences at Royal Holloway, said: "This is an important breakthrough. Our findings provide us with a greater understanding of how this region of the genome appears to influence key vascular functions, which could have major implications for the treatment of these severe and disabling conditions. "

In the largest study of its kind ever undertaken, researchers from around the world screened the entire genome of 1,400 patients with cervical artery dissection, along with 14,400 people without the disease. Cervical artery dissection can lead to compression of adjacent nerves and to blood clotting, potentially causing blockage of vessels and brain damage.

Professor Sharma, Professor of Clinical Neurology at Royal Holloway, added: "Further genetic analyses and worldwide collaborations of this kind provide hope of pinpointing the underlying mechanisms that cause stroke. The Bio-Repository of DNA in Stroke (BRAINS) study I am leading is creating a large stroke DNA biobank which will give an exciting opportunity to identify the genes directly linked to the condition."

Source: University of Royal Holloway London

'Microlesions' in epilepsy discovered by novel technique

Clusters of differentially expressed genes predict cellular abnormalities. Credit: Jeffrey Loeb

Using an innovative technique combining genetic analysis and mathematical modeling with some basic sleuthing, researchers have identified previously undescribed microlesions in brain tissue from epileptic patients. The millimeter-sized abnormalities may explain why areas of the brain that appear normal can produce severe seizures in many children and adults with epilepsy.

The findings, by researchers at the University of Illinois at Chicago College of Medicine, Wayne State University and Montana State University, are reported in the journal Brain.

Epilepsy affects about 1 percent of people worldwide. Its hallmark is unpredictable seizures that occur when groups of neurons in the brain abnormally fire in unison. Sometimes epilepsy can be traced back to visible abnormalities in the brain where seizures start, but in many cases, there are no clear abnormalities or scaring that would account for the epileptic activity.

"Understanding what is wrong in human brain tissues that produce seizures is critical for the development of new treatments because roughly one third of patients with epilepsy don't respond to our currently available medications," said Dr. Jeffrey Loeb, professor and head of neurology and rehabilitation in the UIC College of Medicine and corresponding author on the study. "Knowing these microlesions exist is as huge step forward in our understanding of human epilepsy and present new targets for treating this disease."

Loeb and colleagues searched for cellular changes associated with epilepsy by analyzing thousands genes in tissues from 15 patients who underwent surgery to treat their epilepsy. They used a mathematical modeling technique called cluster analysis to sort through huge amounts of genetic data.

Using the model, they were able to predict and then confirm the presence of tiny regions of cellular abnormalities -- the microlesions -- in human brain tissue with high levels of epileptic electrical activity, or 'high-spiking' areas where seizures begin.

"Using cluster analysis is like using a metal detector to find a needle in a haystack," said Loeb. The model, he said, revealed 11 gene clusters that "jumped right out at us" and were either up-regulated or down-regulated in tissue with high levels of epileptic electrical activity compared to tissue with less epileptic activity from the same patient.

When they matched the genes to the types of cells they came from, the results predicted that there would be reductions of certain types of neurons and increases in blood vessels and inflammatory cells in brain tissue with high epileptic activity.

When Fabien Dachet, an expert in bioinformatics research at UIC and first author of the study, went back to the tissue samples and stained for these cells, he found that all of the prediction were correct- there was a marked increase in blood vessels, inflammatory cells, and there were focal microlesions made up of neurons that had lost most of their normal connections that allow them to communicate with one another. "We think that these newly found microlesions lead to spontaneous, abnormal electrical currents in the brain that lead to epileptic seizures," said Loeb.

Loeb and his colleagues at UIC are using the same approach to look for the clusters of differentially expressed genes associated with ALS, a neurodegenerative disease, and in brain tumors. "We now have a way to predict cellular changes by simply measuring the genetic composition, with some fairly simple calculations, between more- and less-affected epileptic human tissues," explained Loeb.

"This technique gives us the ability to discover previously unknown cellular abnormalities in almost any disease where we have access to human tissues," Loeb said. He is currently developing at UIC a national 'neurorepository' of electrically mapped and genetically analyzed brain tissue for such studies.

Source: University of Illinois at Chicago

Neck manipulation may be associated with stroke

Vertebral artery as it passes through the neck vertebrae of the spine and enters the skull base. Arrows indicate head movement during lateral rotation and lateral flexion, motions that may be performed as part of a neck manipulation. Credit: © 2013 Trial FX.

Manipulating the neck has been associated with cervical dissection, a type of arterial tear that can lead to stroke. Although a direct cause-and-effect link has not been established between neck manipulation and the risk of stroke, healthcare providers should inform patients of the association before they undergo neck manipulation.

Treatments involving neck manipulation may be associated with stroke, though it cannot be said with certainty that neck manipulation causes strokes, according to a new scientific statement published in the American Heart Association's journal Stroke.

Cervical artery dissection (CD) is a small tear in the layers of artery walls in the neck. It can result in ischemic stroke if a blood clot forms after a trivial or major trauma in the neck and later causes blockage of a blood vessel in the brain. Cervical artery dissection is an important cause of stroke in young and middle-aged adults.

"Most dissections involve some trauma, stretch or mechanical stress," said José Biller, M.D., lead statement author and professor and chair of neurology at the Loyola University Chicago Stritch School of Medicine. "Sudden movements that can hyperextend or rotate the neck -- such as whiplash, certain sports movements, or even violent coughing or vomiting -- can result in CD, even if they are deemed inconsequential by the patient."

Although techniques for cervical manipulative therapy vary, some maneuvers used as therapy by health practitioners also extend and rotate the neck and sometimes involve a forceful thrust.

There are four arteries that supply blood to the brain: the two carotid arteries on each side of the neck, and the two vertebral arteries on the back of the neck. The influence of neck manipulation seems more important in vertebral artery dissection than in internal carotid artery dissection.

"Although a cause-and-effect relationship between these therapies and CD has not been established and the risk is probably low, CD can result in serious neurological injury," Biller said. "Patients should be informed of this association before undergoing neck manipulation."

The association between cervical artery dissection and cervical manipulative therapies was identified in case control studies, which aren't designed to prove cause and effect. An association means that there appears to be a relationship between two things, i.e., manipulative therapy of the neck and a greater incidence of cervical dissection/stroke. 

However, it's not clear whether other factors could account for the apparent relationship.

The relationship between neck manipulation and cervical artery dissection is difficult to evaluate because patients who already are beginning to have a cervical artery dissection may seek treatment to relieve neck pain, a common symptom of cervical artery dissection that can precede symptoms of stroke by several days.

You should seek emergency medical evaluation if you develop neurological symptoms after neck manipulation or trauma, such as:

• Pain in the back of your neck or in your head;
• Dizziness/vertigo;
• Double vision;
• Unsteadiness when walking;
• Slurred speech;
• Nausea and vomiting;
• Jerky eye movements.

"Tell the physician if you have recently had a neck trauma or neck manipulation," Biller said. 

"Some symptoms, such as dizziness or vertigo, are very common and can be due to minor conditions rather than stroke, but giving the information about recent neck manipulation can raise a red flag that you may have a CD rather than a less serious problem, particularly in the presence of neck pain."

Source: American Heart Association

New way to diagnose brain damage from concussions, strokes, and dementia

A new tool to assess cerebrovascular health: Coherent Hemodynamics Spectroscopy (CHS).
Credit: Tufts University Professor of Biomedical Engineering Sergio Fantini

New optical diagnostic technology developed at Tufts University School of Engineering promises new ways to identify and monitor brain damage resulting from traumatic injury, stroke or vascular dementia -- in real time and without invasive procedures.

Coherent hemodynamics spectroscopy (CHS), developed and published by Tufts Professor of Biomedical Engineering Sergio Fantini, measures blood flow, blood volume, and oxygen consumption in the brain. It uses non-invasive near infrared (NIR) light technology to scan brain tissue, and then applies mathematical algorithms to interpret that information.

"CHS is based on measurements of brain hemodynamics that are interpreted according to unique algorithms that generate measures of cerebral blood flow, blood volume and oxygen consumption," says Fantini. "This technique can be used not only to assess brain diseases but also to study the blood flow and how it is regulated in the healthy brain."

Tufts has licensed CHS on a non-exclusive basis to ISS, a Champaign, Ill.-based company that specializes in technology to measure hemoglobin concentration and oxygenation in brain and muscle tissue.

"Potentially the market for CHS is large as it encompasses several applications from the monitoring of cerebrovascular disorders to assessing neurological disorders," says Beniamino Barbieri, president of ISS. "It reminds me of the introduction of ultrasound technology at beginning of the seventies; nobody back then knew how to utilize the new technology and of course, nowadays, its applications are ubiquitous in any medical center."

How It Works

CHS uses laser diodes which emit NIR light that is delivered to the scalp by fiber optics. Light waves are absorbed by the blood vessels in the brain. Remaining light is reflected back to sensors, resulting in optical signals that oscillate with time as a result of the heartbeat, respiration, or other sources of variations in the blood pressure.

By analyzing the light signals with algorithms developed for this purpose, Fantini's model is able to evaluate blood flow and the way the brain regulates it--which is one marker for brain health.

CHS technology has been tested among patients undergoing hemodialysis at Tufts Medical Center. Published research reported a lower cerebral blood flow in dialysis patients compared with healthy patients.

"Non-invasive ways to measure local changes in cerebral blood flow, particularly during periods of stress such as hemodialysis, surgeries, and in the setting of stroke, could have major implications for maintaining healthy brain function," says Daniel Weiner, M.D., a nephrologist at Tufts Medical Center (Tufts MC) and associate professor of medicine at Tufts University School of Medicine (TUSM), who is a member of the research team.

Josh Kornbluth, M.D., a neurologist at Tufts MC and associate professor of medicine at TUSM, is also working with Fantini to explore CHS's potential to assess the cerebrovascular state of patients who suffer traumatic brain injury or stroke. They hope to test CHS further among neurological critical care patients.

"Having data about local cerebral blood flow and whether it is properly regulated can allow us to more accurately develop individualized therapy and interventions instead of choosing a 'one size fits all' approach to traumatic brain injury, stroke, or subarachnoid hemorrhage," Kornbluth says.

Source: Tufts University