Entries in Brain Health (2)

Monday
Jun292015

Can the Bacteria in Your Gut Explain Your Mood?

The Dolder Grand
Health & Rejuvenation

PD Dr. Rainer Arendt
Internal Medicine & Cardiology FMH
Prevention & Regenerative Medicine


We offer gut microbiome exchange (transplantation) as novel opportunity in prevention and treatment of various and so far difficult to treat ailments (auto-immune diseases, metabolic disorders, neuro-psychiatric diseases and addictions, cardiovascular disease, endocrine disorders and infertility, cancer).

 

It is the rich array of microbiota in our intestines that makes us the human beings we are and preserves our health.

 

Since 2007, when scientists announced plans for a Human Microbiome Project to catalog the micro-organisms living in our body, the profound appreciation for the influence of such organisms has grown rapidly with each passing year. Bacteria in the gut produce vitamins and break down our food; their presence or absence has been linked to obesity, inflammatory bowel disease and the toxic side effects of prescription drugs. Biologists now believe that much of what makes us human depends on microbial activity. The two million unique bacterial genes found in each human microbiome can make the 23,000 genes in our cells seem paltry, almost negligible, by comparison. ‘‘It has enormous implications for the sense of self,’’ Tom Insel, the director of the National Institute of Mental Health, told me. ‘‘We are, at least from the standpoint of DNA, more microbial than human. That’s a phenomenal insight and one that we have to take seriously when we think about human development.’’

Given the extent to which bacteria are now understood to influence human physiology, it is hardly surprising that scientists have turned their attention to how bacteria might affect the brain. Micro-organisms in our gut secrete a profound number of chemicals, and researchers have found that among those chemicals are the same substances used by our neurons to communicate and regulate mood, like dopamine, serotonin and gamma-aminobutyric acid (GABA). These, in turn, appear to play a function in intestinal disorders, which coincide with high levels of major depression and anxiety. Last year, for example, a group in Norway examined feces from 55 people and found certain bacteria were more likely to be associated with depressive patients.

Anxiety, depression and several pediatric disorders, including autism and hyperactivity, have been linked with gastrointestinal abnormalities. Microbial transplants can be performed safely, it is not invasive brain surgery, and that is the point: Changing a patient’s bacteria can be done, altering his genes is still far away.

When Mark Lyte from the Texas Tech University Health Sciences Center campus in Abilene, Tex., as one of the first, began his work on the link between microbes and the brain three decades ago, it was dismissed as a curiosity. By contrast, last September, the National Institute of Mental Health awarded four grants worth up to $1 million each to spur new research on the gut microbiome’s role in mental disorders, affirming the legitimacy of a field that had long struggled to attract serious scientific credibility. Lyte and one of his longtime colleagues, Christopher Coe, at the Harlow primate lab, received one of the four. ‘‘What Mark proposed going back almost 25 years now has come to fruition,’’ Coe told me. ‘‘Now what we’re struggling to do is to figure out the logic of it.’’ It seems plausible that we might use microbes to diagnose neurodevelopmental disorders, treat mental illnesses and perhaps even fix them in the brain.

In 2011, a team of researchers at University College Cork, in Ireland, and McMaster University, in Ontario, published a study in Proceedings of the National Academy of Science that has become one of the best-known experiments linking bacteria in the gut to the brain. Laboratory mice were dropped into tall, cylindrical columns of water in what is known as a forced-swim test, which measures over six minutes how long the mice swim before they realize that they can neither touch the bottom nor climb out, and instead collapse into a forlorn float. Researchers use the amount of time a mouse floats as a way to measure what they call ‘‘behavioral despair.’’ (Antidepressant drugs, like Zoloft and Prozac, were initially tested using this forced-swim test.)

For several weeks, the team, led by John Cryan, the neuroscientist who designed the study, fed a small group of healthy rodents a broth infused with Lactobacillus rhamnosus, a common bacterium that is found in humans and also used to ferment milk into probiotic yogurt. Lactobacilli are one of the dominant organisms babies ingest as they pass through the birth canal. Recent studies have shown that mice stressed during pregnancy pass on lowered levels of the bacterium to their pups. This type of bacteria is known to release immense quantities of GABA; as an inhibitory neurotransmitter, GABA calms nervous activity, which explains why the most common anti-anxiety drugs, like Valium and Xanax, work by targeting GABA receptors.

Cryan found that the mice that had been fed the bacteria-laden broth kept swimming longer and spent less time in a state of immobilized woe. ‘‘They behaved as if they were on Prozac,’’ he said. ‘‘They were more chilled out and more relaxed.’’ The results suggested that the bacteria were somehow altering the neural chemistry of mice.

Until he joined his colleagues at Cork 10 years ago, Cryan thought about microbiology in terms of pathology: the neurological damage created by diseases like syphilis or H.I.V. ‘‘There are certain fields that just don’t seem to interact well,’’ he said. ‘‘Microbiology and neuroscience, as whole disciplines, don’t tend to have had much interaction, largely because the brain is somewhat protected.’’ He was referring to the fact that the brain is anatomically isolated, guarded by a blood-brain barrier that allows nutrients in but keeps out pathogens and inflammation, the immune system’s typical response to germs. Cryan’s study added to the growing evidence that signals from beneficial bacteria nonetheless find a way through the barrier. Somehow — though his 2011 paper could not pinpoint exactly how — micro-organisms in the gut tickle a sensory nerve ending in the fingerlike protrusion lining the intestine and carry that electrical impulse up the vagus nerve and into the deep-brain structures thought to be responsible for elemental emotions like anxiety. Soon after that, Cryan and a co-author, Ted Dinan, published a theory paper in Biological Psychiatry calling these potentially mind-altering microbes ‘‘psychobiotics.’’

It has long been known that much of our supply of neurochemicals — an estimated 50 percent of the dopamine, for example, and a vast majority of the serotonin — originate in the intestine, where these chemical signals regulate appetite, feelings of fullness and digestion. But only in recent years has mainstream psychiatric research given serious consideration to the role microbes might play in creating those chemicals. Lyte’s own interest in the question dates back to his time as a postdoctoral fellow at the University of Pittsburgh in 1985, when he found himself immersed in an emerging field with an unwieldy name: psychoneuroimmunology, or PNI, for short. The central theory, quite controversial at the time, suggested that stress worsened disease by suppressing our immune system.

By 1990, at a lab in Mankato, Minn., Lyte distilled the theory into three words, which he wrote on a chalkboard in his office: Stress->Immune->Disease. In the course of several experiments, he homed in on a paradox. When he dropped an intruder mouse in the cage of an animal that lived alone, the intruder ramped up its immune system — a boost, he suspected, intended to fight off germ-ridden bites or scratches. Surprisingly, though, this did not stop infections. It instead had the opposite effect: Stressed animals got sick. Lyte walked up to the board and scratched a line through the word ‘‘Immune.’’ Stress, he suspected, directly affected the bacterial bugs that caused infections.

To test how micro-organisms reacted to stress, he filled petri plates with a bovine-serum-based medium and laced the dishes with a strain of bacterium. In some, he dropped norepinephrine, a neurochemical that mammals produce when stressed. The next day, he snapped a Polaroid. The results were visible and obvious: The control plates were nearly barren, but those with the norepinephrine bloomed with bacteria that filigreed in frostlike patterns. Bacteria clearly responded to stress.

Then, to see if bacteria could induce stress, Lyte fed white mice a liquid solution of Campylobacter jejuni, a bacterium that can cause food poisoning in humans but generally doesn’t prompt an immune response in mice. To the trained eye, his treated mice were as healthy as the controls. But when he ran them through a plexiglass maze raised several feet above the lab floor, the bacteria-fed mice were less likely to venture out on the high, unprotected ledges of the maze. In human terms, they seemed anxious. Without the bacteria, they walked the narrow, elevated planks.

Each of these results was fascinating, but Lyte had a difficult time finding microbiology journals that would publish either. ‘‘It was so anathema to them,’’ he told me. When the mouse study finally appeared in the journal Physiology & Behavior in 1998, it garnered little attention. And yet as Stephen Collins, a gastroenterologist at McMaster University, told me, those first papers contained the seeds of an entire new field of research. ‘‘Mark showed, quite clearly, in elegant studies that are not often cited, that introducing a pathological bacterium into the gut will cause a change in behavior.’’

Lyte went on to show how stressful conditions for newborn cattle worsened deadly E. coli infections. In another experiment, he fed mice lean ground hamburger that appeared to improve memory and learning — a conceptual proof that by changing diet, he could change gut microbes and change behavior. After accumulating nearly a decade’s worth of evidence, in July 2008, he flew to Washington to present his research. He was a finalist for the National Institutes of Health’s Pioneer Award, a $2.5 million grant for so-called blue-sky biomedical research. Finally, it seemed, his time had come. When he got up to speak, Lyte described a dialogue between the bacterial organ and our central nervous system. At the two-minute mark, a prominent scientist in the audience did a spit take.

‘‘Dr. Lyte,’’ he later asked at a question-and-answer session, ‘‘if what you’re saying is right, then why is it when we give antibiotics to patients to kill bacteria, they are not running around crazy on the wards?’’

Can antibiotics given prior to surgery increase chances of depression after surgery? I know a person who suffered severe depression after...

Lyte knew it was a dismissive question. And when he lost out on the grant, it confirmed to him that the scientific community was still unwilling to imagine that any part of our neural circuitry could be influenced by single-celled organisms. Lyte published his theory in Medical Hypotheses, a low-ranking journal that served as a forum for unconventional ideas. The response, predictably, was underwhelming. ‘‘I had people call me crazy,’’ he said.

But by 2011 — when he published a second theory paper in Bioessays, proposing that probiotic bacteria could be tailored to treat specific psychological diseases — the scientific community had become much more receptive to the idea. A Canadian team, led by Stephen Collins, had demonstrated that antibiotics could be linked to less cautious behavior in mice, and only a few months before Lyte, Sven Pettersson, a microbiologist at the Karolinska Institute in Stockholm, published a landmark paper in Proceedings of the National Academy of Science that showed that mice raised without microbes spent far more time running around outside than healthy mice in a control group; without the microbes, the mice showed less apparent anxiety and were more daring. In Ireland, Cryan published his forced-swim-test study on psychobiotics. There was now a groundswell of new research. In short order, an implausible idea had become a hypothesis in need of serious validation.

Late last year, Sarkis Mazmanian, a microbiologist at the California Institute of Technology, gave a presentation at the Society for Neuroscience, ‘‘Gut Microbes and the Brain: Paradigm Shift in Neuroscience.’’ Someone had inadvertently dropped a question mark from the end, so the speculation appeared to be a definitive statement of fact. But if anyone has a chance of delivering on that promise, it’s Mazmanian, whose research has moved beyond the basic neurochemicals to focus on a broader class of molecules called metabolites: small, equally druglike chemicals that are produced by micro-organisms. Using high-powered computational tools, he also hopes to move beyond the suggestive correlations that have typified psychobiotic research to date, and instead make decisive discoveries about the mechanisms by which microbes affect brain function.

Two years ago, Mazmanian published a study in the journal Cell with Elaine Hsiao, then a graduate student in the lab of Paul Patterson, another author of the study, and now a neuroscientist at Caltech, that made a provocative link between a single molecule and behavior. Their research found that mice exhibiting abnormal communication and repetitive behaviors, like obsessively burying marbles, were mollified when they were given one of two strains of the bacterium Bacteroides fragilis.

The study added to a working hypothesis in the field that microbes don’t just affect the permeability of the barrier around the brain but also influence the intestinal lining, which normally prevents certain bacteria from leaking out and others from getting in. When the intestinal barrier was compromised in his model, normally ‘‘beneficial’’ bacteria and the toxins they produce seeped into the bloodstream and raised the possibility they could slip past the blood-brain barrier. As one of his colleagues, Michael Fischbach, a microbiologist at the University of California, San Francisco, said: ‘‘The scientific community has a way of remaining skeptical until every last arrow has been drawn, until the entire picture is colored in. Other scientists drew the pencil outlines, and Sarkis is filling in a lot of the color.’’

Mazmanian knew the results offered only a provisional explanation for why restrictive diets and antibacterial treatments seemed to help some children with autism: Altering the microbial composition might be changing the permeability of the intestine. ‘‘The larger concept is, and this is pure speculation: Is a disease like autism really a disease of the brain or maybe a disease of the gut or some other aspect of physiology?’’ Mazmanian said. For any disease in which such a link could be proved, he saw a future in drugs derived from these small molecules found inside microbes. In his view, the prescriptive solutions probably involve more than increasing our exposure to environmental microbes in soil, dogs or even fermented foods; he believed there were wholesale failures in the way we shared our microbes and inoculated children with these bacteria. So far, though, the only conclusion he could draw was that disorders once thought to be conditions of the brain might be symptoms of microbial disruptions, and it was the careful defining of these disruptions that promised to be helpful in the coming decades.

The list of potential treatments incubating in labs around the world is startling. Several international groups have found that psychobiotics had subtle yet perceptible effects in healthy volunteers in a battery of brain-scanning and psychological tests. Another team in Arizona recently finished an open trial on fecal transplants in children with autism. (Simultaneously, at least two offshore clinics, in Australia and England, began offering fecal microbiota treatments to treat neurological disorders, like multiple sclerosis.) Mazmanian: ‘‘We’ve reached the stage where there’s a lot of, you know, ‘The microbiome is the cure for everything,’ ’’ he said. ‘‘I have a vested interest if it does. But I’d be shocked if it did.’’

 

Excerpted from Peter Andrey Smith, a reporter living in Brooklyn. He frequently writes about the microbial world.

Reporting for his New York Times' article was supported by the UC Berkeley-11th Hour Food and Farming Journalism Fellowship.

PD Dr. med. Rainer Arendt
FMH Cardiology, Internal Medicine
Regenerative Medicine 

SWISS  PREVENTION  CLINIC
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T +41 43 336 7260
M +41 78 825 0803
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rainer.arendt@swisspreventionclinic.ch

www.swisspreventionclinic.ch
www.patientcircle.org

Tuesday
Apr072015

The Gut Microbiome and Brain Health: What's the Connection?

Based on Sarah R. Dash. The Microbiome and Brain Health: What's the Connection? Medscape. Mar 24, 2015.

 

Introduction

Researchers are now beginning to understand the ways in which bacteria living in the human gut—the gut microbiota or microbiome—communicate with and influence brain health. The concept of a faulty "gut/brain axis" has been associated with various neurologic and psychiatric outcomes and is thought to be explained, at least in part, by immune dysfunction and inflammation triggered by poor gut health.

The gut microbiota has emerged as an important focus in the understanding of noncommunicable diseases, including type 2 diabetes and cardiovascular disease, as well as disorders of the brain. Brain-related conditions place a great burden on society, and the limitations of current interventions reflects the need for ongoing investigations into understanding and treating brain disorders, in part by exploring the close relationship between our biome and our brain.

Biome and Brain Overview

The human intestinal microbiome is seeded at birth; it is influenced initially by delivery and feeding mode, and reaches an adult-like state within the first few years of life. Alterations in the composition, diversity, and stability of gut microbiota have been linked to a broad range of diseases, including cancer, autoimmune, metabolic, gastrointestinal, and brain disorders.

Although the composition of the gut microbiota remains relatively stable during our middle years, it continues to be influenced by such factors as geography, antibiotics, exercise, and diet. This is particularly important when considering possible prevention and intervention in brain disorders.

It is well known that bidirectional gut/brain communication may occur directly and indirectly via the central and enteric nervous systems, the vagus nerve, and the endocrine and immunoinflammatory systems and through the modulation of neurotransmitters. Diet could also utilize these pathways, because the gut microbiota supports optimal nutritional bioavailability—for example, by maintaining normal plasma tryptophan levels, an important building block for making serotonin, a key central nervous system neurotransmitter. Advances in this field have come from the development of DNA sequencing technology, which allows researchers to conduct large-scale screening of the bacteria in the gut and their associated physiologic functions. This has helped researchers to link disruption of the gut microbiota with biological markers of the communication pathways mentioned above.

It is important to note that there is so far no "gold standard" healthy intestinal microbial profile. Genetic and environmental factors mean that there may be significant variability in gut composition from person to person. In general, a "healthy," diverse gut microbiota promotes gut health and maintains essential structural, metabolic and signaling functions. The human gut can be "unhealthy" for a variety of reasons. Typically, a shift away from normal gut microbiota diversity and stability—termed "dysbiosis"—means it is unable to sustain one or more of the functions of a healthy gut, and this may contribute to cancer, metabolic, autoimmune, and brain disorders.

Increased intestinal permeability, often called "leaky gut," occurs when the mucosal gut barrier fails to prevent potentially harmful molecules from entering the bloodstream; these molecules include lipopolysaccharides, which are found on the outer membrane of gram-negative bacteria and may elicit inflammatory responses in the body. Increased intestinal permeability is a common feature of an unhealthy gut.

Keeping in mind that each gut microbiome looks different, the terms "healthy" and "unhealthy" used here refer to instances in which gut microbiota functioning, composition, or ratio may deviate from a person's individual-specific "normal" state.

The Biome and Brain Disorders

Microbial and neurologic development share similar windows of developmental vulnerability, during which they are particularly susceptible to damage. The mother provides an infant's first bacterial exposure; thus, maternal health is very important to a how a child's microbiome develops. Maternal illness and use of medications may disrupt an optimal microbiota transfer to the infant.

Early life continues to be developmentally critical; disruptions, such as stress or severe illness, can be damaging to gut/brain signaling and have been linked to brain disorders later in life. Several animal studies have shown that early life stress can alter the development of the key stress response system, the hypothalamic-pituitary-adrenal axis, establishing a lifelong alteration in how a mammal responds to stress. The impact on the two-way relationship between stress and the gut microbiota may be at the root of this problem. Maternal stress and infection during pregnancy have been linked to neurologic and central nervous system disorders, such as schizophrenia, autism spectrum disorders, and distinct cognitive and behavioral symptoms later in life, and these outcomes may be mediated by the bacteria living in the gut.

Microbiota and Neurologic Disease

Gut disturbances—both gastrointestinal discomfort and altered microbiota —have been linked to neurologic disorders, including multiple sclerosis (MS), autism spectrum disorders, and Parkinson disease. Environmental risk factors for neurologic disease often promote the immunoinflammatory response.

There is suggestion that the misfolding of proteins in the brain may be an etiologic explanation for some neurologic disorders. Brain inflammation, which may originate from the gut, is one notable hypothesis behind protein misfolding.

The proinflammatory state prompted by gut dysbiosis has also been linked to various autoimmune disorders, again including MS. MS is most common in Western countries, where dietary patterns thought to promote a proinflammatory profile and disrupt optimal gut microbiota states are common. Of note, lipopolysaccharides and antibodies against various antigens have been observed in patients with MS and Parkinson disease, with both markers signaling an increase in intestinal permeability.

Relatedly, neurodegenerative diseases, such as Alzheimer disease and generalized cognitive decline, are marked by age-related brain changes, along with disturbed immune function and increased oxidative stress; these factors have been shown in animals to be influenced by diet and the gut microbiota. Brain-derived neurotrophic factor, a neurotrophin that protects and encourages survival of healthy brain cells and whose production may be influenced by gut bacteria, is shown to be decreased in people with Alzheimer disease. It appears that age-related changes in the gut microbiota might be bidirectionally linked to age-related neurodegeneration.

It is notable that the unhealthy dietary patterns that negatively influence the gut microbiome are also risk factors for depression in older adults, whereas healthier diets protect against cognitive decline.

The Microbiota and Psychiatric Disorders

The notion of the gut/mental health connection has recently started to gain traction. It is now thought that various psychological disorders, depression in particular, may be inflammatory disorders, and that the gut may be an important mediator of these conditions. In numerous animal studies, microbial manipulation produced behaviors related to anxiety or depression, and one study demonstrated that the anxious phenotype could be transferred via the intestinal microbiota between animals.

The coping mechanisms for dealing with psychological stress appear to be programmed in early life, so this development may set us up to deal with stress throughout our lives—with some coping mechanisms working better than others. Given the amount of serotonin in the gut and the influence of the gut microbiota on serotonin's precursor, tryptophan, examining its role in mental health is worthwhile. Early correlational evidence has linked functional and structural damage in the gut with depression, schizophrenia, and autism.

Promoting a Healthy Biome: Strategies

In both neurologic and psychiatric conditions, it is possible that gut dysbiosis is responsible for both disease risk and the severity of a disorder.

It is clear that the causes and symptomology of some neurologic/neurodegenerative and psychiatric disorders have a similar underlying pathophysiology and that an unhealthy gut influences these through several overlapping pathways. Although it is difficult to tease out the individual contribution of each of these systems, given their complexity and the difficulty of isolating them clinically, the gut appears to be a key driver of a high-risk, inflammatory state in the body and brain and may prove to be the key in unlocking a new understanding of the etiology of brain diseases that supports new clinical and public health interventions.

Although gut microbial composition appears to be quite resilient, it is also readily modified. Lifestyle factors are particularly important to the composition, diversity, and stability of the gut microbiome. Below are several strategies that research suggests could contribute to overall gut health and that, in turn, may promote the health and protection of the brain.

Diet

There is good evidence for the role of individual nutrients, such as omega-3 fatty acids and zinc, in both physical and mental health; it is therefore useful to consume these nutrients as part of an overall healthful diet.

A healthful diet composed of fruits, vegetables, and whole grains has also been linked to higher levels of Bacteroidetes. These types of bacteria are particularly good at producing short-chain fatty acids, which help regulate gut inflammation.

Three main food components are proposed to benefit gut health: living microorganisms known as "probiotics" (found in such foods as yogurt, kefir, and kimchi); nondigestible carbohydrates (eg, dietary fiber found in fruits, vegetables, and whole grains); and secondary plant metabolites, such as flavonoids (found in brightly colored fruits, vegetables, and red wine). Persons who consume a Western-style diet experience less of the protective benefits of plant foods and simultaneously provoke other metabolic disruptions through high fat and sugar consumption, which contribute to gut dysbiosis and inflammation.

Exercise

Evidence suggests that exercise may increase the diversity of bacteria living in the gut. One study showed increased gut bacterial diversity and fewer markers of inflammation in athletes compared with controls. However, moderate exercise may be best; one study found that persons who exercised one to 30 times per month had higher levels of brain-protecting BDNF than nonexercisers or extreme exercisers. Exercise has been shown to have positive anti-inflammatory benefits, which may promote both gut and brain health.

Pre- and Probiotics and Fermented Foods

There is some support for the benefits of probiotic and prebiotic supplements and fermented foods within the gut, with some groups calling for the inclusion of probiotic or fermented foods in national food guide recommendations. The anti-inflammatory benefits of fiber fermentation in the colon occur naturally during digestion of healthy, fiber-rich foods, resulting in metabolic by-products that include various vitamins and antioxidants. Although some studies show promising results, larger, high-quality trials are needed to fully elucidate this relationship.

Future Directions

Understanding the role of the gut microbiota in neurologic and psychiatric disorders is an exciting prospect, with both conditions contributing significantly to individuals' quality of life and to global disease burden. Identifying measurable and modifiable microbial "therapies" presents a valuable opportunity for new prevention and treatment strategies for brain disorders.

The possibility of being able to prevent or alleviate neurologic or psychiatric conditions through lifestyle interventions has significant public health implications. However, a full understanding of the gut/brain connection and its health implications is still evolving, and quality clinical trials are needed that include assessments of immune, inflammatory, and gut biomarkers to elucidate the function, behavior, and modifiability of bacteria living in the gut.

We introduce gut microbiome transplantation as new treatment for neurologic and psychiatric disorders

It would be an oversimplification to imply that microbial modification is a cure-all solution. However, we have successfully treated depression, alcohol dependency, anxiety, obesity with craving for specific foods by gut microbiome transplantation from young healthy human donors. Such transplants appear to benefit overall physical health, gut health and the health of the brain.

 

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