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
Klausstrasse 10
CH-8008 ZURICH
T +41 43 336 7260
M +41 78 825 0803
F +41 43 336 7261

rainer.arendt@swisspreventionclinic.ch

www.swisspreventionclinic.ch
www.patientcircle.org

Saturday
Jun132015

THE INSIDE STORY OF THE  MICROBIOME

The Dolder Grand
Health & Rejuvenation

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

 

by Clive Cookson, the FT’s science editor, Financial Times, June 12, 2015

Photograph: Alexandr Khrapichev/University of Oxford/Wellcome Images

 

Cross-sections of some of the fruit and vegetables that make for a healthy microbiome, as captured by magnetic resonance imaging (MRI)

 

What is the greatest advance in scientific understanding of the human body so far this century? With due respect to the progress made in human genetics, oncology and neuroscience, my answer is appreciation of the microbiome: the vast population of microbes that live within all of us and play a vital role in our health and wellbeing.

Although microbiologists have known for many decades that everyone hosts resident bacteria, beneficial and malign, their diversity and biological significance are only now becoming clear as scientists deploy new techniques of molecular biology to probe the microbiome. A healthy adult is made up of about 10tn human cells; microbial cells are smaller but there are 10 times more of them, weighing in at 3lb in total, roughly the same as the brain.

Recent research shows that the hundreds of microbial species populating this teeming inner world play essential roles in the most fundamental processes of our lives, from digestion to immune response and even behaviour. Imbalances in the microbiome, caused by aspects of the modern lifestyle such as medication, sanitation and diet, have been linked with diseases from obesity and diabetes to asthma and eczema.

The microbiome is fertile territory for popular publishing, combining as it does exciting and fast-paced science with medical self-help — how to adjust your own microbiome for a healthier life. The three titles reviewed here are good examples of this new biomedical genre. All focus on the gut, where the bulk of our bacteria live and work, while looking, too, at the significant populations inhabiting mouth, skin, genitals and other parts of the human body. And all three are models of clear, accessible and entertaining science writing by active researchers.

Tim Spector, author of The Diet Myth, is professor of genetic epidemiology at King’s College London — and famous for leading the Twins UK team that compares identical and non-identical twins to untangle the genetic and environmental influences on disease and physical appearance. He also leads the British Gut Project and is currently using DNA sequencing to study the microbiomes of 5,000 twins. Spector’s book is the most comprehensive of the three, with dietary advice detailing what is known about the impact on the microbiome of different categories of food ingredient (fats, proteins, carbohydrates, fibre, vitamins and sweeteners) as well as alcohol, caffeine, antibiotics and other drugs.

Rob Knight, who wrote Follow Your Gut with science journalist Brendan Buhler, is another high-profile author: a professor of paediatrics, and computer science and engineering, at the University of California, San Diego, and co-founder of the American Gut Project. His book is relatively concise but still manages to pack in colourful stories.

Giulia Enders, the author of Gut, is a young medical researcher working on her doctorate at Frankfurt’s Institute for Microbiology. Her book was originally published last year in German as Darm mit Charme (“Charming Bowels”) and the text retains a charming freshness in David Shaw’s translation, leavened further with some sweetly naive illustrations by the author’s sister, Jill Enders.

 

The average American child goes through 17 courses of antibiotic, most of them unnecessary

 

The key point made by all three books is that you cannot maintain a healthy diet if you ignore the impact of food and drink on your gut microbes, which are essential intermediaries in the digestive process. Indeed, Spector claims that examining the DNA of our microbiome is much better for predicting obesity than looking at human genes.

Over millions of years we have evolved together with microbes for mutual survival, yet recently this fine-tuning and selection has gone wrong. Studies comparing urban Americans and Europeans with people living in the Amazon rainforest or rural Papua New Guinea, enjoying rich and varied diets and without antibiotics, show how much microbial diversity has been lost in the industrialised world.

We are endowed with a microbiome at birth. A baby born in the conventional way is swarming with millions of microbes by the time she emerges from her mother, as Spector puts it. The first dose consists of vaginal bacteria from the birth canal. “Then because of their close proximity and the pressure on all the body’s sphincters, a light mixture of urinary and faecal microbes are sprinkled onto her face and hands, followed by a different set of microbes covering the rest of her body as a result of rubbing against the skin of her mother’s legs.”

All three authors point out the microbial deprivation suffered by babies born by caesarean section, who cannot pick up bacteria in the same natural way. Caesarean births are associated with higher rates of a broad range of diseases associated with the microbiome, according to Knight. Spector quotes a study showing that C-section birth increases the risk of obesity by 20 per cent. And Enders blames her own caesarean delivery and her mother’s inability to breastfeed her — maternal milk provides another good dose of bacteria — for the multiplicity of health problems she suffered during childhood.

Although the best advice for parents is to opt for natural childbirth and breastfeeding, an emergency may make a C-section unavoidable — which is what happened to Knight’s partner Amanda. “Our daughter was born via an unplanned caesarean section, and I was holding her 20 minutes later,” he writes. “But today’s medical technology doesn’t supply everything. When it came to her microbes, we took matters into our own hands and swabbed her with samples from Amanda’s vagina. Our baby needed those microbes.” A clinical trial of this process, now called “vaginal inoculation”, has started in Puerto Rico.

The microbiome grows and diversifies further during early childhood, picking up beneficial bacteria from the environment. Here we encounter the “hygiene hypothesis”, first formulated in the 1980s to explain the exploding epidemic of autoimmune and allergic disorders such as asthma and eczema. In its original form the hypothesis proposed that the young immune system needs “training” through exposure to diverse bacterial and viral pathogens; problems emerge in excessively clean modern homes that fail to provide sufficient immunological challenges.

The current version of the hygiene hypothesis focuses more on the essential role that the microbiome plays in our immune defences. As Enders points out, about 80 per cent of the human immune system is located in the gut. It has to be extremely careful to suppress its defensive instincts and allow the many beneficial bacteria to live there in peace, while recognising dangerous elements in the crowd and weeding them out.

All of which requires careful training through exposure to multiple microbes, good and bad, Spector explains. Gut microbes communicate with the human immune system through so-called regulatory T-cells, or Treg cells, in the intestinal walls. High Treg levels are generally healthy because they damp down excessive activity in the immune system.

Evidence to support the hygiene hypothesis is growing fast. For instance, Erika von Mutius of Dr von Hauner Children’s Hospital in Munich, a pioneer in this field, has shown that exposure to farming in early life reduces substantially the risk of allergies and asthma — and some of this effect can be explained by children’s contact with farm animals and unpasteurised raw milk.

“In general,” says Knight, “exposure to diverse microbes, whether through older siblings, pets, or livestock — or through good old-fashioned playing outdoors — seems to help, even if scientists are still sorting out the specific microbes involved. It may be that diversity itself is most important.”

Enders goes further. “Disinfectants have no place in a normal household,” she writes. “The aim of cleaning . . . should be to reduce bacteria numbers, but not to eliminate them. Even harmful bacteria can be good for us when the immune system uses them for training — a couple of thousand salmonella bacteria in the kitchen sink provide our immune system with the opportunity to do a little sightseeing. Salmonella become dangerous only when they turn up in greater numbers.”

Needless to say, all these authors advise against antibiotics unless you need them to fight a serious drug-sensitive infection, because the side-effects of killing beneficial bacteria alongside the pathogens can also be serious. Yet the average American child goes through 17 courses of antibiotic before reaching adulthood, most of them unnecessary, according to Spector.

How, then, can people restore their ravaged microbiomes? Besides eating a varied diet rich in fruit, vegetables and nuts, taking probiotics and prebiotics may help. To illustrate the difference between these two easily confused categories, Knight invites us to think of our microbiome as a lawn. Prebiotics are like fertilisers; they are mostly soluble vegetable and fruit fibres that can be fermented by bacteria in the large intestine to provide essential nutrients. Foods rich in prebiotics include artichokes, chicory, leeks and celeriac.

Taking probiotics is more like reseeding an unhealthy lawn with desirable grasses. Probiotics, often referred to as “good bacteria” or “helpful bacteria”, are typically yoghurt-based foods or drinks containing a few species of live microbes. Although taking these will do you no harm, there is not much convincing evidence of their benefit from well-conducted clinical trials. As Spector says, this is probably because we all have different microbiomes to start with; without knowing which microbes to replace, it is a lottery whether particular yoghurt concoctions will work for you. In the future it may be possible to tailor probiotics for people to compensate for their individual microbial deficits.

A more drastic option, which Knight compares with ripping out a weed-infested lawn and laying down fresh turf, is to have a faecal or stool transplant from someone with a healthy microbiome. This procedure has proven remarkably successful in curing people who are seriously ill with Clostridium difficile infection and have very abnormal gut microbes. Research is now under way to extend faecal transplants to other disorders.

If you want to discover the health or otherwise of your own microbiome, this is now possible through the British Gut Project or American Gut Project, in return for a contribution to their research funds (a minimum £75 for UK residents). Just Google them to discover how to proceed.

But bear in mind Knight’s cautionary words: “Much of the news you hear about disease in the microbiome can be confusing, contradictory, or sometimes overhyped . . . This complexity is worth keeping in mind anytime you hear sweeping claims about it or simple fixes for a variety of its ailments.”

Although the authors of these three books are enthusiastic practitioners of microbiome research, they stop short of making excessive claims. The revelation that each of us depends on our individual living world, with far more inhabitants than there are people on earth, is surely sensational enough.

 

The Diet Myth: The Real Science Behind What We Eat, by Tim Spector, Weidenfeld & Nicolson, RRP£14.99, 320 pages

Follow Your Gut: The Enormous Impact of Tiny Microbes, by Rob Knight with Brendan Buhler, Simon & Schuster, RRP£7.99/RRP$16.99, 128 pages

Gut: The Inside Story of Our Body’s Most Underrated Organ, by Giulia Enders, Scribe RRP£14.99/Greystone Books RRP$17.95, 272 pages

 


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).

 

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

SWISS  PREVENTION  CLINIC
Klausstrasse 10
CH-8008 ZURICH
T +41 43 336 7260
M +41 78 825 0803
F +41 43 336 7261

rainer.arendt@swisspreventionclinic.ch

www.swisspreventionclinic.ch
www.patientcircle.org

Monday
Apr132015

Atrial Fibrillation Care: Put the Catheter (and Rx Pad) Down

The Dolder Grand
Medical Wellness & Rejuvenation

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

 

 

My approach to patients with atrial fibrillation (AF) has changed. Completely and fundamentally. This is a before-and-after moment in AF care.

Before: We saw atrial fibrillation as a disease rather than seeing it as a result of other diseases. That explains why our treatments (drugs and ablation) have performed so poorly. It is a wrong-target problem. It is akin to stenting an artery and saying atherosclerosis is fixed or prescribing an antipyretic for bacterial infection.

After: Atrial fibrillation in the vast majority of patients (excluding those with brief episodes that are a form of focal atrial tachycardia) is a sign that something is awry in the body—usually exposure to an excess. The atria, with their sensitivity to stretch, neural connections, and plastic cells, are a window onto overall health.

Year after year I have watched the drugs fail and the AF return after ablation. It is a relief to (better) understand AF and to be able to cite evidence that supports the concept that the atria fibrillate for a reason. And that reason is the main therapeutic target.

 

You may know the story. A group of researchers in Adelaide have shown—first in animal models [1,2] and now in humans [3,4]—that promoting basic health dramatically improves AF burden. Their methods and results have taught us how AF happens. Although work remains, it is clear that lifestyle diseases (with inflammation due to diet-induced intestinal dysbiosis, see below), via pressure- and volume-induced atrial stretch, inflammation, or neural imbalances, induce disease in and around the cells of the heart.

 

The coolest part about these data are that treatment of lifestyle diseases—mostly, the removal of excesses—not only reduces AF burden but also improves the structure of the heart. Even fibrosis (aka scar) can regress, which is a novel way to think about cardiac biology.

This "upstream" approach to AF is no longer a radical idea. Nearly all the leaders in cardiology agree. It changes the way doctors should treat people with AF. Namely, the idea that AF is fixable with rhythm drugs or ablation is as wrong as thinking a stent fixes atherosclerosis or that treating fever cures infection.

Before I go on, let me make a note of caution. I am not saying AF drugs or ablation have no role. They do. But their (much smaller) role now is similar to stents or beta-blockers in patients with coronary artery disease: to stabilize an acute situation or to help transiently restore regular rhythm so that patients can feel well enough to exercise and enjoy life—things that make the atria healthier.

I no longer think of an antiarrhythmic drug as long-term therapy. For instance, I cardiovert and medicate so that patients can feel well enough to exercise every day they eat. I buy time. Then patients can lose weight or address other lifestyle issues, such as sleep disorders, alcohol intake, and perhaps overexercise and overwork. This improves glucose handling, lowers blood pressure, and relieves inflammation. People start to feel better. When they come back for follow-up, I discuss stopping the rhythm drugs—because they have served their adjunctive purpose.

On the matter of stroke risk: think about what it means to improve high blood pressure, diabetes, inflammation, and hyperlipidemia. Now think what it means to do so in millions of people.

You can see how this new approach upends the role of AF ablation. It is one thing to prescribe a pill; it is yet another to deliver 60 to 80 burns to the left atrium. Recall that patients who choose AF ablation walk into the hospital the morning of the procedure. They may not be perfect, they have AF after all, but they are alive and functioning. What awaits them in the EP lab is nothing small. They will endure 2 to 3 hours of general anesthesia, vascular access in both legs, two transseptal punctures, a fluid load, and purposeful damage to the heart done in proximity to the esophagus, phrenic nerve, pulmonary veins, and the thin left atrial appendage.

And . . . that $100 000 procedure, with its (real-world) 5% to 7% risk,[5] often fails. Repeat procedures are required in one of four patients. Even when the procedure is done well, recent research [3] shows that long-term success is fivefold lower when patients do not remove excesses from their lives.

This new approach to patients with AF has significant implications for the cardiology and healthcare community.

Consider those affected:

•             Hospitals invest in expensive ablation labs. They have banked on the epidemic of new atrial-fibrillation patients who will "need" procedures. Recently, I did a marketing video for my hospital on AF treatment. We filmed in our EP lab, the ablation machines as the backdrop. I was excited to speak about the new discoveries in AF care. But I stammered when the interviewer asked me about the "procedures we do here." I thought to myself: we do procedures here, we do them well, we do them safely, but we are sure to do a lot fewer in the future.

•             Doctors—like me—have reaped the rewards of AF misthink. We are paid well to do and redo AF ablation. The financial reward for helping people help themselves pales in comparison. Yet I urge you not to blame overtreatment on fee for service. The main reasons doctors overtreat are do-something bias and the disease model of care. First, doing things is what we are taught, and it is what society expects. We might give cursory mention to lifestyle but then we rush to drugs and procedures. Second, the disease model of care tricks us into putting problems—like AF—into silos (cardiac, renal, pulmonary, etc), which we treat in isolation. So ingrained is the silo model that it has been daring to use the word holistic. As if things are not connected in the body.

•             Workforce needs will be disrupted. A few years ago, cardiology groups and hospitals felt like they needed more electrophysiologists to handle the epidemic of atrial fibrillation. Now it is clear that what we need more of is not people with catheter skills, but people with people skills. The painful truth is that American cities and American hospitals do not need more EP labs.

•             Policy makers and payers are bound to notice. Think about the billions of dollars spent to care for the millions of patients with AF. Why would any insurer pay for drugs and procedures that are doomed to fail unless lifestyle measures are addressed? I wonder whether this could be the spark that gets payers to see the value of helping people live healthier lives?

•             Industry will have to adjust. Imagine the boardrooms of pharmaceutical and medical device companies in the past decade: they saw atrial fibrillation as a major opportunity. We will develop drugs, catheters, and mapping systems to treat the millions of afflicted patients. What these companies should see now is that AF drugs and ablation will go the way of renal denervation—useful in very selected cases, but no gold mine.

•             Patients are most affected by this new discovery. Although there will be small numbers of people afflicted by fluky focal AF (a confusing fact), the vast majority of patients with AF will enjoy the best results when they and their caregivers treat the root causes. From now forward, when a patient with AF sees a doctor who recommends rhythm drugs or ablation without first exploring how that person sleeps, eats, drinks, moves, and deals with stress, it will be a signal to get another opinion. Rushing to drugs or ablation will be as wrong as prescribing antibiotics for a viral infection.

This discovery about atrial fibrillation teaches us that focal (easy) solutions for systemic diseases due to lifestyle are destined to fail. Given the rise of lifestyle-related diseases, this is a critical lesson, one we should learn sooner rather than later.

Source: John Mandrola, Atrial Fibrillation Care: Put the Catheter (and Rx Pad) Down. Medscape. Apr 07, 2015.

References

1.            Abed HS, Samuel CS, Lau DH, et al. Obesity results in progressive atrial structural and electrical remodeling: Implications for atrial fibrillation. Heart Rhythm 2013; 10:90-100. Article

2.            Mahajan R, Brooks AG, Shipp N, et al. AF and obesity: Impact of weight reduction on the atrial substrate. Heart Rhythm Society 2013 Annual Scientific Sessions; May 8-11, 2013; Denver, CO. Abstract YIA-01

3.            Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol 2014; 64:2222-2231. Article

4.            Pathak R, et al. Long-term effect of goal directed weight management in an atrial fibrillation cohort: A long-term follow-up study (LEGACY Study). J Am Coll Cardiol 2015; DOI:101016/jacc.2015.03.002. Abstract

5.            Deshmukh A, Patel NJ, Pant S, et al. In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: Analysis of 93 801 procedures. Circulation 2013; 128:2104-2112. Article

Sunday
Apr122015

Gut microbiota serve as new targets for the prevention and treatment of cardiovascular disease

The Dolder Grand
Medical Wellness & Rejuvenation

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

 

We are living in a bacterial world, and it's impacting us more than previously thought.

 

 

 

Recent studies reveal a contribution of intestinal microbes in the expression of metabolic or cardiovascular disease. The mechanisms through which intestinal microbiota and/or their metabolic products alter systemic homoeostasis and cardio-metabolic disease risks are just beginning to be dissected. Intervention studies in humans aiming to either selectively alter the composition of the intestinal microbiota or to pharmacologically manipulate the microbiota to influence production of their metabolites are crucial next steps. The intestinal microbiome represents a new potential therapeutic target for the treatment of cardio-metabolic diseases.

Vinjé S1, Stroes E, Nieuwdorp M, Hazen SL.: The gut microbiome as novel cardio-metabolic target: the time has come! Eur Heart J. 2014 Apr;35(14):883-7. doi: 10.1093/eurheartj/eht467. Epub 2013 Nov 11.


 

The human gastrointestinal tract is home to trillions of bacteria, which vastly outnumber host cells in the body. Although generally overlooked in the field of endocrinology, gut microbial symbionts organize to form a key endocrine organ that converts nutritional cues from the environment into hormone-like signals that impact both normal physiology and chronic disease in the human host. Recent evidence suggests that several gut microbial-derived products are sensed by dedicated host receptor systems to alter cardiovascular disease progression. In fact, gut microbial metabolism of dietary components results in the production of proatherogenic circulating factors that act through a meta-organismal endocrine axis to impact cardiovascular disease risk.

Brown JM1, Hazen SL.: The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu Rev Med. 2015;66:343-59. doi: 10.1146/annurev-med-060513-093205.


 

It has recently been discovered that certain dietary nutrients possessing a trimethylamine (TMA) moiety, namely choline/phosphatidylcholine and L-carnitine, participate in the development of atherosclerotic heart disease. A meta-organismal pathway was elucidated involving gut microbiota-dependent formation of TMA and host hepatic flavin monooxygenase 3-dependent (FMO3-dependent) formation of TMA-N-oxide (TMAO), a metabolite shown to be both mechanistically linked to atherosclerosis and whose levels are strongly linked to cardiovascular disease (CVD) risks. Collectively, these studies reveal that gut microbiota serve as new targets for the prevention and treatment of cardiovascular disease.

Tang WH, Hazen SL.: The contributory role of gut microbiota in cardiovascular disease. J Clin Invest. 2014 Oct;124(10):4204-11. doi: 10.1172/JCI72331. Epub 2014 Oct 1.



We offer gut microbiome exchange (transplantation) as novel opportunity in prevention and treatment of cardiovascular disease.

Sunday
Apr122015

How Gut Bacteria Make Us Fat or Thin

Based on http://www.scientificamerican.com/article/how-gut-bacteria-help-make-us-fat-and-thin/ and Claudia Wallis‘ article "Gut Reactions."

 

For the 35 percent of American adults who do daily battle with obesity, the main causes of their condition are all too familiar: an unhealthy diet, a sedentary lifestyle and perhaps some unlucky genes. In recent years, however, researchers have become increasingly convinced that important hidden players literally lurk in human bowels: billions on billions of gut microbes.

Throughout our evolutionary history, the microscopic denizens of our intestines have helped us break down tough plant fibers in exchange for the privilege of living in such a nutritious broth. Yet their roles appear to extend beyond digestion. New evidence indicates that gut bacteria determine if and how we read our genes, alter the way we store fat, how we balance levels of glucose in the blood, and how we respond to hormones that make us feel hungry or full. The wrong mix of microbes, it seems, can help set the stage for obesity and diabetes from the moment of birth.

Fortunately, researchers are beginning to understand the differences between the wrong mix and a healthy one, as well as the specific factors that shape those differences. They hope to learn how to cultivate this inner ecosystem in ways that could prevent—and possibly treat—obesity, which doctors define as having a particular ratio of height and weight, known as the body mass index, that is greater than 30 kg/m2. Imagine, for example, foods, baby formulas or supplements devised to promote virtuous microbes while suppressing the harmful types. Keeping our gut microbes happy could be the elusive secret to weight control.

An Inner Rain Forest

Researchers have long known that the human body is home to all manner of microorganisms, but only in the past decade or so have they come to realize that these microbes outnumber our own cells 10 to one. Rapid gene-sequencing techniques have revealed that the biggest and most diverse metropolises of “microbiota” reside in the large intestine and mouth, although impressive communities also flourish in the genital tract and on our skin.

Each of us begins to assemble a unique congregation of microbes the moment we pass through the birth canal, acquiring our mother's bacteria first and continuing to gather new members from the environment throughout life. By studying the genes of these various microbes—collectively referred to as the microbiome—investigators have identified some of the most common residents, although these can vary greatly from person to person and among different human populations. In recent years researchers have begun the transition from mere census taking to determining the kind of jobs these minute inhabitants fill in the human body and the effect they have on our overall health.

An early hint that gut microbes might play a role in obesity came from studies comparing intestinal bacteria in obese and lean individuals. In studies of twins who were both lean or both obese, researchers found that the gut community in lean people was like a rain forest brimming with many species but that the community in obese people was less diverse—more like a nutrient-overloaded pond where relatively few species dominate. Lean individuals, for example, tended to have a wider variety of Bacteroidetes, a large tribe of microbes that specialize in breaking down bulky plant starches and fibers into shorter molecules that the body can use as a source of energy.

To demonstrate cause and effect, Gordon and his colleagues conducted an elegant series of experiments with so-called humanized mice, published recently in Science. First, they raised genetically identical baby rodents in a germ-free environment so that their bodies would be free of any bacteria. Then they populated their guts with intestinal microbes collected from obese women and their lean twin sisters (three pairs of fraternal female twins and one set of identical twins were used in the studies). The mice ate the same diet in equal amounts, yet the animals that received bacteria from an obese twin grew heavier and had more body fat than mice with microbes from a thin twin. As expected, the fat mice also had a less diverse community of microbes in the gut.

Gordon's team then repeated the experiment with one small twist: after giving the baby mice microbes from their respective twins, they moved the animals into a shared cage. This time both groups remained lean. Studies showed that the mice carrying microbes from the obese human had picked up some of their lean roommates' gut bacteria—especially varieties of Bacteroidetes—probably by consuming their feces, a typical mouse behavior. To further prove the point, the researchers transferred 54 varieties of bacteria from some lean mice to those with the obese-type community of germs and found that the animals that had been destined to become obese developed a healthy weight instead. Transferring just 39 strains did not do the trick. “Taken together, these experiments provide pretty compelling proof that there is a cause-and-effect relationship and that it was possible to prevent the development of obesity,” Gordon says.

Gordon theorizes that the gut community in obese mice has certain “job vacancies” for microbes that perform key roles in maintaining a healthy body weight and normal metabolism. His studies, as well as those by other researchers, offer enticing clues about what those roles might be. Compared with the thin mice, for example, Gordon's fat mice had higher levels in their blood and muscles of substances known as branched-chain amino acids and acylcarnitines. Both these chemicals are typically elevated in people with obesity and type 2 diabetes.

Another job vacancy associated with obesity might be one normally filled by a stomach bacterium called Helicobacter pylori. Research by Martin Blaser of New York University suggests that it helps to regulate appetite by modulating levels of ghrelin—a hunger-stimulating hormone. H. pylori was once abundant in the American digestive tract but is now rare, thanks to more hygienic living conditions and the use of antibiotics, says Blaser, author of a new book entitled Missing Microbes.

Diet is an important factor in shaping the gut ecosystem. A diet of highly processed foods, for example, has been linked to a less diverse gut community in people. Gordon's team demonstrated the complex interaction among food, microbes and body weight by feeding their humanized mice a specially prepared unhealthy chow that was high in fat and low in fruits, vegetables and fiber (as opposed to the usual high-fiber, low-fat mouse kibble). Given this “Western diet,” the mice with obese-type microbes proceeded to grow fat even when housed with lean cagemates. The unhealthy diet somehow prevented the virtuous bacteria from moving in and flourishing.

The interaction between diet and gut bacteria can predispose us to obesity from the day we are born, as can the mode by which we enter the world. Studies have shown that both formula-fed babies and infants delivered by cesarean section have a higher risk for obesity and diabetes than those who are breast-fed or delivered vaginally. Working together, Rob Knight of the University of Colorado Boulder and Maria Gloria Dominguez-Bello of N.Y.U. have found that as newborns traverse the birth canal, they swallow bacteria that will later help them digest milk. C-section babies skip this bacterial baptism. Babies raised on formula face a different disadvantage: they do not get substances in breast milk that nurture beneficial bacteria and limit colonization by harmful ones. According to a recent Canadian study, babies drinking formula have bacteria in their gut that are not seen in breast-fed babies until solid foods are introduced. Their presence before the gut and immune system are mature, says Dominguez-Bello, may be one reason these babies are more susceptible to allergies, asthma, eczema and celiac disease, as well as obesity.

A new appreciation for the impact of gut microbes on body weight has intensified concerns about the profligate use of antibiotics in children. Blaser has shown that when young mice are given low doses of antibiotics, similar to what farmers give livestock, they develop about 15 percent more body fat than mice that are not given such drugs. Antibiotics may annihilate some of the bacteria that help us maintain a healthy body weight. “Antibiotics are like a fire in the forest,” Dominguez-Bello says. “The baby is forming a forest. If you have a fire in a forest that is new, you get extinction.” When Laurie Cox, a graduate student in Blaser's laboratory, combined a high-fat diet with the antibiotics, the mice became obese. “There's a synergy,” Blaser explains. He notes that antibiotic use varies greatly from state to state in the U.S., as does the prevalence of obesity, and intriguingly, the two maps line up—with both rates highest in parts of the South.

 

 

Beyond Probiotics

Many scientists who work on the microbiome think their research will inspire a new generation of tools to treat and prevent obesity. A number of scientists are actively developing potential treatments. Dominguez-Bello, for example, is conducting a clinical trial in Puerto Rico in which babies born by cesarean section are immediately swabbed with a gauze cloth laced with the mother's vaginal fluids and resident microbes. She will track the weight and overall health of the infants in her study, comparing them with C-section babies who did not receive the gauze treatment.

 

We offer gut microbiome exchange (transplantation) as new treatment for obesity and diabetes mellitus

Along with exercising and eating right, we need to enlist our inner microbial army, transferring colonic bacteria from lean to overweight people will lead to weight loss.