microbiome

Researchers explore stroke's effects on microbiome

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.

 

Intestinal disorganization

 

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."

https://www.sciencedaily.com/releases/2019/03/190312123714.htm

Young children's oral bacteria may predict obesity

September 19, 2018

Science Daily/Penn State

Weight gain during early childhood is related to the composition of oral bacteria of two-year-old children, suggesting this understudied aspect of a children's collection of microorganisms could serve as an early indicator for childhood obesity.

 

Weight gain trajectories in early childhood are related to the composition of oral bacteria of two-year-old children, suggesting that this understudied aspect of a child's microbiota -- the collection of microorganisms, including beneficial bacteria, residing in the mouth -- could serve as an early indicator for childhood obesity. A study describing the results appears September 19 in the journal Scientific Reports.

 

"One in three children in the United States is overweight or obese," said Kateryna Makova, Pentz Professor of Biology and senior author of the paper. "If we can find early indicators of obesity in young children, we can help parents and physicians take preventive measures."

 

The study is part of a larger project with researchers and clinicians at the Penn State Milton S. Hershey Medical Center called INSIGHT, led by Ian Paul, professor of pediatrics at the Medical Center, and Leann Birch, professor of foods and nutrition at the University of Georgia. The INSIGHT trial includes nearly 300 children and tests whether a responsive parenting intervention during a child's early life can prevent the development of obesity. It is also designed to identify biological and social risk factors for obesity.

 

"In this study, we show that a child's oral microbiota at two years of age is related to their weight gain over their first two years after birth," said Makova.

 

The human digestive tract is filled with a diverse array of microorganisms, including beneficial bacteria, that help ensure proper digestion and support the immune system. This "microbiota" shifts as a person's diet changes and can vary greatly among individuals. Variation in gut microbiota has been linked to obesity in some adults and adolescents, but the potential relationship between oral microbiota and weight gain in children had not been explored prior to this study.

 

"The oral microbiota is usually studied in relation to periodontal disease, and periodontal disease has in some cases been linked to obesity," said Sarah Craig, a postdoctoral scholar in biology at Penn State and first author of the paper. "Here, we explored any potential direct associations between the oral microbiota and child weight gain. Rather than simply noting whether a child was overweight at the age of two, we used growth curves from their first two years after birth, which provides a more complete picture of how the child is growing. This approach is highly innovative for a study of this kind, and gives greater statistical power to detect relationships."

 

Among 226 children from central Pennsylvania, the oral microbiota of those with rapid infant weight gain -- a strong risk factor for childhood obesity -- was less diverse, meaning it contained fewer groups of bacteria. These children also had a higher ratio of Firmicutes to Bacteroidetes, two of the most common bacteria groups found in the human microbiota.

 

"A healthy person usually has a lot of different bacteria within their gut microbiota," said Craig. "This high diversity helps protect against inflammation or harmful bacteria and is important for the stability of digestion in the face of changes to diet or environment. There's also a certain balance of these two common bacteria groups, Firmicutes and Bacteroidetes, that tends to work best under normal healthy conditions, and disruptions to that balance could lead to dysregulation in digestion."

 

Lower diversity and higher Firmicutes to Bacteroidetes (F:B) ratio in gut microbiota are sometimes observed as a characteristic of adults and adolescents with obesity. However, the researchers did not see a relationship of weight gain with either of these measures in gut microbiota of two-year-olds, suggesting that the gut microbiota may not be completely established at two years of age and may still be undergoing many changes.

 

"There are usually dramatic changes to an individual's microbiota as they develop during early childhood," said Makova. "Our results suggest that signatures of obesity may be established earlier in oral microbiota than in gut microbiota. If we can confirm this in other groups of children outside of Pennsylvania, we may be able to develop a test of oral microbiota that could be used in clinical care to identify children who are at risk for developing obesity. This is particularly exciting because oral samples are easier to obtain than those from the gut, which require fecal samples."

 

Interestingly, weight gain in children was also related to diversity of their mother's oral microbiota. This could reflect a genetic predisposition of the mother and child to having a similar microbiota, or the mother and child having a similar diet and environment.

 

"It could be a simple explanation like a shared diet or genetics, but it might also be related to obesity," said Makova. "We don't know for sure yet, but if there is an oral microbiome signature linked to the dynamics of weight gain in early childhood, there is a particular urgency to understand it. Now we are using additional techniques to look at specific species of bacteria -- rather than larger taxonomic groups of bacteria -- in both the mothers and children to see whether specific bacteria species influence weight gain and the risk of obesity."

https://www.sciencedaily.com/releases/2018/09/180919083508.htm

Modeling the microbiome

Physicists develop new mathematical approaches to analyze interactions between gut bacteria

December 5, 2018

Science Daily/University of California - Santa Barbara

The gut microbiome -- the world of microbes that inhabit the human intestinal tract -- has captured the interest of scientists and clinicians for its critical role in health. However, parsing which of those microbes are responsible for effects on our wellbeing remains a mystery.

 

Taking us one step closer to solving this puzzle, UC Santa Barbara physicists Eric Jones and Jean Carlson have developed a mathematical approach to analyze and model interactions between gut bacteria in fruit flies. This method could lead to a more sophisticated understanding of the complex interactions between human gut microbes.

 

Their finding appear in the Proceedings of the National Academy of Sciences.

 

"Especially over the past 20 years or so, scientists have been finding that the microbiome interacts with the rest of your body, with your immune system, with your brain," said Jones, a graduate student researcher in Carlson's lab. "Many diseases are associated with certain microbial compositions in the gut."

 

The human gut microbiome as yet is too diverse to fully analyze. Instead, the research team, led by Carnegie Institution for Science biologist Will Ludington, used the fruit fly as a model organism to tease apart how the presence of particular gut bacteria could lead to physical and behavioral effects in the host organism.

 

In their paper, "Microbiome interactions shape host fitness," Carlson, Jones, Ludington and colleagues examine the interactions between five core species of bacteria found in the fly gut, and calculate how the presence or absence of individual species influences aspects of the fly's fitness, including lifespan, fertility and development. "The classic way we think about bacterial species is in a black-and-white context as agents of disease -- either you have it or you don't," Ludington said. "Our work shows that isn't the case for the microbiome. The effects of a particular species depend on the context of which other species are also present."

 

Building on previous research that found the presence versus the absence of bacteria affected the longevity of an organism (sterile hosts lived longer), the researchers' work on this project revealed that the situation is far more nuanced. For example, the presence of certain bacteria might increase the host's fecundity, while others might decrease longevity. "As we examined the total of what we call a fly's fitness -- it's chances of surviving and creating offspring -- we found that there was a tradeoff between having a short lifespan with lots of offspring, versus having a long lifespan with few offspring," Ludington explained. "This tradeoff was mediated by microbiome interactions."

 

To decipher these interactions, Ludington performed a combinatorial assay, rearing 32 batches of flies each inhabited by a unique combination of the five bacteria. For each bacterial combination, Ludington measured the fly's development, fecundity and longevity. The analysis of the interactions required Carlson and Jones to develop new mathematical approaches.

 

"One model that often would be a starting point would be to consider the interactions between pairs of bacteria," said Carlson, whose research delves into the physics of complex systems. "This research shows us that a strictly pairwise model does not capture all of the observed fly traits."

 

What the study shows, the researchers said, is that the interactions between the bacterial populations are as significant to the host's overall fitness as their presence -- the microbiome's influence cannot be solely attributed to the presence or absence of individual species. "In a sense," said Jones, "the microbiome's influence on the host is more than the sum of its parts."

 

The newly developed models could be extended to better understand the interactions of the thousands of different species of bacteria in the human microbiome, which could, in turn, shed light on the many connections to microbiome-affiliated diseases including mood disorders, neurological dysfunctions, autoimmune diseases and antibiotic-resistant superbugs.

 

"In many cases infections are caused by bacteria that we all have in ourselves all the time, and are kept in check by native gut bacteria," Carlson said. It's not so much that the infection is some new, horrible bacteria, she explained, but that the populations of other bacteria have changed, resulting in unrestricted growth for the infectious bacteria.

 

"It's really about understanding the population dynamics of these systems," she said.

https://www.sciencedaily.com/releases/2018/12/181205152208.htm

 

Health of mom's gut a key contributor to autism risk

Could reducing risk of autism involve changing expectant mothers' diets?

July 18, 2018

Science Daily/University of Virginia Health System

The mother's microbiome, the collection of microscopic organisms that live inside us, is a key contributor to the risk of autism and other neurodevelopmental disorders in her offspring, new research suggests. The work raises the possibility that we could help prevent autism by altering expectant moms' diets.

 

Further, the UVA scientists were able to use their discovery to prevent the development of autism-like neurodevelopmental disorders in lab mice. They found they could halt the development of such disorders by blocking a particular inflammatory molecule produced by the immune system. Targeting this molecule, interleukin-17a, offers another potential avenue for preventing autism in people, the researchers say. They caution, however, that this approach would be much more complex because of the risk of side effects.

 

"We determined that the microbiome is a key contributor in determining susceptibility [to autism-like disorders], so it suggests that you could target either the maternal microbiome or this inflammatory molecule, IL-17a," said lead researcher John Lukens, PhD, of UVA's Department of Neuroscience. "You could also use this [IL-17a] as a biomarker for early diagnosis."

 

The groundbreaking work from Lukens and his colleagues sheds light on the complex relationship between the health of the mother's microbiome and the healthy development of her children. "The microbiome can shape the developing brain in multiple ways," explained Lukens, of UVA's Center for Brain Immunology and Glia (BIG) and UVA's Carter Immunology Center. "The microbiome is really important to the calibration of how the offspring's immune system is going to respond to an infection or injury or stress."

 

But an unhealthy microbiome in the mom can create problems: Lukens' work shows that it can make her unborn offspring susceptible to neurodevelopmental disorders. The researchers found that the IL-17a molecule was a key contributor to the development of autism-like symptoms in lab mice.

 

The good news: The microbiome can be modified easily, either through diet, probiotic supplements or fecal transplant. All of these approaches seek to restore a healthy equilibrium among the different microorganisms that live in the gut.

 

"In terms of translating our work to humans, I think the next big step would be to identify features of the microbiome in pregnant mothers that correlate with autism risk," Lukens said. "I think the really important thing is to figure out what kind of things can be used to modulate the microbiome in the mother as effectively and safely as we can."

 

Another Option for Preventing Autism

 

Blocking IL-17a also might offer a way to prevent autism, but Lukens said that path carries much more risk. "If you think about pregnancy, the body is basically accepting foreign tissue, which is a baby," he said. "As a result, maintenance of embryonic health demands a complex balance of immune regulation, so people tend to shy away from manipulating the immune system during pregnancy."

 

IL-17a previously has been implicated in conditions such as rheumatoid arthritis, multiple sclerosis and psoriasis, and there are already drugs available that target it. But Lukens noted that the molecule has an important purpose in stopping infections, especially fungal infections. Blocking it, he said, "could make you susceptible to all kinds of infections." And doing so during pregnancy could have complex ripple effects on a child's development that scientists would need to sort out.

 

For their next steps, Lukens and his team plan to explore the potential role of other immune molecules in the development of autism and other such conditions. IL-17a may be just one piece in a much larger puzzle, he said.

 

While Lukens' work links the immune system with neurodevelopmental disorders, he emphasized that this in no way suggests that vaccines are contributing to the development of autism. "There's a definite link between the immune response and the developing brain," he said. "It just doesn't have anything to do with vaccines. It's much, much earlier."

 

Lukens' work is but the latest research from UVA to speak to the importance of the microbiome in maintaining good health. For example, one of Lukens' colleagues in the Department of Neuroscience, Alban Gaultier, PhD, found that probiotics in yogurt can reverse depression symptoms.

https://www.sciencedaily.com/releases/2018/07/180718113343.htm

Gut feeling: Research examines link between stomach bacteria, PTSD

April 25, 2016

Science Daily/Office of Naval Research

Could bacteria in your gut be used to cure or prevent neurological conditions such as post-traumatic stress disorder (PTSD), anxiety or even depression? Two researchers think that's a strong possibility.

Dr. John Bienenstock and Dr. Paul Forsythe--who work in The Brain-Body Institute at McMaster University in Ontario, Canada--are investigating intestinal bacteria and their effect on the human brain and mood.

 

"This is extremely important work for U.S. warfighters because it suggests that gut microbes play a strong role in the body's response to stressful situations, as well as in who might be susceptible to conditions like PTSD," said Dr. Linda Chrisey, a program officer in ONR's Warfighter Performance Department, which sponsors the research.

 

The trillions of microbes in the intestinal tract, collectively known as the gut microbiome, profoundly impact human biology--digesting food, regulating the immune system and even transmitting signals to the brain that alter mood and behavior. ONR is supporting research that's anticipated to increase warfighters' mental and physical resilience in situations involving dietary changes, sleep loss or disrupted circadian rhythms from shifting time zones or living in submarines.

 

Through research on laboratory mice, Bienenstock and Forsythe have shown that gut bacteria seriously affect mood and demeanor. They also were able to control the moods of anxious mice by feeding them healthy microbes from fecal material collected from calm mice.

 

Bienenstock and Forsythe used a "social defeat" scenario in which smaller mice were exposed to larger, more aggressive ones for a couple of minutes daily for 10 consecutive days. The smaller mice showed signs of heightened anxiety and stress--nervous shaking, diminished appetite and less social interaction with other mice. The researchers then collected fecal samples from the stressed mice and compared them to those from calm mice.

 

"What we found was an imbalance in the gut microbiota of the stressed mice," said Forsythe. "There was less diversity in the types of bacteria present. The gut and bowels are a very complex ecology. The less diversity, the greater disruption to the body."

 

Bienenstock and Forsythe then fed the stressed mice the same probiotics (live bacteria) found in the calm mice and examined the new fecal samples. Through magnetic resonance spectroscopy (MRS), a non-invasive analytical technique using powerful MRI technology, they also studied changes in brain chemistry.

 

"Not only did the behavior of the mice improve dramatically with the probiotic treatment," said Bienenstock, "but it continued to get better for several weeks afterward. Also, the MRS technology enabled us to see certain chemical biomarkers in the brain when the mice were stressed and when they were taking the probiotics."

 

Both researchers said stress biomarkers could potentially indicate if someone is suffering from PTSD or risks developing it, allowing for treatment or prevention with probiotics and antibiotics.

 

Later this year, Bienenstock and Forsythe will perform experiments involving fecal transplants from calm mice to stressed mice. They also hope to secure funding to conduct clinical trials to administer probiotics to human volunteers and use MRS to monitor brain reactions to different stress levels.

 

Gut microbiology is part of ONR's program in warfighter performance. ONR also is looking at the use of synthetic biology to enhance the gut microbiome. Synthetic biology creates or re-engineers microbes or other organisms to perform specific tasks like improving health and physical performance. The field was identified as a top ONR priority because of its potential far-ranging impact on warfighter performance and fleet capabilities.

https://www.sciencedaily.com/releases/2016/04/160425161324.htm

 

'Ridiculously healthy' elderly have the same gut microbiome as healthy 30-year-olds

October 11, 2017

Science Daily/University of Western Ontario

In one of the largest microbiota studies conducted in humans, researchers have shown a potential link between healthy aging and a healthy gut.

 

With the establishment of the China-Canada Institute, the researchers studied the gut bacteria in a cohort of more than 1,000 Chinese individuals in a variety of age-ranges from 3 to over 100 years-old who were self-selected to be extremely healthy with no known health issues and no family history of disease. The results showed a direct correlation between health and the microbes in the intestine.

 

"The aim is to bring novel microbiome diagnostic systems to populations, then use food and probiotics to try and improve biomarkers of health," said Gregor Reid, professor at Western's Schulich School of Medicine & Dentistry and Scientist at Lawson Health Research Institute. "It begs the question -- if you can stay active and eat well, will you age better, or is healthy ageing predicated by the bacteria in your gut?"

 

The study, published this month in the journal mSphere, showed that the overall microbiota composition of the healthy elderly group was similar to that of people decades younger, and that the gut microbiota differed little between individuals from the ages of 30 to over 100.

 

"The main conclusion is that if you are ridiculously healthy and 90 years old, your gut microbiota is not that different from a healthy 30 year old in the same population," said Greg Gloor, the principal investigator on the study and also a professor at Western's Schulich School of Medicine & Dentistry and Scientist at Lawson Health Research Institute. Whether this is cause or effect is unknown, but the study authors point out that it is the diversity of the gut microbiota that remained the same through their study group.

 

"This demonstrates that maintaining diversity of your gut as you age is a biomarker of healthy aging, just like low-cholesterol is a biomarker of a healthy circulatory system," Gloor said. The researchers suggest that resetting an elderly microbiota to that of a 30-year-old might help promote health.

 

"By studying healthy people, we hope to know what we are striving for when people get sick," said Reid.

 

The study also found a distinct anomaly in the group aged 19 to 24 that has not been observed in large-scale analyses of other populations and they suspect may be unique to this healthy cohort in China. The distinct gut microbiota of this group was a surprising finding and requires further study.

https://www.sciencedaily.com/releases/2017/10/171011123728.htm

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