Researchers connect brain blood vessel lesions to intestinal bacteria

bac 111.JPGNIH-funded pre-clinical study links gut microbes and the immune system to a genetic disorder that can cause stroke and seizures.

 A study in mice and humans suggests that bacteria in the gut can influence the structure of the brain’s blood vessels, and may be responsible for producing malformations that can lead to stroke or epilepsy.

The research, published in Nature, adds to an emerging picture that connects intestinal microbes and disorders of the nervous system. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health.

Cerebral cavernous malformations (CCMs) are clusters of dilated, thin-walled blood vessels that can lead to seizures or stroke when blood leaks into the surrounding brain tissue. A team of scientists at the University of Pennsylvania investigated the mechanisms that cause CCM lesions to form in genetically engineered mice and discovered an unexpected link to bacteria in the gut. When bacteria were eliminated the number of lesions was greatly diminished.

“This study is exciting because it shows that changes within the body can affect the progression of a disorder caused by a genetic mutation,” said Jim I. Koenig, Ph.D., program director at NINDS.

The researchers were studying a well-established mouse model that forms a significant number of CCMs following the injection of a drug to induce gene deletion. However, when the animals were relocated to a new facility, the frequency of lesion formation decreased to almost zero.

“It was a complete mystery. Suddenly, our normally reliable mouse model was no longer forming the lesions that we expected,” said Mark L. Kahn, M.D., professor of medicine at the University of Pennsylvania, and senior author of the study. “What’s interesting is that this variability in lesion formation is also seen in humans, where patients with the same genetic mutation often have dramatically different disease courses.”

While investigating the cause of this sudden variability, Alan Tang, a graduate student in Dr. Kahn’s lab, noticed that the few mice that continued to form lesions had developed bacterial abscesses in their abdomens — infections that most likely arose due to the abdominal drug injections.

The abscesses contained Gram-negative bacteria, and when similar bacterial infections were deliberately induced in the CCM model animals, about half of them developed significant CCMs.

“The mice that formed CCMs also had abscesses in their spleens, which meant that the bacteria had entered the bloodstream from the initial abscess site,” said Tang. “This suggested a connection between the spread of a specific type of bacteria through the bloodstream and the formation of these blood vascular lesions in the brain.”

The question remained as to how bacteria in the blood could influence blood vessel behavior in the brain. Gram-negative bacteria produce molecules called lipopolysaccharides (LPS) that are potent activators of innate immune signaling. When the mice received injections of LPS alone, they formed numerous large CCMs, similar to those produced by bacterial infection. Conversely, when the LPS receptor, TLR4, was genetically removed from these mice they no longer formed CCM lesions.  The researchers also found that, in humans, genetic mutations causing an increase in TLR4 expression were associated with a greater risk of forming CCMs.

“We knew that lesion formation could be driven by Gram-negative bacteria in the body through LPS signaling,” said Kahn.

“Our next question was whether we could prevent lesions by changing the bacteria in the body.”

The researchers explored changes to the body’s bacteria (microbiome) in two ways. First, newborn CCM mice were raised in either normal housing or under germ-free conditions. Second, these mice were given a course of antibiotics to “reset” their microbiome. In both the germ-free conditions and following the course of antibiotics, the number of lesions was significantly reduced, indicating that both the quantity and quality of the gut microbiome could affect CCM formation. Finally, a drug that specifically blocks TLR4 also produced a significant decrease in lesion formation. This drug has been tested in clinical trials for the treatment of sepsis, and these findings suggest a therapeutic potential for the drug in the treatment of CCMs, although considerable research remains to be done.

“These results are especially exciting because they show that we can take findings in the mouse and possibly apply them at the human patient population,” said Koenig. “The drug used to block TLR4 has already been tested in patients for other conditions, and it may show therapeutic potential in the treatment of CCMs, although considerable research still remains to be done.”

Kahn and his colleagues plan to continue to study the relationship between the microbiome and CCM formation, particularly as it relates to human disease. Although specific gene mutations have been identified in humans that can cause CCMs to form, the size and number varies widely among patients with the same mutations. The group next aims to test the hypothesis that differences in the patients’ microbiomes could explain this variability in lesion number.

This work was supported by the NINDS (NS092521, NS075168, NS100252, NS065705), the National Heart, Lung, and Blood Institute (HL094326, HL07439), NIDDK (DK007780), the DFG (German Research Foundation), Penn-CHOP, and the National Health and Medical Research Council, Australia.

The NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at https://www.nhlbi.nih.gov.

The NIDDK conducts and supports research on diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic, and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe, and disabling conditions affecting Americans. For more information about the NIDDK and its programs, visit www.niddk.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Article

Tang et al. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. May 10, 2017.

Early life history and genetics may play crucial role in shaping gut microbiome

 

The findings by a team of scientists from the Department of Energy’s Pacific Northwest National Laboratory and Lawrence Berkeley National Laboratory (Berkeley Lab) represent an attempt to untangle the forces that shape the gut microbiome, which plays an important role in keeping us healthy.

In the study, scientists linked specific genes in an animal – in this case, a mouse – to the presence and abundance of specific microbes in its gut.

“We are starting to tease out the importance of different variables, like diet, genetics and the environment, on microbes in the gut,” said PNNL’s Janet Jansson, a corresponding author of the study. “It turns out that early life history and genetics both play a role.”

Scientists studied more than 50,000 genetic variations in mice and ultimately identified more than 100 snippets that affect the population of microbes in the gut. Some of those genes in mice are very similar to human genes that are involved in the development of diseases like arthritis, colon cancer, Crohn’s disease, celiac disease and diabetes.

The abundance of one microbe in particular, a probiotic strain of Lactobacillales, was affected by several host genes and was linked to higher levels of important immune cells known as T-helper cells. These results support the key role of the microbiome in the body’s immune response, and suggest the possibility that controlling the microbes in the gut could influence the immune system and disease vulnerability.

“We know the microbiome likely plays an important role in fighting infections,” said first author Antoine Snijders of the Berkeley Lab. “We found that the level of T-helper cells in the blood of mice is well explained by the level of Lactobacillales in the gut. It’s the same family of bacteria found in yogurt and very often used as a probiotic.”

To do the research, the team drew upon a genetically diverse set of “collaborative cross” mice that capture the genetic variation in human populations. Scientists studied 30 strains of the mice, which were housed in two facilities with different environments for the first four weeks of their lives. The scientists took fecal samples from the mice to characterize their gut microbiomes before transferring them to a third facility.

The researchers found that the microbiome retained a clear microbial signature formed where the mice were first raised – effectively their “hometown.” Moreover, that microbial trait carried over to the next generation, surprising the scientists.

“The early life environment is very important for the formation of an individual’s microbiome,” said Jian-Hua Mao, a corresponding author from Berkeley Lab. “The first dose of microbes one gets comes from the mom, and that remains a strong influence for a lifetime and even beyond.”

In brief, the team found that:

  • Both genetics and early environment play a strong role in determining an organism’s microbiome
  • The genes in mice that were correlated to microbes in the gut are very similar to genes that are involved in many diseases in people

The researchers also found indications that moderate shifts in diet play a role in determining exactly what functions the microbes carry out in the gut.

“Our findings could have some exciting implications for people’s health,” said Jansson. “In the future, perhaps people could have designer diets, optimized according to their genes and their microbiome, to digest foods more effectively or to modulate their susceptibility to disease.”

Source:

DOE/Pacific Northwest National Laboratory

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Fatty acid produced by gut bacteria boosts the immune system

 

Fatty acid produced by gut bacteria boosts the immune system
In a mouse model for experimental colitis, a diet supplemented with butyric acid (SB, right panels) leads to decreased infiltration of inflammatory cells (CD4+ T cells [green] in the upper panels, and CD11b+ macrophages [red] and CD11c+ …more

New research from the RIKEN Center for Integrative Medical Sciences in Japan sheds light on the role of gut bacteria on the maturation of the immune system and provides evidence supporting the use of butyrate as therapy for inflammatory bowel diseases like Crohn’s disease.

Published in the journal Nature today, the Japanese study shows that butyrate, a by-product of the digestion of dietary fiber by gut microbes, acts as an epigenetic switch that boosts the by inducing the production of regulatory T in the gut.

Previous studies have shown that patients suffering from lack butyrate-producing bacteria and have lower levels of butyrate in their gut. However, butyrate’s anti-inflammatory properties were attributed to its role as main energy source for the cells lining the colon. This study is the first to provide a molecular basis for the role of butyrate on the production of regulatory T lymphocytes

The Japanese team, lead by Dr Hiroshi Ohno from RIKEN in collaboration with the University of Tokyo and Keio University, investigated the molecular mechanisms by which commensal microbes augment the number of regulatory T cells (Treg cells) present in the colon of mice that were bred germ-free.

Their research demonstrates that butyric acid, a short-chain fatty acid produced by commensal bacteria acts on naïve T cells to promote their differentiation into Treg cells. It achieves this through epigenetic changes that regulate the expression of the genes responsible for differentiation of naïve T cells into Treg cells.

The study shows that mice suffering from colitis see their levels of Treg cells increase and their symptoms improve after administration of butyrate as part of their diet.

“Regulatory T cells are important for the containment of excessive inflammatory responses as well as autoimmune disorders. Therefore these findings could be applicable for the prevention and treatment of inflammatory bowel disease (IBD), allergy and autoimmune disease,” said Dr Hiroshi Ohno.

“Butyrate is natural and safe as a therapy and in addition to that it is cheap, which could reduce costs for both patients and society,” Dr Ohno added.

Explore further: Collaborative effects of multiple bacterial strains in the gut may help prevent onset of certain inflammatory diseases

More information: Furusawa et al. “Commensal microbe-derived butyrate induces colonic regulatory T cells” Nature, 2013. DOI: 10.1038/nature12721

Pasteurised intestinal bacterium reduces effects of obesity and diabetes

 
Pasteurised intestinal bacterium reduces effects of obesity and diabetes
A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Hubert Plovier, Amandine Everard, Céline Druart et al. Advance Online Publication on Nature Medicine’s on …more

The intestinal bacterium Akkermansia proves to offer enduring benefits for the intestines of overweight mice and diabetic animals. In experiments, the strengthening effects of this bacterium on the intestinal barrier remained even after pasteurisation. This is the conclusion drawn by researchers of the Louvain Drug Research Institute of the University of Leuven in collaboration with researchers of the Wageningen University & Research and the University of Helsinki in Nature Medicine on 28 November. Their results help to pave the way for treatments against diabetes and obesity, but also against cardiovascular diseases and gastroenteritis.

In experiments with , the Leuven research groups led by Patrice Cani and the Wageningen and Helsinki groups led by Willem M. De Vos were able to stop the progression of obesity and diabetes type 2 in . To this end, the mice were given a special treatment with the intestinal bacterium Akkermansia muciniphila discovered in Wageningen.

The Leuven group established that the living form of Akkermansia reduces the effects of obesity and diabetes. Jointly the teams were able to establish that even after pasteurisation – heating above 70 degrees Celsius – Akkermansia still stopped the diseases’ progress in mice. Pasteurisation was performed in an attempt to make the bacterium inactive, but without destroying it or its characteristics. However, in its inactive state the bacterium continued to effectively combat the diseases. “This came as a complete surprise,” says Willem de Vos. “Even more surprising was the fact that the bacterium was partially more active after pasteurisation: not only reducing obesity and diabetes, but preventing these diseases from developing in the first place.”

Obesity and diabetes

Akkermansia’s effectiveness derives primarily from its inhibiting effect on , such as colitis or chronic .

The intestinal bacterium is currently being tested in Brussels on its applicability for patients suffering from and . The results are still expected, but the first clinical trial on the safety of administering the intestinal bacterium in inactivated form is positive.

The team discovered that the unexpected effect of the pasteurised Akkermansia bacterium is due to a protein in the external membrane of the bacterium, which was investigated in the Wageningen team by Dr Noora Ottman and Dr Clara Belzer. This protein – Amuc_1100* – remained functional after heating. Pasteurisation did inactivate the bacterium as a whole, but not the functional membrane protein that turns out to be responsible for the beneficial effect in mice. Isolating this protein makes it possible to develop a drug in concentrated form that could also be used in therapies against intestinal inflammation as a result of stress, alcoholism, liver disease and cancer.

The researchers have applied for a number of patents on their findings. In addition, a spin-off company is being developed to scale up production of both the Akkermansia bacterium and the protein.

Explore further: Gut microbe battles obesity

More information: Hubert Plovier et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice, Nature Medicine(2016). DOI: 10.1038/nm.4236

Bacterial Immunization Prevents PTSD-Like Symptoms in Mice

Summary: According to a new study, mice injected with a specific bacterium became more resilient to stress, showing less anxiety and fear in stressful situations.

Source: UCL.

Injecting mice with a UCL-discovered bacterium can reduce stress and inflammation, preventing them from developing PTSD-like conditions, finds a new international study led by the University of Colorado Boulder.

The research, published in Proceedings of the National Academy of Sciences, found that mice injected with the bacterium were more resilient to stress, showing less fear and anxiety in stressful situations. The immunization also changed serotonin activity in the brain, with similar beneficial effects to antidepressants or long-term exercise. Additionally, immunized mice were protected against colon inflammation which was caused or worsened by stress in unimmunized mice.

The bacterium, Mycobacterium vaccae (M. vaccae), is found naturally in soil and was first isolated and characterised at UCL by Professor John Stanford. Its immunological properties were investigated by Professor Graham Rook (UCL Infection & Immunity), a co-author on the new study. “The idea that a bacterium found in soil could prevent serious mental health problems might sound far-fetched, but bacteria can have a profound effect on both mental and physical health,” says Professor Rook. “Microorganisms in our bodies play a vital role regulating our immune systems and can help to reduce inflammation. As well as causing physical problems, inflammation is also a risk factor for several psychiatric disorders. Previous research has found that US Marines with evidence of inflammation in their body are more likely to develop PTSD, and the latest work suggests that bacterial immunization might help to reduce this risk. It shows that M. vaccae simultaneously prevents colitis and psychiatric symptoms by switching on regulatory pathways in the immune system.”

The study supports the ‘old friends’ hypothesis, which was first proposed by Professor Rook in 2003 as an update of the ‘hygiene hypothesis’.

“Our ancestors lived among a rich variety of microorganisms and our immune system evolved to function in this environment,” explains Professor Rook. “We now have much less contact with common microorganisms such as soil bacteria and our diets have changed leaving fewer nutrients available to gut bacteria. Without these ‘old friends’ helping to regulate the immune system, we are left at higher risk of inflammatory diseases and psychiatric disorders linked to chronic low-level inflammation. The new study supports the strategy of re-introducing humans to their ‘old friends’ to improve both mental and physical health.”

To test the effect of the M. vaccae bacteria on stress resilience, the researchers injected male mice with either a heat-killed sample of the bacterium or a placebo. The mice were then housed individually or with a dominant male for 19 days. Living with a dominant male is stressful and leads to submissive behaviour.

Image shows bacteria.

Mice that had been given M. vaccae were better at coping in this situation, acting less submissively and spending less time fleeing from or avoiding the dominant male. They were also less fearful and more willing to explore open environments when they were taken out of the housing on day 20. Previous studies in rodents and humans suggest that this response is a marker for reduced vulnerability to long-term anxiety and depressive-like symptoms.

“The immunized mice responded with a more proactive behavioural coping response to stress, a strategy that has been associated with stress resilience in animals and humans,” says Professor Christopher Lowry from the University of Colorado Boulder, senior author of the new research. “An injection of M. vaccae is not designed to target a particular antigen the way a vaccine would, but instead activates the individual’s immunoregulatory responses to protect from inappropriate inflammation.”

ABOUT THIS PTSD RESEARCH ARTICLE

Funding: This study was supported in part by a 2010 NARSAD Young Investigator Award (to C.A.L.); German Research Foundation Grant RE 2911/5-1 (to S.O.R.); the University of Colorado Boulder (C.A.L.); Award NSF-IOS 0845550 (to C.A.L.); and donations through the CU Foundation. The research of S.D.P. was supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES101744-04).

Source: Harry Dayantis – UCL
Image Source: This NeuroscienceNews.com image is adapted from the UCL press release.
Original Research: Full open access research for “Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice” by Stefan O. Reber, Philip H. Siebler, Nina C. Donner, James T. Morton, David G. Smith, Jared M. Kopelman, Kenneth R. Lowe, Kristen J. Wheeler, James H. Fox, James E. Hassell Jr., Benjamin N. Greenwood, Charline Jansch, Anja Lechner, Dominic Schmidt, Nicole Uschold-Schmidt, Andrea M. Füchsl, Dominik Langgartner, Frederick R. Walker, Matthew W. Hale, Gerardo Lopez Perez, Will Van Treuren, Antonio González, Andrea L. Halweg-Edwards, Monika Fleshner, Charles L. Raison, Graham A. Rook, Shyamal D. Peddada, Rob Knight, and Christopher A. Lowry in PNAS. Published online May 16 2016 doi:10.1073/pnas.1600324113

CITE THIS NEUROSCIENCENEWS.COM ARTICLE
UCL. “Bacterial Immunization Prevents PTSD-Like Symptoms in Mice.” NeuroscienceNews. NeuroscienceNews, 17 May 2016.
<http://neurosciencenews.com/ptsd-bacteria-psychology-4239/&gt;.

Abstract

Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice

The prevalence of inflammatory diseases is increasing in modern urban societies. Inflammation increases risk of stress-related pathology; consequently, immunoregulatory or antiinflammatory approaches may protect against negative stress-related outcomes. We show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation. Repeated immunization with a heat-killed preparation of Mycobacterium vaccae, an immunoregulatory environmental microorganism, reduced subordinate, flight, and avoiding behavioral responses to a dominant aggressor in a murine model of chronic psychosocial stress when tested 1–2 wk following the final immunization. Furthermore, immunization with M. vaccaeprevented stress-induced spontaneous colitis and, in stressed mice, induced anxiolytic or fear-reducing effects as measured on the elevated plus-maze, despite stress-induced gut microbiota changes characteristic of gut infection and colitis. Immunization with M. vaccae also prevented stress-induced aggravation of colitis in a model of inflammatory bowel disease. Depletion of regulatory T cells negated protective effects of immunization with M. vaccae on stress-induced colitis and anxiety-like or fear behaviors. These data provide a framework for developing microbiome- and immunoregulation-based strategies for prevention of stress-related pathologies.

“Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccaepromotes stress resilience in mice” by Stefan O. Reber, Philip H. Siebler, Nina C. Donner, James T. Morton, David G. Smith, Jared M. Kopelman, Kenneth R. Lowe, Kristen J. Wheeler, James H. Fox, James E. Hassell Jr., Benjamin N. Greenwood, Charline Jansch, Anja Lechner, Dominic Schmidt, Nicole Uschold-Schmidt, Andrea M. Füchsl, Dominik Langgartner, Frederick R. Walker, Matthew W. Hale, Gerardo Lopez Perez, Will Van Treuren, Antonio González, Andrea L. Halweg-Edwards, Monika Fleshner, Charles L. Raison, Graham A. Rook, Shyamal D. Peddada, Rob Knight, and Christopher A. Lowry in PNAS. Published online May 16 2016 doi:10.1073/pnas.1600324113

Single Species of Gut Bacteria Can Reverse Autism Related Social Behavior: Mouse Study

Summary: Researchers culture a strain of Lactobacillus reuteri from human breast milk and introduced it to mice. They discovered treatment with this bacterial strain appeared to rescue social behaviors.

Source: Cell Press.

The absence of a one specific species of gut bacteria causes social deficits in mice, researchers at Baylor College of Medicine report June 16, 2016 in Cell. By adding this bacteria species back to the guts of affected mice, the researchers were able to reverse some of their behavioral deficits, which are reminiscent of symptoms of autism spectrum disorders (ASDs) in humans. The investigators are now looking to explore the effects of probiotics on neurodevelopmental disorders in future work.

“Other research groups are trying to use drugs or electrical brain stimulation as a way to reverse some of the behavioral symptoms associated with neurodevelopmental disorders — but here we have, perhaps, a new approach,” says senior author Mauro Costa-Mattioli, a neuroscientist at Baylor College of Medicine. “Whether it would be effective in humans, we don’t know yet, but it is an extremely exciting way of affecting the brain from the gut.”

Diagram shows how dysbiosis causes the autism like behavior in mice.

The inspiration for the paper came from human epidemiological studies that have found that maternal obesity during pregnancy could increase children’s risk of developing neurodevelopmental disorders, including ASDs. In addition, some individuals with ASD also report recurring gastrointestinal problems. With emerging research showing how diet can change the gut microbiome and how gut microbes can influence the brain, Costa-Mattioli and his co-authors suspected there could be a connection.

To begin, the researchers fed approximately 60 female mice a high-fat diet that was the rough equivalent of consistently eating fast food multiple times a day. They bred the mice daily and waited for them to bear young. The offspring stayed with their mother for three weeks and then were weaned onto a normal diet. After a month, these offspring showed behavioral deficits, such as spending less time in contact with their peers and not initiating interactions.

“First we wanted to see if there was a difference in the microbiome between the offspring of mouse mothers fed a normal diet versus those of mothers fed a high-fat diet. So, we used 16S ribosomal RNA gene sequencing to determine the bacterial composition of their gut. We found a clear difference in the microbiota of the two maternal diet groups,” says first author Shelly Buffington, a postdoctoral fellow in Costa-Mattioli’s lab. “The sequencing data was so consistent that by looking at the microbiome of an individual mouse we could predict whether its behavior would be impaired.”

Buffington next tested whether the specific differences in the microbiome were causative factors underlying the social impairments in offspring of mothers fed a high-fat diet. Because mice eat each other’s poop, the researchers housed the animals together so that they would acquire microbiota from their cagemates. When socially impaired three-week-old mice born to mothers on a high-fat diet were paired with normal mice, a full restoration of the gut microbiome and a concurrent improvement in behavior was observed within four weeks. The investigators concluded that one or more beneficial bacterial species might be important for normal social behavior. Fecal-transplant experiments in mice without microbiota (germ-free mice) provided causal evidence that an imbalanced microbial ecology in the mice born to mothers on a high-fat diet is responsible for their social deficits.

The investigators next wanted to know the specific bacterial species that could be affecting the social behavior of the mice. Whole-genome shotgun sequencing revealed one type of bacteria, Lactobacillus reuteri, which was reduced more than nine-fold in the microbiome of mice born to mothers on the high-fat diet.

“We cultured a strain of Lactobacillus (L.) reuteri originally isolated from human breast milk and introduced it into the water of the high-fat-diet offspring. We found that treatment with this single bacterial strain was able to rescue their social behavior,” Buffington says. Other ASD-related behaviors, such as anxiety, were not restored by the reconstitution of the bacteria. Interestingly, the authors found that L. reuteri also promoted the production of the “bonding hormone” oxytocin, which is known to play a crucial role in social behavior and has been associated with autism in humans.

Can mom’s diet during pregnancy impact offspring social behavior? In this video, Mauro Costa-Mattioli and colleagues at Baylor College of Medicine describe a potential link between mouse maternal diet-induced changes in the gut microbiome and autism-like social behavior in offspring.

The authors wondered whether the reward circuitry in the socially impaired mice was dysfunctional. “We found that in response to social interaction there was a lack of synaptic potentiation in a key reward area of the brain that could be seen in the normal control mice,” Costa-Mattiol says. “When we put the bacteria back in the maternal-high-fat-diet offspring, we could also restore the changes in synaptic function in the reward circuitry.”

The researchers believe that their work, which uses a human bacteria species to promote oxytocin levels and improve social behavioral deficits in deficient mice, could be explored as a probiotic intervention for the treatment of neurodevelopmental disorders in humans. “This is where the science is unexpectedly leading us. We could potentially see this type of approach developing quite quickly not only for the treatment of ASD but also for other neurodevelopmental disorders; anyway, this is my gut feeling,” Costa-Mattioli says.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Others who contributed to the research include Gonzalo Viana Di Prisco, Thomas A. Auchtung, Nadim J. Ajami, and Joseph F. Petrosino, all at Baylor College of Medicine.

Funding: The research was supported by funding from the National Institutes of Health, the Alkek Foundation, and Baylor College of Medicine.

Source: Joseph Caputo – Cell Press
Image Source: This NeuroscienceNews.com image is credited to Costa-Mattioli et al./Cell Press
Video Source: The video is credited to Baylor College of Medicine.
Original Research: Full open access research for “Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring” by Shelly A. Buffington, Gonzalo Viana Di Prisco, Thomas A. Auchtung, Nadim J. Ajami, Joseph F. Petrosino, and Mauro Costa-Mattioli in Cell. Published online June 16 2016 doi:10.1016/j.cell.2016.06.001

CITE THIS NEUROSCIENCENEWS.COM ARTICLE
Cell Press. “Single Species of Gut Bacteria Can Reverse Autism Related Social Behavior: Mouse Study.” NeuroscienceNews. NeuroscienceNews, 16 June 2016.
<http://neurosciencenews.com/autism-behavior-gut-bacteria-4493/&gt;.

Abstract

Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring

Highlights
•Maternal high-fat diet (MHFD) induces behavioral alterations in offspring
•MHFD causes alterations in gut microbial ecology in offspring
•MHFD offspring show deficient synaptic plasticity in the VTA and oxytocin production
•L. reuteri treatment restores oxytocin levels, VTA plasticity and social behaviors

Summary
Maternal obesity during pregnancy has been associated with increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. Here, we report that maternal high-fat diet (MHFD) induces a shift in microbial ecology that negatively impacts offspring social behavior. Social deficits and gut microbiota dysbiosis in MHFD offspring are prevented by co-housing with offspring of mothers on a regular diet (MRD) and transferable to germ-free mice. In addition, social interaction induces synaptic potentiation (LTP) in the ventral tegmental area (VTA) of MRD, but not MHFD offspring. Moreover, MHFD offspring had fewer oxytocin immunoreactive neurons in the hypothalamus. Using metagenomics and precision microbiota reconstitution, we identified a single commensal strain that corrects oxytocin levels, LTP, and social deficits in MHFD offspring. Our findings causally link maternal diet, gut microbial imbalance, VTA plasticity, and behavior and suggest that probiotic treatment may relieve specific behavioral abnormalities associated with neurodevelopmental disorders.

“Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring” by Shelly A. Buffington, Gonzalo Viana Di Prisco, Thomas A. Auchtung, Nadim J. Ajami, Joseph F. Petrosino, and Mauro Costa-Mattioli in Cell. Published online June 16 2016 doi:10.1016/j.cell.2016.06.001

Chronic Fatigue Syndrome Is Not in Your Head, It’s in Your Gut

Summary: Researchers have identified biomarkers for chronic fatigue syndrome in gut bacteria and in inflammatory microbial agents in the blood.

Source: Cornell University.

Physicians have been mystified by chronic fatigue syndrome, a condition where normal exertion leads to debilitating fatigue that isn’t alleviated by rest. There are no known triggers, and diagnosis requires lengthy tests administered by an expert.

Now, for the first time, Cornell University researchers report they have identified biological markers of the disease in gut bacteria and inflammatory microbial agents in the blood.

In a study published June 23 in the journal Microbiome, the team describes how they correctly diagnosed myalgic encephalomyeletis/chronic fatigue syndrome (ME/CFS) in 83 percent of patients through stool samples and blood work, offering a noninvasive diagnosis and a step toward understanding the cause of the disease.

“Our work demonstrates that the gut bacterial microbiome in chronic fatigue syndrome patients isn’t normal, perhaps leading to gastrointestinal and inflammatory symptoms in victims of the disease,” said Maureen Hanson, the Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell and the paper’s senior author. “Furthermore, our detection of a biological abnormality provides further evidence against the ridiculous concept that the disease is psychological in origin.”

“In the future, we could see this technique as a complement to other noninvasive diagnoses, but if we have a better idea of what is going on with these gut microbes and patients, maybe clinicians could consider changing diets, using prebiotics such as dietary fibers or probiotics to help treat the disease,” said Ludovic Giloteaux, a postdoctoral researcher and first author of the study.

In the study, Ithaca campus researchers collaborated with Dr. Susan Levine, an ME/CFS specialist in New York City, who recruited 48 people diagnosed with ME/CFS and 39 healthy controls to provide stool and blood samples.

The researchers sequenced regions of microbial DNA from the stool samples to identify different types of bacteria. Overall, the diversity of types of bacteria was greatly reduced and there were fewer bacterial species known to be anti-inflammatory in ME/CFS patients compared with healthy people, an observation also seen in people with Crohn’s disease and ulcerative colitis.

Image shows gut bacteria.

At the same time, the researchers discovered specific markers of inflammation in the blood, likely due to a leaky gut from intestinal problems that allow bacteria to enter the blood, Giloteaux said.

Bacteria in the blood will trigger an immune response, which could worsen symptoms.

The researchers have no evidence to distinguish whether the altered gut microbiome is a cause or a whether it is a consequence of disease, Giloteaux added.

In the future, the research team will look for evidence of viruses and fungi in the gut, to see whether one of these or an association of these along with bacteria may be causing or contributing to the illness.

ABOUT THIS NEUROLOGY RESEARCH ARTICLE

Funding: The study was funded by the National Institutes of Health.

Source: Melissa Osgood – Cornell University
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Original Research: Full open access research for for “Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome” by Ludovic Giloteaux, Julia K. Goodrich, William A. Walters, Susan M. Levine, Ruth E. Ley and Maureen R. Hanson in Microbiome. Published online June 23 2016 doi:10.1186/s40168-016-0171-4

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Cornell University. “Chronic Fatigue Syndrome Is Not in Your Head, It’s in Your Gut.” NeuroscienceNews. NeuroscienceNews, 27 June 2016.
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Abstract

Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome

Background
Gastrointestinal disturbances are among symptoms commonly reported by individuals diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, whether ME/CFS is associated with an altered microbiome has remained uncertain. Here, we profiled gut microbial diversity by sequencing 16S ribosomal ribonucleic acid (rRNA) genes from stool as well as inflammatory markers from serum for cases (n = 48) and controls (n = 39). We also examined a set of inflammatory markers in blood: C-reactive protein (CRP), intestinal fatty acid-binding protein (I-FABP), lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble CD14 (sCD14).

Results
We observed elevated levels of some blood markers for microbial translocation in ME/CFS patients; levels of LPS, LBP, and sCD14 were elevated in ME/CFS subjects. Levels of LBP correlated with LPS and sCD14 and LPS levels correlated with sCD14. Through deep sequencing of bacterial rRNA markers, we identified differences between the gut microbiomes of healthy individuals and patients with ME/CFS. We observed that bacterial diversity was decreased in the ME/CFS specimens compared to controls, in particular, a reduction in the relative abundance and diversity of members belonging to the Firmicutes phylum. In the patient cohort, we find less diversity as well as increases in specific species often reported to be pro-inflammatory species and reduction in species frequently described as anti-inflammatory. Using a machine learning approach trained on the data obtained from 16S rRNA and inflammatory markers, individuals were classified correctly as ME/CFS with a cross-validation accuracy of 82.93 %.

Conclusions
Our results indicate dysbiosis of the gut microbiota in this disease and further suggest an increased incidence of microbial translocation, which may play a role in inflammatory symptoms in ME/CFS.

“Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome” by Ludovic Giloteaux, Julia K. Goodrich, William A. Walters, Susan M. Levine, Ruth E. Ley and Maureen R. Hanson in Microbiome. Published online June 23 2016 doi:10.1186/s40168-016-0171-4