Gut microbes illustration. Credit: © nobeastsofierce / Adobe Stock
Knowledge of stress biology may eventually yield bacterial treatments for psychiatric disorders
May 6, 2019
Science Daily/Children's Hospital of Philadelphia
Scientists have shown that transplanting gut bacteria, from an animal that is vulnerable to social stress to a non-stressed animal, can cause vulnerable behavior in the recipient. The research reveals details of biological interactions between the brain and gut that may someday lead to probiotic treatments for human psychiatric disorders such as depression.
"In rats that show depressive-type behavior in a laboratory test, we found that stress changes their gut microbiome -- the population of bacteria in the gut," said study leader Seema Bhatnagar, PhD, a neuroscientist in Department of Anesthesiology and Critical Care at Children's Hospital of Philadelphia (CHOP). "Moreover, when we transplanted bacteria from those stress-vulnerable rats into rats that had not been stressed, the recipient animals showed similar behavior."
Bhatnagar added that stress also increased inflammation in the brains of vulnerable rats, and that this inflammation appeared in unstressed rats after they received transplants from vulnerable animals.
The study team published its findings online March 4, 2019 in Molecular Psychiatry.
Bhatnagar leads the Stress Neurobiology Program at CHOP, and many of her co-authors are members of the PennCHOP Microbiome Program, a collaboration between researchers at CHOP and the Perelman School of Medicine at the University of Pennsylvania. The program aims to better understand the communities of microbes inside our bodies and alter their properties to improve human health. Chunyu Zhao, PhD, of that program, performed microbiome data analysis and is a co-author of the paper.
Scientists already know that brain and gut influence each other. In humans, patients with psychiatric disorders have different populations of gut microbes compared to microbes in healthy individuals, with parallel findings also seen in animal models of psychiatric disease. This study investigated mechanisms related to brain inflammation, microbiomes and stress.
"Humans do not all react identically to the same stresses -- some are more vulnerable than others to developing psychiatric disorders, others are more resilient," said Bhatnagar. "Something similar happens in laboratory animals as well."
In rodents, social hierarchies and territoriality are major sources of stress. In the laboratory, researchers model stressors with validated behavioral tools such as a forced swim test or a social defeat test to examine how animals use coping strategies to deal with stress. Rats that cope more passively are more vulnerable to the effects of stress because they also exhibit more anxiety- and depressive-type behaviors, while rats that cope more actively are resilient to the effects of social stress. Based on these assessments, the researchers classified the animals as either vulnerable or resilient.
The study team then analyzed the fecal microbiomes of vulnerable rats, resilient rats, a non-stressed control group, and a placebo group. They found that vulnerable rats had higher proportions of certain bacteria, such as Clostridia, than the other groups.
They then performed fecal transplants from three donor groups -- vulnerable rats, resilient rats or control non-stressed rats -- into naïve rats, animals that had not been stressed. They found that different microbiomes changed depressive-like behavior. Rats receiving transplants from vulnerable rats were more likely to adopt depressive-like behaviors, whereas rats receiving transplants from resilient animals or non-stressed animals did not exhibit any changes in behavior or in neural measures. Patterns of brain inflammatory processes in recipients also resembled those seen in the brains of vulnerable animals, suggesting that immune-modulating effects of gut bacteria such as Clostridia may have promoted that inflammation. However, transplants did not significantly change anxiety-like behavior.
The finding that gut transplants from vulnerable rats increased depressive-type behavior but not anxiety-type behavior in non-stressed recipients may point to different mechanisms. The authors said this difference suggests that depressive-type behaviors are more regulated by the gut microbiome, whereas anxiety-type behaviors are primarily influenced by neural activity changes produced by stress experience.
"Although much more research remains to be done, we can envision future applications in which we could leverage knowledge of microbiome-brain interactions to treat human psychiatric disorders," said Bhatnagar. "People already are taking over-the-counter probiotics as supplements. If we can eventually validate beneficial behavioral effects from specific bacteria, we could set the stage for new psychiatric treatments."
March 12, 2019
Science Daily/West Virginia University
Researchers are investigating how having a stroke can disrupt the community of bacteria that lives in the gut. These bacteria -- known collectively as the microbiome -- can interact with the central nervous system and may influence stroke patients' recovery.
Tumult in the bacterial community that occupies your gut -- known as your microbiome -- doesn't just cause indigestion. For people recovering from a stroke, it may influence how they get better.
A recent study by Allison Brichacek and Candice Brown, researchers in the West Virginia University School of Medicine, suggests that stroke patients' microbiomes -- and even the structure of their guts -- may still be out of kilter a month after the stroke has passed.
"We're interested in the gut-brain axis -- how the gut influences the brain and vice versa," said Brichacek, a doctoral student in the immunology and microbial pathogenesis graduate program. She presented her findings at the International Stroke Conference in February.
Previous studies indicated the immediate effects a stroke can have on someone's microbiome, but they didn't explore whether these effects lingered. To find out, Brichacek, Brown and their colleagues -- including Sophia Kenney, an undergraduate majoring in immunology and medical microbiology, and Stan Benkovic, a researcher in Brown's lab -- induced a stroke in animal models. Other models -- the control group -- didn't have a stroke. The researchers compared the two groups' microbiomes three days, 14 days and 28 days post-stroke. They also scrutinized their intestines for microscopic disparities.
Bacterial friend or foe?
One of the researchers' discoveries was that a certain family of bacteria -- Bifidobacteriaceae -- was less prominent in post-stroke models than in healthy ones both 14 and 28 days out. If the name of the family sounds familiar, that's probably because Bifidobacterium -- a genus within the Bifidobacteriaceae family -- is a common ingredient in yogurt and probiotics. These bacteria are known for supporting digestive health and may be associated with better outcomes in stroke patients.
Thatmay sound like bad news for people who have had a stroke, but the loss of Bifidobacteriaceae bacteria isn't the only long-term change their microbiomes undergo. Another family associated with worse outcomes -- Helicobacteraceae -- was also more common in post-stroke models 28 days out. The practical implications of these microbiotic shifts are still unknown.
The team also found that the ratio of one type of bacteria -- Firmicutes -- to another -- Bacteriodetes -- was higher in post-stroke models. After 14 days, the ratio in the experimental group was almost six times higher than in the control group. After 28 days, the experimental group's ratio had fallen, but it was still more than triple that of the control group. Having a high Firmicutes-to-Bacteriodetes ratio can be concerning because of its link to obesity, diabetes and inflammation.
The gut-brain axis seems to distribute a stroke's effects in another way, too. The research team discovered that a stroke can cause intestinal abnormalities. Under magnification, the intestinal tissues of healthy models resembled an orderly colony of coral. The branches of "coral" were actually villi -- tiny projections that increase the surface area of the intestinal wall and multiply the amount of nutrients it can absorb.
But in post-stroke models, the intestinal tissue looked scrambled, even a month after researchers triggered the stroke. "There's disorganization here," Brichacek said. "There's also less space between the villi to allow nutrients to move around." Poor circulation of nutrients can lead to compromised stroke recovery.
Treating the brain by treating the gut
What does all of this mean for stroke recovery? "Big picture: seeing a persistent, chronic change 28 days after stroke that is associated with this increase in some of the negative bacteria means that this could have negative effects on brain function and behavior. Ultimately, this could slow or prevent post-stroke recovery," said Brown, an assistant professor in Department of Neuroscience and faculty member in the Rockefeller Neuroscience Institute.
Her and Brichacek's findings may point to new therapeutic options for stroke. "If it ends up being that the gut has an influence on the repair of the brain, maybe our stroke treatments shouldn't just be focused on what we can do for the brain. Maybe we need to think about what can we do for the gut," Brichacek said.
For example, some bacteria in the gut produce short-chain fatty acids that affect brain function. "Some of these short-chain fatty acids are good, and some are bad," said Brown. "If the bacteria that produce some of the bad short-chain fatty acids are proliferating, that could have a negative outcome for brain function." Could nudging a stroke patient's microbiome in a healthier direction -- using probiotic supplements or prebiotic foods, for instance -- help prevent emotional or cognitive decline?
Likewise, might it be possible to lower a stroke patient's Firmicutes-to-Bacteriodetes ratio and promote weight loss, decrease diabetes risk and make subsequent strokes less likely?
The researchers' next step is to study intestinal changes in more depth. Just as the blood-brain barrier isolates the brain from the blood circulating elsewhere in the body, a barrier seals off the intestine from its surroundings. Brown and Brichacek want to know how a breach in the intestinal barrier could affect the central nervous system. Protecting this barrier is critical for the function of the enteric nervous system -- a part of the peripheral nervous system that includes the gut and often is called our "second brain" or "little brain."
"People don't appreciate the gut. It controls much more than digestion," Brown said. "Our results suggest that stroke targets both brains -- the brain in our head and the brain in our gut."
February 4, 2019
Science Daily/VIB (the Flanders Institute for Biotechnology)
The first population-level study on the link between gut bacteria and mental health identifies specific gut bacteria linked to depression and provides evidence that a wide range of gut bacteria can produce neuroactive compounds.
In their manuscript entitled 'The neuroactive potential of the human gut microbiota in quality of life and depression' Jeroen Raes and his team studied the relation between gut bacteria and quality of life and depression. The authors combined faecal microbiome data with general practitioner diagnoses of depression from 1,054 individuals enrolled in the Flemish Gut Flora Project. They identified specific groups of microorganisms that positively or negatively correlated with mental health. The authors found that two bacterial genera, Coprococcus and Dialister, were consistently depleted in individuals with depression, regardless of antidepressant treatment. The results were validated in an independent cohort of 1,063 individuals from the Dutch LifeLinesDEEP cohort and in a cohort of clinically depressed patients at the University Hospitals Leuven, Belgium.
Prof Jeroen Raes (VIB-KU Leuven): 'The relationship between gut microbial metabolism and mental health is a controversial topic in microbiome research. The notion that microbial metabolites can interact with our brain -- and thus behaviour and feelings -- is intriguing, but gut microbiome-brain communication has mostly been explored in animal models, with human research lagging behind. In our population-level study we identified several groups of bacteria that co-varied with human depression and quality of life across populations.'
Previously, Prof Raes and his team identified a microbial community constellation or enterotype characterized by low microbial count and biodiversity that was observed to be more prevalent among Crohn's disease patients. In their current study, they surprisingly found a similar community type to be linked to depression and reduced quality of life.
Prof Jeroen Raes (VIB-KU Leuven): 'This finding adds more evidence pointing to the potentially dysbiotic nature of the Bacteroides2 enterotype we identified earlier. Apparently, microbial communities that can be linked to intestinal inflammation and reduced wellbeing share a set of common features.'
The authors also created a computational technique allowing the identification of gut bacteria that could potentially interact with the human nervous system. They studied genomes of more than 500 bacteria isolated from the human gastrointestinal tract in their ability to produce a set of neuroactive compounds, assembling the first catalogue of neuroactivity of gut species. Some bacteria were found to carry a broad range of these functions.
Mireia Valles-Colomer (VIB-KU Leuven): 'Many neuroactive compounds are produced in the human gut. We wanted to see which gut microbes could participate in producing, degrading, or modifying these molecules. Our toolbox not only allows to identify the different bacteria that could play a role in mental health conditions, but also the mechanisms potentially involved in this interaction with the host. For example, we found that the ability of microorganisms to produce DOPAC, a metabolite of the human neurotransmitter dopamine, was associated with better mental quality of life.'
These findings resulted from bioinformatics analyses and will need to be confirmed experimentally, however, they will help direct and accelerate future human microbiome-brain research.
Jeroen Raes and his team are now preparing another sampling round of the Flemish Gut Flora Project that is going to start next spring, five years after the first sampling effort.
Findings reveal tripling of blood levels of TMAO from red meat diet, but dietary effects can be reversed
December 11, 2018
Science Daily/NIH/National Heart, Lung and Blood Institute
Researchers have identified another reason to limit red meat consumption: high levels of a gut-generated chemical called trimethylamine N-oxide (TMAO), that also is linked to heart disease. Scientists found that people who eat a diet rich in red meat have triple the TMAO levels of those who eat a diet rich in either white meat or mostly plant-based proteins, but discontinuation of red meat eventually lowers those TMAO levels.
TMAO is a dietary byproduct that is formed by gut bacteria during digestion and is derived in part from nutrients that are abundant in red meat. While high saturated fat levels in red meat have long been known to contribute to heart disease -- the leading cause of death in the United States -- a growing number of studies have identified TMAO as another culprit. Until now, researchers knew little about how typical dietary patterns influence TMAO production or elimination.
The findings suggest that measuring and targeting TMAO levels -- something doctors can do with a simple blood test -- may be a promising new strategy for individualizing diets and helping to prevent heart disease. The study was funded largely by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health. It will be published Dec. 10 in the European Heart Journal, a publication of the European Society of Cardiology.
"These findings reinforce current dietary recommendations that encourage all ages to follow a heart-healthy eating plan that limits red meat," said Charlotte Pratt, Ph.D., the NHLBI project officer for the study and a nutrition researcher and Deputy Chief of the Clinical Applications & Prevention Branch, Division of Cardiovascular Sciences, NHLBI. "This means eating a variety of foods, including more vegetables, fruits, whole grains, low-fat dairy foods, and plant-based protein sources such as beans and peas."
"This study shows for the first time what a dramatic effect changing your diet has on levels of TMAO, which is increasingly linked to heart disease," said Stanley L. Hazen, M.D., Ph.D., senior author of the study and section head of Preventive Cardiology & Rehabilitation at the Cleveland Clinic. "It suggests that you can lower your heart disease risk by lowering TMAO."
Hazen estimated that as many as a quarter of middle-aged Americans have naturally elevated TMAO levels, which are made worse by chronic red meat consumption. However, every person's TMAO profile appears to be different, so tracking this chemical marker, Hazen suggested, could be an important step in using personalized medicine to fight heart disease.
For the study, researchers enrolled 113 healthy men and women in a clinical trial to examine the effects of dietary protein -- in the form of red meat, white meat, or non-meat sources -- on TMAO production. All subjects were placed on each diet for a month in random order. When on the red meat diet, the participants consumed roughly the equivalent of about 8 ounces of steak daily, or two quarter-pound beef patties. After one month, researchers found that, on average, blood levels of TMAO in these participants tripled, compared to when they were on the diets high in either white meat or non-meat protein sources.
While all diets contained equal amounts of calories, half of the participants were also placed on high-fat versions of the three diets, and the researchers observed similar results. Thus, the effects of the protein source on TMAO levels were independent of dietary fat intake.
Importantly, the researchers discovered that the TMAO increases were reversible. When the subjects discontinued their red meat diet and moved to either a white meat or non-meat diet for another month, their TMAO levels decreased significantly.
The exact mechanisms by which TMAO affects heart disease is complex. Prior research has shown TMAO enhances cholesterol deposits into cells of the artery wall. Studies by the researchers also suggest that the chemical interacts with platelets -- blood cells that are responsible for normal clotting responses -- in a way that increases the risk for clot-related events such as heart attack and stroke.
TMAO measurement is currently available as a quick, simple blood test first developed by Hazen's laboratory. In recent published studies, he and his colleagues reported development of a new class of drugs that are capable of lowering TMAO levels in the blood and reducing atherosclerosis and clotting risks in animal models, but those drugs are still experimental and not yet available to the public.
November 15, 2018
Science Daily/University of Copenhagen The Faculty of Health and Medical Sciences
When healthy people eat a low-gluten and fiber-rich diet compared with a high-gluten diet they experience less intestinal discomfort including less bloating which researchers show are due to changes of the composition and function of gut bacteria. The new study also shows a modest weight loss following low-gluten dieting. The researchers attribute the impact of diet on healthy adults more to change in composition of dietary fibers than gluten itself.
An increasing number of people choose a low-gluten diet, even though they are not allergic to the dietary substance. This trend has sparked public debate about whether or not low-gluten diets are recommendable for people without allergies. Now, researchers from University of Copenhagen among others have looked into just that.
In an intervention study of healthy Danish adults, reported today in Nature Communications, an international team of scientists shows that a low-gluten but fibre-rich diet changes the community of gut bacteria and decreases gastrointestinal discomfort such as bloating and is linked to a modest weight loss. The changes in intestinal comfort and body weight relate to changes in gut bacteria composition and function.
"We demonstrate that, in comparison with a high-gluten diet, a low-gluten, fibre-rich diet induces changes in the structure and function of the complex intestinal ecosystem of bacteria, reduces hydrogen exhalation, and leads to improvements in self-reported bloating. Moreover, we observed a modest weight loss, likely due to increased body combustion triggered by the altered gut bacterial functions," explains the leading principal investigator of the trial, Professor Oluf Pedersen, Novo Nordisk Foundation Center for Basic Metabolic Research at University of Copenhagen.
Change in dietary fibre composition seems to be the cause
The researchers undertook a randomised, controlled, cross-over trial involving 60 middle-aged healthy Danish adults with two eight week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day).
The two diets were balanced in number of calories and nutrients including the same amount of dietary fibres. However, the composition of fibres differed markedly between the two diets.
Based on their observations of altered food fermentation patterns of the gut bacteria, the researchers conclude that the effects of low-gluten dieting in healthy people may not be primarily due to reduced intake of gluten itself but rather to a change in dietary fibre composition by reducing fibres from wheat and rye and replacing them with fibres from vegetables, brown rice, corn, oat and quinoa.
No basis for change of diet recommendation yet
A low-gluten diet has previously been proposed to diminish gastrointestinal symptoms in patients with inflammatory bowel diseases and irritable bowel syndrome, disorders which occur in up to 20 percent of the general Western population.
The present study suggests that even some healthy individuals may prefer a low-gluten diet to combat intestinal discomfort or excess body weight.
"More long-term studies are definitely needed before any public health advice can be given to the general population. Especially, because we find dietary fibres -- not the absence of gluten alone -- to be the primary cause of the changes in intestinal discomfort and body weight. By now we think that our study is a wake-up call to the food industry. Gluten-free may not necessarily be the healthy choice many people think it is.
Most gluten-free food items available on the market today are massively deprived of dietary fibers and natural nutritional ingredients. Therefore, there is an obvious need for availability of fibre-enriched, nutritionally high-quality gluten-free food items which are fresh or minimally processed to consumers who prefer a low-gluten diet. Such initiatives may turn out to be key for alleviating gastro-intestinal discomfort and in addition to help facilitating weight control in the general population via modification of the gut microbiota," concludes senior lead investigator, Professor Oluf Pedersen.
New approach to weight loss and diabetes prevention published
September 19, 2018
Science Daily/University of North Carolina Health Care
Scientists have discovered that the anti-inflammatory protein NLRP12 normally helps protect mice against obesity and insulin resistance when they are fed a high-fat diet. The researchers also reported that the NLRP12 gene is underactive in people who are obese, making it a potential therapeutic target for treating obesity and diabetes, both of which are risk factors for cardiovascular disease and other serious conditions.
The study, published in Cell Host & Microbe, showed that NLRP12's anti-inflammatory effect promotes the growth of a "good" family of gut-dwelling bacteria, called Lachnospiraceae, that produce small molecules butyrate and propionate, which in turn promote gut health and protect mice against obesity and insulin resistance.
"Obesity is influenced by inflammation, not just by overeating and lack of exercise, and this study suggests that reducing inflammation promotes 'good' bacteria that can help maintain a healthy weight," said study senior author Jenny P-Y Ting, PhD, a William R. Kenan, Jr. Distinguished Professor of Genetics. "In mice, we showed that NLRP12 reduces inflammation in the gut and in adipose fat tissues. Although a direct causal effect is difficult to show in humans, our collaborators did help us show there are reduced expression levels of NLRP12 in individuals who are considered obese."
In humans, NLRP12 is produced by several types of immune cells and appears to function as a brake on excessive inflammation. Ting and colleagues in recent years have published studies showing that mice lacking the NLRP12 gene are highly susceptible to excessive inflammation, including experimental colon inflammation (colitis) and associated colon cancer.
In recent years, researchers have found evidence that inflammation in the gut and in where fat is deposited promotes obesity. About 40 percent of adults and 20 percent of children and teens age 2 to 19 in the United States are considered obese, according to recent government estimates. Being obese or even overweight can lead to a host of other conditions, including heart disease, stroke, cancers, and diabetes. Ting and colleagues in this study therefore sought to determine whether mice lacking the NLRP12 gene are more susceptible to obesity. The findings showed that they are.
The scientists fed mice that lacked the NLRP12 gene (NLRP12-knockout mice) and ordinary mice a high-fat diet for several months. The NLRP12-knockout mice ate and drank no more than their healthy cousins but accumulated significantly more fat and became heavier. The knockout mice also showed signs of insulin resistance, which involves a reduced ability to clear glucose from the bloodstream and tends to follow the development of obesity.
The absence of NLRP12 in these mice led to increased signs of inflammation in the gut and in fat deposits, but it wasn't clear how this led to extra weight gain until the researchers moved the animals from one facility to another. Following standard safety protocols to prevent disease spread, the researchers dosed the mice with antibiotics before the move.
"We noticed that the mice treated with antibiotics gained less weight than the mice that stayed in the old facility," said study co-first author Agnieszka Truax, PhD, a postdoctoral researcher in the Ting lab during the study. "That led us to suspect that gut bacteria were involved in promoting obesity."
Further tests showed that when NLRP12-knockout mice were kept in a bacteria-free condition, the mice did not gain weight because there were no bacteria. The deficiency of NLRP12 didn't matter as much. This suggested that "bad" bacteria had been driving the excess weight gain during a high-fat diet.
Remarkably, the knockout mice were also protected from excess weight gain when they were co-housed with control mice, hinting that "good" bacteria from the control mice were getting into them and helping to protect them.
Scientists have known that high-fat diets, as compared to low-fat diets, tend to reduce the diversity of bacterial species in the gut by suppressing some species and allowing a few others to proliferate abnormally. The UNC researchers confirmed this in their high-fat-eating mice, and they observed that the loss of bacterial diversity was much worse in the Nlrp12-knockout mice.
The experiments suggested that inflammation caused by a high-fat diet and worsened by the absence of NLRP12 was a major cause of this shift. Killing off rival bacterial species allowed a sharp rise in the levels of a bacterial family called Erysipelotrichaceae. These microbes became more prominent as gut inflammation worsened and exacerbated the weight-gain from a high-fat diet when put into the guts of otherwise germ-free mice.
By contrast, the Lachnospiraceae family of bacteria, which tended to die off in mice fed a high-fat diet, appeared to be highly beneficial. The researchers fed Lachnospiraceae to NLRP12-knockout mice prior to and during three weeks of high-fat eating and found that these "good" bacteria reduced gut inflammation, eliminated the hegemony of harmful Erysipelotrichaceae, and promoted more bacterial diversity. The Lachnospiraceae also significantly protected the animals against obesity and associated insulin-resistance.
"All the inflammatory and metabolic changes we had seen in the NLRP12-knockout mice during a high-fat diet were essentially reversed when we re-supplied Lachnospiraceae," Truax said.
Lachnospiraceae contain enzymes that convert carbs and fiber into small molecules called short-chain fatty acids (SCFAs). The scientists observed that two in particular, butyrate and propionate, appeared in significantly greater abundance when Lachnospiracea levels rose. Butyrate and propionate are known to have anti-inflammatory properties that promote gut health. The UNC team fed these SCFAs to the NLRP12-knockout mice and found that SCFAs protected the animals from the absence of NLRP12 just as well as the Lachnospiraceae had done.
Butyrate, propionate, and other SCFAs are already widely available as health supplements. But are these results in mice relevant to humans? A further test suggested that they are. Collaborating scientists Mihai Netea, MD, PhD, and Rinke Stienstra, PhD, from Radboud University Medical Center in the Netherlands examined fat cells from obese human patients and observed that the higher the measure of obesity -- the body-mass index -- the lower the activity of the NLRP12 gene tended to be.
Thus, treating people with "good" bacteria or the beneficial SCFAs they produce might one day be a relatively inexpensive strategy to combat obesity as well as diabetes and other obesity-driven conditions. Ting and colleagues plan to continue their investigations in that direction.
January 30, 2019
Science Daily/American Heart Association
The makeup of bacteria and other microbes in the gut may have a direct association with dementia risk, according to preliminary research to be presented in Honolulu at the American Stroke Association's International Stroke Conference 2019, a world premier meeting for researchers and clinicians dedicated to the science and treatment of cerebrovascular disease.
Researchers studying the population of bacteria and microbes in the intestines, known as gut microbiota, have found these "bugs" impact risks for diseases of the heart and more. Japanese researchers studied 128 (dementia and non-dementia) patients' fecal samples and found differences in the components of gut microbiota in patients with the memory disorder suggesting that what's in the gut influences dementia risk much like other risk factors.
The analysis revealed that fecal concentrations of ammonia, indole, skatole and phenol were higher in dementia patients compared to those without dementia. But levels of Bacteroides -- organisms that normally live in the intestines and can be beneficial -- were lower in dementia patients.
"Although this is an observational study and we assessed a small number of the patients, the odds ratio is certainly high suggesting that gut bacteria may be a target for the prevention of dementia," said Naoki Saji, M.D., Ph.D., study author and vice director of the Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology in Japan.
Study suggests that bacteria may regulate neuronal circuits behind movement in flies
November 1, 2018
Science Daily/NIH/National Institute of Neurological Disorders and Stroke
A new study puts a fresh spin on what it means to 'go with your gut.' The findings suggest that gut bacteria may control movement in fruit flies and identify the neurons involved in this response.
"This study provides additional evidence for a connection between the gut and the brain, and in particular outlines how gut bacteria may influence behavior, including movement," said Margaret Sutherland, Ph.D., program director at NINDS.
Researchers led by Sarkis K. Mazmanian, Ph.D., professor of microbiology at the California Institute of Technology in Pasadena, and graduate student Catherine E. Schretter, observed that germ-free flies, which did not carry bacteria, were hyperactive. For instance, they walked faster, over greater distances, and took shorter rests than flies that had normal levels of microbes. Dr. Mazmanian and his team investigated ways in which gut bacteria may affect behavior in fruit flies.
"Locomotion is important for a number of activities such as mating and searching for food. It turns out that gut bacteria may be critical for fundamental behaviors in animals," said Dr. Mazmanian.
Fruit flies carry between five and 20 different species of bacteria and Dr. Mazmanian's team treated the germ-free animals with individual strains of those microbes. When the flies received Lactobacillus brevis, their movements slowed down to normal speed. L. brevis was one of only two species of bacteria that restored normal behavior in the germ-free flies.
Dr. Mazmanian's group also discovered that the molecule xylose isomerase (Xi), a protein that breaks down sugar and is found in L. brevis, may be critical to this process. Isolating the molecule and treating germ-free flies with it was sufficient to slow down the speedwalkers.
Additional experiments showed that Xi may regulate movement by fine-tuning levels of certain carbohydrates, such as trehalose, which is the main sugar found in flies and is similar to mammalian glucose. Flies that were given Xi had lower levels of trehalose than did untreated germ-free flies. When Xi-treated flies, which showed normal behavior, were given trehalose alone, they resumed fast movements suggesting that the sugar was able to reverse the effects of Xi.
Next, the researchers looked into the flies' nervous system to see what cells were involved in bacteria-directed movement. When Dr. Mazmanian's team turned on neurons that produce the chemical octopamine, that activation canceled out the effect of L. brevis on the germ-free flies. As a result, the flies, which had previously slowed down after receiving the bacterium or Xi, resumed their speedwalking behavior. Turning on octopamine-producing nerve cells in flies with normal levels of bacteria also caused them to move faster. However, activating neurons that produce other brain chemicals did not influence the flies' movements.
According to Dr. Mazmanian, Schretter and their colleagues, Xi may be monitoring the flies' metabolic state, including levels of nutrients, and then signaling to octopamine neurons whether they should turn on or off, resulting in changes in behavior.
Instead of octopamine, mammals produce a comparable chemical called noradrenaline, which has been shown to control movement.
"Gut bacteria may play a similar role in mammalian locomotion, and even in movement disorders such as Parkinson's disease," said Dr. Mazmanian.
More research is needed to see whether bacteria control movement in other species, including mammals. In addition, future studies will further investigate how Xi is involved in these behaviors.
October 25, 2017
Science Daily/Stellenbosch University
The bacteria in your gut could hold clues to whether or not you will develop posttraumatic stress disorder (PTSD) after experiencing a traumatic event.
PTSD is a serious psychiatric disorder that can develop after a person experiences a life-threatening trauma. However, not everyone exposed to a traumatic event will develop PTSD, and several factors influence an individual's susceptibility, including living conditions, childhood experiences and genetic makeup. Stellenbosch University researchers are now also adding gut bacteria to this list.
In recent years, scientists have become aware of the important role of microbes existing inside the human gastrointestinal tract, called the gut microbiome. These microbes perform important functions, such as metabolising food and medicine, and fighting infections. It is now believed that the gut microbiome also influences the brain and brain function by producing neurotransmitters/hormones, immune-regulating molecules and bacterial toxins.
In turn, stress and emotions can change the composition of the gut microbiome. Stress hormones can affect bacterial growth and compromise the integrity of the intestinal lining, which can result in bacteria and toxins entering the bloodstream. This can cause inflammation, which has been shown to play a role in several psychiatric disorders.
"Our study compared the gut microbiomes of individuals with PTSD to that of people who also experienced significant trauma, but did not develop PTSD (trauma-exposed controls). We identified a combination of three bacteria (Actinobacteria, Lentisphaerae and Verrucomicrobia) that were different in people with PTSD," explains the lead researcher, Dr Stefanie Malan-Muller. She is a postdoctoral fellow in the Department of Psychiatry at the Faculty of Medicine and Health Sciences.
Individuals with PTSD had significantly lower levels of this trio of bacteria compared to trauma-exposed control groups. Individuals who experienced trauma during their childhood also had lower levels of two of these bacteria (Actinobacteria and Verrucomicrobia). "What makes this finding interesting, is that individuals who experience childhood trauma are at higher risk of developing PTSD later in life, and these changes in the gut microbiome possibly occurred early in life in response to childhood trauma," says Malan-Muller. She collaborated with researchers from the University of Colorado Boulder on the study.
One of the known functions of these bacteria is immune system regulation, and researchers have noted increased levels of inflammation and altered immune regulation in individuals with PTSD. "Changes in immune regulation and increased inflammation also impact the brain, brain functioning and behaviour. Levels of inflammatory markers measured in individuals shortly after a traumatic event, was shown to predict later development of PTSD.
"We therefore hypothesise that the low levels of those three bacteria may have resulted in immune dysregulation and heightened levels of inflammation in individuals with PTSD, which may have contributed to their disease symptoms," explains Malan-Muller.
However, researchers are unable to determine whether this bacterial deficit contributed to PTSD susceptibility, or whether it occurred as a consequence of PTSD.
"It does, however, bring us one step closer to understanding the factors that might play a role in PTSD. Factors influencing susceptibility and resilience to developing PTSD are not yet fully understood, and identifying and understanding all these contributing factors could in future contribute to better treatments, especially since the microbiome can easily be altered with the use of prebiotics (non-digestible food substances), probiotics (live, beneficial microorganisms), and synbiotics (a combination of probiotics and prebiotics), or dietary interventions."
September 14, 2018
Science Daily/University of Illinois College of Agricultural, Consumer and Environmental Sciences
As mammals age, immune cells in the brain known as microglia become chronically inflamed. In this state, they produce chemicals known to impair cognitive and motor function. That's one explanation for why memory fades and other brain functions decline during old age. But, according to a new study, there may be a remedy to delay the inevitable: dietary fiber.
Dietary fiber promotes the growth of good bacteria in the gut. When these bacteria digest fiber, they produce short-chain-fatty-acids (SCFAs), including butyrate, as byproducts.
"Butyrate is of interest because it has been shown to have anti-inflammatory properties on microglia and improve memory in mice when administered pharmacologically," says Rodney Johnson, professor and head of the Department of Animal Sciences at U of I, and corresponding author on the Frontiers in Immunology study.
Although positive outcomes of sodium butyrate -- the drug form -- were seen in previous studies, the mechanism wasn't clear. The new study reveals, in old mice, that butyrate inhibits production of damaging chemicals by inflamed microglia. One of those chemicals is interleukin-1?, which has been associated with Alzheimer's disease in humans.
Understanding how sodium butyrate works is a step forward, but the researchers were more interested in knowing whether the same effects could be obtained simply by feeding the mice more fiber.
"People are not likely to consume sodium butyrate directly, due to its noxious odor," Johnson says. "A practical way to get elevated butyrate is to consume a diet high in soluble fiber."
The concept takes advantage of the fact that gut bacteria convert fiber into butyrate naturally.
"We know that diet has a major influence on the composition and function of microbes in the gut and that diets high in fiber benefit good microbes, while diets high in fat and protein can have a negative influence on microbial composition and function. Diet, through altering gut microbes, is one way in which it affects disease," says Jeff Woods, professor in the Department of Kinesiology and Community Health at U of I, and co-author on the study.
Butyrate derived from dietary fiber should have the same benefits in the brain as the drug form, but no one had tested it before. The researchers fed low- and high-fiber diets to groups of young and old mice, then measured the levels of butyrate and other SCFAs in the blood, as well as inflammatory chemicals in the intestine.
"The high-fiber diet elevated butyrate and other SCFAs in the blood both for young and old mice. But only the old mice showed intestinal inflammation on the low-fiber diet," Johnson says. "It's interesting that young adults didn't have that inflammatory response on the same diet. It clearly highlights the vulnerability of being old."
On the other hand, when old mice consumed the high-fiber diet, their intestinal inflammation was reduced dramatically, showing no difference between the age groups. Johnson concludes, "Dietary fiber can really manipulate the inflammatory environment in the gut."
The next step was looking at signs of inflammation in the brain. The researchers examined about 50 unique genes in microglia and found the high-fiber diet reduced the inflammatory profile in aged animals.
The researchers did not examine the effects of the diets on cognition and behavior or the precise mechanisms in the gut-brain axis, but they plan to tackle that work in the future as part of a new, almost-$2 million grant from the National Institute on Aging, part of the National Institutes of Health.
Although the study was conducted in mice, Johnson is comfortable extending his findings to humans, if only in a general sense. "What you eat matters. We know that older adults consume 40 percent less dietary fiber than is recommended. Not getting enough fiber could have negative consequences for things you don't even think about, such as connections to brain health and inflammation in general."
Study in mice links gut microbes with signs of negative feelings and brain chemistry
June 17, 2018
Science Daily/Joslin Diabetes Center
Like everyone, people with type 2 diabetes and obesity suffer from depression and anxiety, but even more so. Researchers now have demonstrated a surprising potential contributor to these negative feelings -- and that is the bacteria in the gut or gut microbiome, as it is known.
Studying mice that become obese when put on a high-fat diet, the Joslin scientists found that mice on a high-fat diet showed significantly more signs of anxiety, depression and obsessive behavior than animals on standard diets. "But all of these behaviors are reversed or improved when antibiotics that will change the gut microbiome were given with the high fat diet," says C. Ronald Kahn, M.D., co-Head of the Section on Integrative Physiology and Metabolism at Joslin and the Mary K. Iacocca Professor of Medicine at Harvard Medical School .
"As endocrinologists, we often hear people say that they feel differently when they've eaten different foods," notes Kahn, who is senior author on a paper in Molecular Psychiatry describing the research. "What this study says is that many things in your diet might affect the way your brain functions, but one of those things is the way diet changes the gut bacteria or microbes. Your diet isn't always necessarily just making your blood sugar higher or lower; it's also changing a lot of signals coming from gut microbes and these signals make it all the way to the brain."
His lab has long studied mice that are prone to developing obesity, diabetes and related metabolic diseases when given high-fat diets. Earlier this year, the team showed that at least part of this development is driven by changing bacteria in the gut microbiome. The condition was reversed in mice who were given antibiotics in their drinking water, which altered the microbiome.
In the most recent study, the Joslin scientists followed up by giving mice on a high-fat diet four classic lab animal behavioral tests, which are often employed in screening drugs for anxiety and depression. In each case, mice on high-fat diet showed higher signs of anxiety and depression than mice on a regular diet. However, when the mice were given antibiotics with the high fat diet, their behaviors returned to normal.
One of the ways the researchers showed this was an effect of the microbiome was by transferring gut bacteria from these experimental mice toto germ-free mice, who did not have any bacteria of their own. The animals who received bacteria from mice on a high-fat diet showed began to show increased levels of activity associated with anxiety and obsessive behavior. However, those who received microbes from mice on a high-fat diet plus antibiotics did not, even though they did not receive the antibiotics themselves. "This proves that these behaviors are driven to some significant extent by the gut microbiome," says Kahn.
But what exactly were the microbes doing? The Joslin looked for clues in two areas of the brain, the hypothalamus (which helps to control whole body metabolism) and the nucleus accumbens (which is important in mood and behavior).
"We demonstrated that, just like other tissues of the body, these areas of the brain become insulin resistant in mice on high-fat diets," Kahn says. "And this response to the high fat is partly, and in some cases almost completely, reversed by putting the animals by antibiotics. Again, the response is transferrable when you transfer the gut microbiome from mice on a high-fat diet to germ-free mice. So, the insulin resistance in the brain is mediated at least in part by factors coming from the microbiome."
The Joslin team went on to link the microbiome alterations to the production of certain neurotransmitters -- the chemicals that transfer signals across the brain.
Kahn and his colleagues are now working to identify specific populations of bacteria involved in these processes, and the molecules that the bacteria produce. The eventual goal is to find drugs or supplements that can help to achieve healthier metabolic profiles in the brain.
"Antibiotics are blunt tools that change many bacteria in very dramatic ways," Kahn says. "Going forward, we want to get a more sophisticated understanding about which bacteria contribute to insulin resistance in the brain and in other tissues. If we could modify those bacteria, either by putting in more beneficial bacteria or reducing the number of harmful bacteria, that might be a way to see improved behavior."
Overall, this study highlights how basic research that draws on expertise from multiple fields can lead in unexpected directions, Kahn emphasizes. "Understanding one area of biology, like diabetes and metabolism, can often give new and different perspectives in another field, like psychiatric and behavioral disorders," he says. "Even if that's not what you start out to do!"
September 12, 2017
Science Daily/Faculty of Science - University of Copenhagen
Something as simple as a feces sample reveals whether you can lose weight by following dietary recommendations characterized by a high content of fruit, vegetables, fibers and whole grains. This is a finding of a new study conducted at the Department of Nutrition, Exercise and Sports at the University of Copenhagen, Denmark.
The bacteria we all have in our gut may play a decisive role in personalized nutrition and the development of obesity. This is shown by several studies that have delved into the significance of these bacteria.
"Human intestinal bacteria have been linked to the increasing prevalence of overweight and obesity, and scientists have started to investigate whether the intestinal bacteria can play a role in the treatment of overweight. But it is only now that we have a breakthrough demonstrating that certain bacterial species play a decisive role in weight regulation and weight loss" says Professor Arne Astrup, Head of the Department of Nutrition, Exercise and Sports at the University of Copenhagen, Denmark.
The ratio between the two groups of intestinal bacteria is crucial
A relationship between two groups of intestinal bacteria is decisive for whether overweight people lose weight on a diet that follows the Danish national dietary recommendations and contains a lot of fruit, vegetables, fiber and whole grains. In the study 31 subjects ate the New Nordic Diet for 26 weeks and lost an average of 3.5 kg, whereas the 23 subjects eating an Average Danish Diet lost an average of 1.7 kg. Thus weight loss was on average 1.8 kilos greater in the subjects on the New Nordic Diet.
High proportion of Prevotella bacteria lead to weight loss
When the subjects were divided by their level of intestinal bacteria, it was found that people with a high proportion of Prevotella bacteria in relation to Bacteroides bacteria lost 3.5 kg more in 26 weeks when they ate a diet composed by the New Nordic Diet principles compared to those consuming an Average Danish Diet. Subjects with a low proportion of Prevotella bacteria in relation to Bacteroides did not lose any additional weight on the New Nordic Diet. Overall, approximately 50 percent of the population has a high proportion of Prevotella-bacteria in relation to Bacteroides-bacteria.
"The study shows that only about half of the population will lose weight if they eat in accordance with the Danish national dietary recommendations and eat more fruit, vegetables, fibers and whole grains. The other half of the population doesn't seem to gain any benefit in weight from this change of diet," says Assistant Professor Mads Fiil Hjorth at the Department of Nutrition, Exercise and Sports at the University of Copenhagen. He continues: "These people should focus on other diet and physical activity recommendations until a strategy that works especially well for them is identified."
The researchers emphasize that they have already confirmed the results in two independent studies, so they are certain that these results are credible.
Personalized weight loss guidance
The results show that biomarkers, e.g. faecal samples, blood samples, or other samples from our body, which says something about our state of health, should play a far greater role in nutritional guidance. Simply because biomarkers allow us to adapt the guidance to the individual.
"This is a major step forward in personalized nutritional guidance. Guidance based on this knowledge of intestinal bacteria will most likely be more effective than the "one size fits all" approach that often characterises dietary recommendations and dietary guidance," says Assistant Professor Mads Fiil Hjorth.
At present it is primarily research units at universities and other academic institutions that examine the composition of intestinal bacteria, but as an effect of this breakthrough the University of Copenhagen has licensed a company in Boston, USA, to develop and publish a concept based on this research, that will be of benefit to obese people.