Changing gut bacteria through diet affects brain function

UCLA researchers now have the first evidence that bacteria ingested in food can affect brain function in humans. In an early proof-of-concept study of healthy women, they found that women who regularly consumed beneficial bacteria known as probiotics through yogurt showed altered brain function, both while in a resting state and in response to an emotion-recognition task.

The study, conducted by scientists with UCLA’s Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress and the Ahmanson–Lovelace Brain Mapping Center at UCLA, appears in the current online edition of the peer-reviewed journal Gastroenterology.

The discovery that changing the bacterial environment, or microbiota, in the gut can affect the brain carries significant implications for future research that could point the way toward dietary or drug interventions to improve brain function, the researchers said.

"Many of us have a container of yogurt in our refrigerator that we may eat for enjoyment, for calcium or because we think it might help our health in other ways," said Dr. Kirsten Tillisch, an associate professor of medicine at UCLA’s David Geffen School of Medicine and lead author of the study. "Our findings indicate that some of the contents of yogurt may actually change the way our brain responds to the environment. When we consider the implications of this work, the old sayings ‘you are what you eat’ and ‘gut feelings’ take on new meaning."

Researchers have known that the brain sends signals to the gut, which is why stress and other emotions can contribute to gastrointestinal symptoms. This study shows what has been suspected but until now had been proved only in animal studies: that signals travel the opposite way as well.

"Time and time again, we hear from patients that they never felt depressed or anxious until they started experiencing problems with their gut," Tillisch said. "Our study shows that the gut–brain connection is a two-way street."

The small study involved 36 women between the ages of 18 and 55. Researchers divided the women into three groups: one group ate a specific yogurt containing a mix of several probiotics — bacteria thought to have a positive effect on the intestines — twice a day for four weeks; another group consumed a dairy product that looked and tasted like the yogurt but contained no probiotics; and a third group ate no product at all.

Functional magnetic resonance imaging (fMRI) scans conducted both before and after the four-week study period looked at the women’s brains in a state of rest and in response to an emotion-recognition task in which they viewed a series of pictures of people with angry or frightened faces and matched them to other faces showing the same emotions. This task, designed to measure the engagement of affective and cognitive brain regions in response to a visual stimulus, was chosen because previous research in animals had linked changes in gut flora to changes in affective behaviors.

The researchers found that, compared with the women who didn’t consume the probiotic yogurt, those who did showed a decrease in activity in both the insula — which processes and integrates internal body sensations, like those form the gut — and the somatosensory cortex during the emotional reactivity task.

Further, in response to the task, these women had a decrease in the engagement of a widespread network in the brain that includes emotion-, cognition- and sensory-related areas. The women in the other two groups showed a stable or increased activity in this network.

During the resting brain scan, the women consuming probiotics showed greater connectivity between a key brainstem region known as the periaqueductal grey and cognition-associated areas of the prefrontal cortex. The women who ate no product at all, on the other hand, showed greater connectivity of the periaqueductal grey to emotion- and sensation-related regions, while the group consuming the non-probiotic dairy product showed results in between.

The researchers were surprised to find that the brain effects could be seen in many areas, including those involved in sensory processing and not merely those associated with emotion, Tillisch said.

The knowledge that signals are sent from the intestine to the brain and that they can be modulated by a dietary change is likely to lead to an expansion of research aimed at finding new strategies to prevent or treat digestive, mental and neurological disorders, said Dr. Emeran Mayer, a professor of medicine, physiology and psychiatry at the David Geffen School of Medicine at UCLA and the study’s senior author.

"There are studies showing that what we eat can alter the composition and products of the gut flora — in particular, that people with high-vegetable, fiber-based diets have a different composition of their microbiota, or gut environment, than people who eat the more typical Western diet that is high in fat and carbohydrates," Mayer said. "Now we know that this has an effect not only on the metabolism but also affects brain function."

The UCLA researchers are seeking to pinpoint particular chemicals produced by gut bacteria that may be triggering the signals to the brain. They also plan to study whether people with gastrointestinal symptoms such as bloating, abdominal pain and altered bowel movements have improvements in their digestive symptoms which correlate with changes in brain response.

Meanwhile, Mayer notes that other researchers are studying the potential benefits of certain probiotics in yogurts on mood symptoms such as anxiety. He said that other nutritional strategies may also be found to be beneficial.

By demonstrating the brain effects of probiotics, the study also raises the question of whether repeated courses of antibiotics can affect the brain, as some have speculated. Antibiotics are used extensively in neonatal intensive care units and in childhood respiratory tract infections, and such suppression of the normal microbiota may have long-term consequences on brain development.

Finally, as the complexity of the gut flora and its effect on the brain is better understood, researchers may find ways to manipulate the intestinal contents to treat chronic pain conditions or other brain related diseases, including, potentially, Parkinson’s disease, Alzheimer’s disease and autism.

Answers will be easier to come by in the near future as the declining cost of profiling a person’s microbiota renders such tests more routine, Mayer said.

Engineered stem cell advance points toward treatment for ALS

Transplantation of human stem cells in an experiment conducted at the University of Wisconsin-Madison improved survival and muscle function in rats used to model ALS, a nerve disease that destroys nerve control of muscles, causing death by respiratory failure.

ALS (amyotrophic lateral sclerosis) is sometimes called “Lou Gehrig’s disease.” According to the ALS Association, the condition strikes about 5,600 Americans each year. Only about half of patients are alive three years after diagnosis. 

In work recently completed at the UW School of Veterinary Medicine, Masatoshi Suzuki, an assistant professor of comparative biosciences, and his colleagues used adult stem cells from human bone marrow and genetically engineered the cells to produce compounds called growth factors that can support damaged nerve cells.

The researchers then implanted the cells directly into the muscles of rats that were genetically modified to have symptoms and nerve damage resembling ALS.

In people, the motor neurons that trigger contraction of leg muscles are up to three feet long. These nerve cells are often the first to suffer damage in ALS, but it’s unclear where the deterioration begins. Many scientists have focused on the closer end of the neuron, at the spinal cord, but Suzuki observes that the distant end, where the nerve touches and activates the muscle, is often damaged early in the disease.

The connection between the neuron and the muscle, called the neuro-muscular junction, is where Suzuki focuses his attention. “This is one of our primary differences,” Suzuki says. “We know that the neuro-muscular junction is a site of early deterioration, and we suspected that it might be the villain in causing the nerve cell to die. It might not be an innocent victim of damage that starts elsewhere.”

Previously, Suzuki found that injecting glial cell line-derived neurotropic factor (GDNF) at the junction helped the neurons survive. The new study, published in the journal Molecular Therapy on May 28, expands the research to show a similar effect from a second compound, called vascular endothelial growth factor.

In the study, Suzuki found that using stem cells to deliver vascular endothelial growth factor alone improved survival and delayed the onset of disease and the decline in muscle function. That result mirrored his earlier study with GDNF.

But the real advance, Suzuki says, was finding an even better result from using stem cells that create both of these two growth factors. “In terms of disease-free time, overall survival, and sustaining muscle function, we found that delivering the combination was more powerful than either growth factor alone. The results would provide a new hope for people with this terrible disease.”

The new research was supported by the ALS Association, the National Institutes of Health, the University of Wisconsin Foundation, and other groups. 

The injected stem cells survived for at least nine weeks, but did not become neurons. Instead, their contribution was to secrete one or both growth factors. 

Originally, much of the enthusiasm for stem cells focused on the hope of replacing damaged cells, but Suzuki’s approach is different. “These motor nerve cells have extremely long connections, and replacing these cells is still challenging. But we aim to keep the neurons alive and healthy using the same growth factors that the body creates, and that’s what we have shown here.”

For the test, Suzuki used ALS model rats with a mutation that is found in a small percentage of ALS patients who have a genetic form of the disease. “This model has been accepted as the best test bed for ALS experiments,” says Suzuki. 

By using adult mesenchymal stem cells, the technique avoided the danger of tumor that can arise with the transplant of embryonic stem cells and related “do-anything” cells.  Importantly, mesenchymal stem cells have been already used in clinical trials for various human diseases.

In the future, Suzuki hopes to apply his approach by using clinical grade stem cells. “Because this is a fatal and untreatable disease, we hope this could enter a clinical trial relatively soon.”

Researchers Uncover Key to Development of Peripheral Nervous System

Patients suffering from hereditary neuropathy may have hope for new treatment thanks to a Geisinger study that uncovered a key to the development of the peripheral nervous system.

In an article published today in the online medical journal Nature Communications, Geisinger researchers found that a protein present within immune system cells plays a larger role than previously thought in the development of the peripheral nervous system.

Nikolaos Tapinos, M.D., Ph.D., director of neurosurgery research and staff scientist at Geisinger’s Sigfried and Janet Weis Center for Research, said the findings could have implications in how hereditary neuropathy is treated. Hereditary neuropathy affects the peripheral nervous system, causing subtle symptoms such as muscle weakness, wasting and numbness that worsen over time.

“When the peripheral nervous system develops in utero, certain proteins control how the cells travel throughout the body to the proper locations,” Dr. Tapinos said. “Some of those proteins are already known, but this is the first time that the protein Lck has been identified as integral to this process.”

Lck, or lymphocyte-specific protein tyrosine kinase, is a protein that is found inside specialized cells of the immune system. Dr. Tapinos’ research found that Lck controls how cells called Schwann cells migrate across neurons throughout the peripheral nervous system.

Schwann cells function by creating the myelin sheath, the fatty covering that acts as an insulator around nerve fibers. In humans, the production of myelin begins in the 14th week of fetal development and continues through infancy and adolescence. When errors occur in the creation of myelin, hereditary neuropathy such as Charcot-Marie-Tooth disease (CMT), a motor and sensory neuropathy, can result.

“What we have found is that Lck is essentially the ‘switch’ that signals migration of the Schwann cells and production of the myelin sheath,” Dr. Tapinos said. “This finding sets the stage for further research into the specific molecular mechanisms that occur in order for this process to break down, and eventually toward developing treatments to prevent it.”

(Image: Wikipedia)

Preventing ‘traffic jams’ in brain cells

Imagine if you could open up your brain and look inside.

What you would see is a network of nerve cells called neurons, each with its own internal highway system for transporting essential materials between different parts of the cell.

When this biological machinery is operating smoothly, tiny motor proteins ferry precious cargo up and down each neuron along thread-like roadways called microtubule tracks. Brain cells are able to receive information, make internal repairs and send instructions to the body, telling the fingers to flex or the toes to curl.

But when the neuron gets blocked, this delicate harmony deteriorates. One result: diseases like Alzheimer’s.

Understanding such blockages and how traffic should flow normally in healthy brain cells could offer hope to people with neurodegenerative diseases.

Toward that end, a research team led by University at Buffalo biologist Shermali Gunawardena, PhD, has shown that the protein presenilin plays an important role in controlling neuronal traffic on microtubule highways, a novel function that previously was unknown.

The research results were published online on May 24 in the journal Human Molecular Genetics. Gunawardena’s co-authors are Ge Yang of Carnegie Mellon University and Lawrence S. B. Goldstein of the Howard Hughes Medical Institute and the University of California, San Diego.

Inside the nerves of fruit fly larvae, presenilin helped to control the speed at which molecular motors called kinesins and dyneins moved along neurons. When the scientists halved the amount of presenilin present in the highway system, the motors moved faster; they paused fewer times and their pauses were shorter.

Given this data, Gunawardena thinks that tweaking presenilin levels may be one way to free up traffic and prevent dangerous neuronal blockages in patients with Alzheimer’s disease.

“Our major discovery is that presenilin has a novel role, which is to control the movement of motor proteins along neuronal highways,” said Gunawardena, an assistant professor of biological sciences. “If this regulation/control is lost, then things can go wrong. This is the first time a protein that functions as a controller of motors has been reported.

“In Alzheimer’s disease, transport defects occur well before symptoms, such as cell death and amyloid plaques, are seen in post-mortem brains,” she added. “As a result, developing therapeutics targeted to defects in neuronal transport would be a useful way to attack the problem early.”

The findings are particularly intriguing because scientists have known for several years that presenilin is involved in Alzheimer’s disease.

Presenilin rides along neuronal highways in tiny organic bubbles called vesicles that sit atop the kinesin and dynein motors, and also contain a second protein called the amyloid precursor protein (APP). Presenilin participates in cutting APP into pieces called amyloid beta, which build up to form amyloid plaques in patients with Alzheimer’s disease.

Such buildups can lead to cell death by preventing the transport of essential materials—like proteins needed for cell repair—along neurons.

The findings of the new study mean that presenilin may contribute to Alzheimer’s disease in at least two ways: not just by cleaving APP, but also by regulating the speed of the molecular motors that carry APP along neuronal highways.

“More than 150 mutations in presenilin have been identified in Alzheimer’s disease,” Gunawardena said. “Thus, understanding its function is important to understanding what goes wrong in Alzheimer’s disease.”

To track the movement of the kinesins and dyneins, the team tagged their cargo with a yellow fluorescent protein. This enabled the scientists to view the molecular motors chugging along inside the neuron under a microscope in a living animal. A special computer program then analyzed the motors’ paths, revealing more details about the nature of their movement and how often they paused.

Scientists advance understanding of brain receptor; may help fight neurological disorders

For several years, the pharmaceutical industry has tried to develop drugs that target a specific neurotransmitter receptor in the brain, the NMDA receptor. This receptor is present on almost every neuron in the human brain and is involved in learning and memory. NMDA receptors also have been implicated in several neurological and psychiatric conditions such as Alzheimer’s disease, Parkinson’s disease, schizophrenia and depression.

But drug companies have had little success developing clinically effective drugs that target this receptor.

Now, researchers at Oregon Health & Science University’s Vollum Institute believe they may understand why. And what they’ve discovered may help in the development of new therapies for these conditions.

In a paper published in the current issue of the Journal of Neuroscience, OHSU scientists describe their work on NMDA receptors. There are various types of NMDA receptors, resulting from differences in the protein components that make up the receptor. These differences in the protein components produce receptors with varying properties.

As drug companies have worked to develop compounds that manipulate the activity of these receptors, the focus of much of this drug discovery effort has been on a specific NMDA receptor subtype. In their Journal of Neuroscience paper, the OHSU scientists describe their discovery — that the specific receptor subtype that drug companies have seen as a target is an almost nonexistent contributor of NMDA receptor action.

What does exist, the OHSU scientists found, was a different kind of NMDA receptor subtype — one containing two specific protein components, called GluN2A and GluN2B. NMDA receptors containing these two components were not thought to be very common. The OHSU study found that not only was this NMDA receptor subtype more common than previously believed, it was the most common subtype at synapses. And it was far more common than the receptor subtype that has been the target of drug development efforts.

"What our paper shows is that one reason no drugs have worked well to this point may be because that particular NMDA receptor subtype isn’t there in high quantities. The target they’ve been looking for isn’t the target that’s there," said Ken Tovar, Ph.D., a senior postdoctoral fellow at the Vollum Institute. Tovar’s co-authors on the paper were Gary Westbrook, M.D., senior scientist and co-director of the Vollum Institute, and Matthew McGinley, Ph.D., a former graduate student in the Westbrook laboratory.

Tovar said these findings could provide a new target for drug development.

"If you know what’s there, then you know what to go after — you just have to figure out how to do it," Tovar said.

The OHSU study also provides clues into how the function of this most common NMDA receptor subtype might be manipulated. Highly specific drugs interact with either GluN2A or GluN2B. Tovar and colleagues demonstrated that when GluN2A and GluN2B coexist in the same receptor, molecules that targeted GluN2A change the behavior of the receptor in ways that could be clinically beneficial.

"NMDA receptors have been implicated in a diverse list of neurological and psychiatric conditions. Thus, the more we know about how to modulate the behavior of the receptors that are there — at synapses — the greater chance we have of finding drugs to treat these conditions," Tovar said.

"From the perspective of drug development, knowing the nature of your target is one way to keep drug development costs down," said Tovar. "Spending resources investigating a target that turns out to be unimportant means those costs get passed on to the drugs that are effective."

(Image: iStockphoto)

Too early to learn

Reseachers from Bochum and Warwick suggest consequences for planning school lessons

Large numbers of preterm born babies will place new demands on education system

About 15 million, i.e., more than ten per cent of all babies worldwide are born preterm every year; that is before the 37th week of pregnancy – and the numbers are rising due to improvements in neonatal medicine and demographic changes. Recent studies suggest that delivery at any gestation other than full term (39 to 41 weeks gestational age) may impair brain development, rendering survivors at risk for adverse neuro-cognitive outcomes. Considering that 50 per cent of children are born before the 39th week of pregnancy, even small increases in cognitive impairments may have large effects on a population level. “As the total number of children born preterm increases there will be parallel increases in special education needs placing new demands on the education system,” Julia Jäkel and her colleagues say. To date, uncertainties remain regarding the nature and underlying causes of learning difficulties in preterm children. The new cognitive workload model now reconciles previous inconsistent findings on the relationship of gestational age and cognitive performance.

Cognitive deficits of children born preterm depend on the workload of the task

The research team tested 1326 children, born between weeks 23 and 41 of pregnancy, at an age of eight years. Data were collected as part of the prospective Bavarian Longitudinal Study. The children took part in a range of cognitive tests with varying workload. High workload tasks require the simultaneous integration of different sources of information, thereby placing high demands on the so called working memory. The results: The higher the workload and the shorter the pregnancy duration, the larger were the cognitive performance deficits. Deficits were disproportionally higher for children born before the 34th week of pregnancy compared with children born after week 33. Being born preterm specifically affected the ability to solve high workload tasks, whereas lower workload tasks were largely unaffected.

Results are relevant for cognitive follow-ups and planning of school lessons

According to the researchers, these results should be taken into account for routine cognitive follow-ups of preterm children as well as for planning school lessons. “New studies suggest that computerized training can improve working memory capacity,” Prof Dieter Wolke from Warwick says. “In addition, educational interventions could be developed in which information is not presented simultaneously to preterm children but more slowly and sequentially to promote academic attainment.”

Rats have a double view of the world

Scientists from the Max Planck Institute for Biological Cybernetics in Tübingen, using miniaturised high-speed cameras and high-speed behavioural tracking, discovered that rats move their eyes in opposite directions in both the horizontal and the vertical plane when running around. Each eye moves in a different direction, depending on the change in the animal’s head position. An analysis of both eyes’ field of view found that the eye movements exclude the possibility that rats fuse the visual information into a single image like humans do. Instead, the eyes move in such a way that enables the space above them to be permanently in view – presumably an adaptation to help them deal with the major threat from predatory birds that rodents face in their natural environment.

Like many mammals, rats have their eyes on the sides of their heads. This gives them a very wide visual field, useful for detection of predators. However, three-dimensional vision requires overlap of the visual fields of the two eyes. Thus, the visual system of these animals needs to meet two conflicting demands at the same time; on the one hand maximum surveillance and on the other hand detailed binocular vision.

The research team from the Max Planck Institute for Biological Cybernetics have now, for the first time, observed and characterised the eye movements of freely moving rats. They fitted minuscule cameras weighing only about one gram to the animals’ heads, which could record the lightning-fast eye movements with great precision. The scientists also used another new method to measure the position and direction of the head, enabling them to reconstruct the rats’ exact line of view at any given time.

The Max Planck scientists’ findings came as a complete surprise. Although rats process visual information from their eyes through very similar brain pathways to other mammals, their eyes evidently move in a totally different way. “Humans move their eyes in a very stereotypical way for both counteracting head movements and searching around. Both our eyes move together and always follow the same object. In rats, on the other hand, the eyes generally move in opposite directions,” explains Jason Kerr from the Max Planck Institute for Biological Cybernetics.

In a series of behavioural experiments, the neurobiologists also discovered that the eye movements largely depend on the position of the animal’s head. “When the head points downward, the eyes move back, away from the tip of the nose. When the rat lifts its head, the eyes look forward: cross-eyed, so to speak. If the animal puts its head on one side, the eye on the lower side moves up and the other eye moves down.” says Jason Kerr.

In humans, the direction in which the eyes look must be precisely aligned, otherwise an object cannot be fixated. A deviation measuring less than a single degree of the field of view is enough to cause double vision. In rats, the opposing eye movements between left and right eye mean that the line of vision varies by as much as 40 degrees in the horizontal plane and up to 60 degrees in the vertical plane. The consequence of these unusual eye movements is that irrespective of vigorous head movements in all planes, the eyes movements always move in such a way to ensure that the area above the animal is always in view simultaneously by both eyes –something that does not occur in any other region of the rat’s visual field.

These unusual eye movements that rats possess appear to be the visual system’s way of adapting to the animals’ living conditions, given that they are preyed upon by numerous species of birds. Although the observed eye movements prevent the fusion of the two visual fields, the scientists postulate that permanent visibility in the direction of potential airborne attackers dramatically increases the animals’ chances of survival.