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

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

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

NIH…Turning Discovery Into Health®


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

A Window to the Gut’s Brain

Summary: Researchers have developed a new system that allows for real time viewing of the enteric nervous system, and could provide a new way to identify gastrointestinal disorders.

Source: Duke University.

Real-time view of enteric nervous system provides new way to study gastrointestinal disorders.

Duke researchers have developed a system that allows real-time optical and electrical observations of the gut’s nervous system in a live animal.

And if you weren’t aware that the gut had its own nervous system, don’t worry, you’re not alone.

“The first time I ever heard of the enteric nervous system was two years ago, and I was like ‘What’s that?’” said Xiling Shen, associate professor of biomedical engineering at Duke University and author of the study appearing June 7 in Nature Communications. “Even with neurobiologists, their only exposure to it is typically something like a half-page in a textbook. But it’s actually very important.”

Consisting of five times more neurons than the spinal cord and often termed as a “second brain,” the enteric nervous system is a mesh-like sheath of neurons that controls the gastrointestinal tract. It regulates how food moves through the digestive system and communicates potential problems to the immune system. And while it has a direct line to both the brain and spinal cord, the enteric system has the ability to direct the organs under its control independent of either system.

Image shows ens.

Despite its importance, however, very little is known about the enteric nervous system, such as how it responds to medications or what can go wrong with it to cause disease.

“About one-quarter of the world’s population is affected by a functional gastrointestinal disorder,” Shen said. “You’ve probably heard of the term functional GI disorder, which encompasses diseases like irritable bowel syndrome, constipation and incontinence. If you look at the physiology in these diseases, the gut looks fine. It’s the nerves that are somehow malfunctioning. And the reason the term includes so many diseases is because we really don’t have any idea what’s going on with those nerves.”

Shen is looking to change that by literally installing an observation window.

In the new study, Shen implanted a transparent window made of tough borosilicate glass into the skin over the stomachs of mice. With no skull or bone structures to anchor the window, he needed to devise a 3D-printed surgical insert for stabilization. The device prevents the intestines from moving too much while maintaining normal digestive functions, allowing researchers to look at the same spot over multiple days.

Being the first to get a live look at the enteric nervous system, Shen was not about to waste the view. Because the gut can be a busy, noisy environment, he devised a system to record both electrical and optical activity at the same time — also a first for the field.
The experiment uses transgenic mice with nerves that light up with a green hue when firing. By using a transparent graphene sensor to obtain electrical signals from the nerves, Shen gained an unobstructed view of the neural activity.

uke biomedical engineer Xiling Shen has created the first system that allows direct observation of the neurons that make up the enteric nervous system — your gut’s brain. Genetic alterations make the neurons in this rat’s gut glow green when they fire. This video shows one of the first views of the enteric nervous system in action.

The optical signal gives spatial resolution, allowing researchers to tell which neuron is firing. The electrical signal provides time resolution, which pins down the exact waveform of the firing neurons. Shen said the enteric nervous system is now ready to be explored.

“So much is known about the brain and spinal cord because we can open them up, look at them, record the neural activities and map their behaviors,” said Shen. “Now we can start doing the same for the gut.

We can see how it reacts to different drugs, neurotransmitters or diseases. We have even artificially activated individual neurons in the gut with light, which nobody has ever done before. This innovation will help us understand this ‘dark’ nervous system that we currently have completely no idea about.”


Funding: This research was supported by the DARPA Electrical Prescriptions Program (N66001-15-2-4059) and the National Institutes of Health (R01GM114254).

Source: Ken Kingery – Duke University
Image Source: This image is credited to Cheng Fang.
Video Source: Video is credited to Duke Engineering.
Original Research: Full open access research for “Simultaneous optical and electrical in vivo analysis of the enteric nervous system” by Nikolai Rakhilin, Bradley Barth, Jiahn Choi, Nini L. Muñoz, Subhash Kulkarni, Jason S. Jones, David M. Small, Yu-Ting Cheng, Yingqiu Cao, Colleen LaVinka, Edwin Kan, Xinzand& Xiling Shen in Nature Communications. Published online June 7 2016 doi:10.1038/ncomms11800

Duke University. “A Window to the Gut’s Brain.” NeuroscienceNews. NeuroscienceNews, 7 June 2016.


Simultaneous optical and electrical in vivo analysis of the enteric nervous system

The enteric nervous system (ENS) is a major division of the nervous system and vital to the gastrointestinal (GI) tract and its communication with the rest of the body. Unlike the brain and spinal cord, relatively little is known about the ENS in part because of the inability to directly monitor its activity in live animals. Here, we integrate a transparent graphene sensor with a customized abdominal window for simultaneous optical and electrical recording of the ENS in vivo. The implanted device captures ENS responses to neurotransmitters, drugs and optogenetic manipulation in real time.

“Simultaneous optical and electrical in vivo analysis of the enteric nervous system” by Nikolai Rakhilin, Bradley Barth, Jiahn Choi, Nini L. Muñoz, Subhash Kulkarni, Jason S. Jones, David M. Small, Yu-Ting Cheng, Yingqiu Cao, Colleen LaVinka, Edwin Kan, Xinzand& Xiling Shen in Nature Communications. Published online June 7 2016 doi:10.1038/ncomms11800

Changes Uncovered in Gut Bacteria of People with Multiple Sclerosis

Summary: A new study reveals changes in the gut microbiomes of untreated and treated multiple sclerosis patients.

Source: Bingham and Women’s Hospital.

Study finds alterations in the gut microbiomes of treated and untreated MS patients.

A connection between the bacteria living in the gut and immunological disorders such as multiple sclerosis have long been suspected, but for the first time, researchers have detected clear evidence of changes that tie the two together. Investigators from Brigham and Women’s Hospital (BWH) have found that people with multiple sclerosis have different patterns of gut microorganisms than those of their healthy counterparts. In addition, patients receiving treatment for MS have different patterns than untreated patients. The new research supports recent studies linking immunological disorders to the gut microbiome and may have implications for pursuing new therapies for MS.

“Our findings raise the possibility that by affecting the gut microbiome, one could come up with treatments for MS – treatments that affect the microbiome, and, in turn, the immune response,” said Howard L. Weiner, MD, director of the Partners MS Center and co-director of the Ann Romney Center for Neurologic Disease at Brigham Women’s Hospital, . “There are a number of ways that the microbiome could play a role in MS and this opens up a whole new world of looking at the disease in a way that it’s never been looked at before.”

Weiner and colleagues conducted their investigations using data and samples from subjects who are part of the CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis) study at Brigham and Women’s Hospital. The team analyzed stool samples from 60 people with MS and 43 control subjects, performing gene sequencing to detect differences in the microbial communities of the subjects.

Samples from MS patients contained higher levels of certain bacterial species – including Methanobrevibacter and Akkermansia – and lower levels of others – such as Butyricimonas – when compared to healthy samples. Other studies have found that several of these microorganisms may drive inflammation or are associated with autoimmunity. Importantly, the team also found that microbial changes in the gut correlated with changes in the activity of genes that play a role in the immune system. The team also collected breath samples from subjects, finding that, as a result of increased levels of Methanobrevibacter, patients with MS had higher levels of methane in their breath samples.

Image shows a graph.

The researchers also investigated the gut microbe communities of untreated MS patients, finding that MS disease-modifying therapy appeared to normalize the gut microbiomes of MS patients. The researchers note that further study will be required to determine the exact role that these microbes may be playing in the progression of disease and whether or not modifying the microbiome may be helpful in treating MS. They plan to continue to explore the connection between the gut and the immune system in a larger group of patients and follow changes over time to better understand disease progression and interventions.

“This work provides a window into how the gut can affect the immune system which can then affect the brain,” said Weiner, who is also a professor of Neurology at Harvard Medical School. “Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are at risk.”


Funding: Funding support for this work included grants from the NIH/NINDS, The National Multiple Sclerosis Society and from The Harvard Digestive Disease Center.

Source: Haley Bridger – Bingham and Women’s Hospital
Image Source: This image is credited to Howard Weiner, Brigham and Women’s Hospital.
Original Research: Full open access research for “Alterations of the human gut microbiome in multiple sclerosis” by Sushrut Jangi, Roopali Gandhi, Laura M. Cox, Ning Li, Felipe von Glehn, Raymond Yan, Bonny Patel, Maria Antonietta Mazzola, Shirong Liu, Bonnie L. Glanz, Sandra Cook, Stephanie Tankou, Fiona Stuart, Kirsy Melo, Parham Nejad, Kathleen Smith, Begüm D. Topçuolu, James Holden, Pia Kivisäkk, Tanuja Chitnis, Philip L. De Jager, Francisco J. Quintana, Georg K. Gerber, Lynn Bry and Howard L. Weiner in Nature Communications. Published online June 28 2016 doi:10.1038/ncomms12015

Bingham and Women’s Hospital. “Changes Uncovered in Gut Bacteria of People with Multiple Sclerosis.” NeuroscienceNews. NeuroscienceNews, 12 July 2016.


Alterations of the human gut microbiome in multiple sclerosis

The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis.

“Alterations of the human gut microbiome in multiple sclerosis” by Sushrut Jangi, Roopali Gandhi, Laura M. Cox, Ning Li, Felipe von Glehn, Raymond Yan, Bonny Patel, Maria Antonietta Mazzola, Shirong Liu, Bonnie L. Glanz, Sandra Cook, Stephanie Tankou, Fiona Stuart, Kirsy Melo, Parham Nejad, Kathleen Smith, Begüm D. Topçuolu, James Holden, Pia Kivisäkk, Tanuja Chitnis, Philip L. De Jager, Francisco J. Quintana, Georg K. Gerber, Lynn Bry and Howard L. Weiner in Nature Communications. Published online June 28 2016 doi:10.1038/ncomms12015

Gut Busting: How Gaseous Substances in the Body Affect Psyche and Behavior

Summary: A new study reports on the role gasotransmitters play in behavior and psychology.

Source: Lomonosov Moscow State University.

Professor Alexander Oleskin from the Faculty of Biology of the Lomonosov Moscow State University and his colleague Professor Boris Shenderov from the Gabrichevsky Moscow Research Institute of Epidemiology and Microbiology published an article devoted to the review of gaseous neurotransmitters of microbial origin and their role in the human body.

The results of the research were published in Microbial Ecology in Health and Disease.

‘Our brain cannot work without neurotransmitters, i.e., substances that transmit impulses from one nerve cell to another. One of the classes of neurotransmitters are gaseous substances (gasotransmitters). Our brain uses gases such as hydrogen sulfide, ammonia, and even carbon monoxide to transfer information between cells,’ Alexander Oleskin tells.’Bacteria that inhabit our body (and especially the intestine), also form gasotransmitters that affect our brain, mind and behavior.’

Gasotransmitters are gaseous substances produced in various organs and tissues. The name “gasotransmitters” is related to the term “neurotransmitters”. These are substances that serve for the transmission of impulses between nerve cells, including the brain, where such gas transmitters as NO, CO and H2S are generated by means of special enzymes.

The review article provides an extensive analysis of the data related to the mechanisms of action of gaseous substances of microbial origin (among them: nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S), methane (CH4), hydrogen (H2), ammonia (NH3), etc.). They are considered asregulators ofthe human behavior, neurophysiological and mental disorders. The above mentioned gases are among the smallest biologically active molecules which perform vital functions of both multi-cellular organisms and bacteria.They act as mediators and regulators in intercellular interactions in the bodies of mammals.

Importantly, substances that act as gasotransmitters are synthesized in the gastrointestinal tract both by the cells of the host organism and a variety of gastrointestinal microorganisms that inhabit it, including Archaea, Bacteroides, Bifidobacterium, Butyrivibrio, Clostridium, Collinsella, Coprococcus, Desulfovibrio, Eubacterium, Lactobacillus, Prevotella, Propionibacterium, Roseburia, and others.

The gastrointestinal (GI) tract of an adult contains about 20 ml of various gaseous products, producing from 400 to 1200 ml per day. Nitrogen, oxygen, hydrogen, methane, carbon dioxide and hydrogen sulfide constitute 20-90%, 3.9-10%, 20.9-50% 7.2-10%, 9-30% and 0.00028% respectively of the total volume. Their numbers vary depending on the human’s diet. The gaseous products are formed as the result of various eukaryotic (human) and prokaryotic (bacterial) cells’ activity by enzymatic or non-enzymatic processes, and can also be gripped together with air and food. The majority of the gas molecules is removed from the intestines: they are absorbed and transferred to the bloodstream, and eventually removed from the body through the respiratory system.

Gasotransmitters play a dual role in the body. They may serve as energy sources, also for the inhabiting microbes. For instance, a typical symbiont isthe intestinal bacterium Escherichia coli (E. coli), which lives in the digestive tract, using nitric oxide (NO) generated by the host cells as an energy source for their own metabolism. As nitric oxide is also produced actively by the immune cells during inflammation, it turns out that E. coli is ‘interested’ in thedevelopment of an inflammation in the intestines.

Gasotransmitters are involved both in the communication between microbial cells and the “dialogue” between the microbial “life partners” and the host cells. The nitric oxide (NO)producedby the host organism or microbes regulates the functioning of the immune and cardiovascular systems and acts as a brain neurotransmitter involved inthe regulation of learning and cognitive activities. Under experimental conditions, mice deficient in one of the nitric oxide forming enzymes (neuronal NO-synthase) exhibit increased motor and sexual activity and long-term depression.

Hydrogen sulphide (H2S) at low concentrations regulates a number of processes in various human organs, especially the cardiovascular and nervous systems. Hydrogen sulfide acts as a neuroprotector: the effect of its insufficient concentration on the nervous system was demonstrated in studies with patients with epileptic seizures, psychiatric disorders, or pathological changes in the electroencephalogram. Many of these patients are deficient in enzymes which produce hydrogen sulfide in the body. Patients with the Down syndrome, by contrast, have an increased activity of the enzymes that form hydrogen sulfide.

An excess of ammonia (NH3) in the body (hyperammonemia), may be due to disorders in the gastrointestinal tract microbiota (dysbiosis). It results in accumulation of significant concentrations of NH3 in the brain. This situation is characteristic of liver cirrhosis and poses the threat of hepatic encephalopathy.

Gasotransmitters affect the cell that formed them (autocrine action), adjacent cells (paracrine action), and distant tissues and organs and the whole body systemically (endocrine action). The production of the gas transmitters and the distribution to various areas of the body depends on the activity of the cells forming the material of both of the body and the microbial symbionts. The concentrations and activities of gas transmitters are under a combined influence of the brain and the entire nervous system (including intestinal nerve cells that constitute the enteric nervous system), the immune system.They are also influenced by the gastrointestinal microbiota and that of other body areas (the skin, the respiratory tract, the uro-genital tract etc.).

‘Prospectively the research findings will be implemented in medical and psychiatric practice. They will serve for the treatment and prevention of neuropsychiatric disorders (including depression, increased aggressiveness, and others) using microbial gas transmitters. It seems feasiblefor instance, to attempt to normalize the amount of ammonia with the help of bacteria that will be introduced into the body in a goal-directed fashion’, hypothesizes Alexander Oleskin.

Diagram shows how NO functions in the human body.

There are some developmentsin this direction. They are based on useful microorganisms, i.e., probiotics that can be consumed with milk products (yoghurt, cheese etc.), or in pharmaceutical formulations. The novelty lies in the approach to the use of such probiotics: they help administering potentially poisonous gases in minute amounts to improve human health and promote adequate behavior. Probiotic strains of lactobacilli, bifidobacteria, and E. coli actively synthesize one of the most important multifunctional gas transmitters – nitric oxide; moreover, probiotics additionally stimulate the nitric oxide production by the cells of the host organism.

The term ‘psychobiotics’ has recently been introduced to designate the probiotic bacterial strains that are used as dietary supplements to optimize functioning of the brain and the whole body activities by making good use of h the beneficial effects of microbial products, including gas transmitters, on the brain and behavior.


Source: Vladimir Koryagin – Lomonosov Moscow State University
Image Source: This image is credited to Lomonosov Moscow State University.
Original Research: Full open access research for “Neuromodulatory effects and targets of the SCFAs and gasotransmitters produced by the human symbiotic microbiota” by Alexander V. Oleskin and Boris A. Shenderov in Microbial Ecology in Health and Disease. Published online July 5 2016 doi:10.3402/mehd.v27.30971

Lomonosov Moscow State University. “Gut Busting: How Gaseous Substances in the Body Affect Psyche and Behavior.” NeuroscienceNews. NeuroscienceNews, 26 July 2016.


Neuromodulatory effects and targets of the SCFAs and gasotransmitters produced by the human symbiotic microbiota

The symbiotic gut microbiota plays an important role in the development and homeostasis of the host organism. Its physiological, biochemical, behavioral, and communicative effects are mediated by multiple low molecular weight compounds. Recent data on small molecules produced by gut microbiota in mammalian organisms demonstrate the paramount importance of these biologically active molecules in terms of biology and medicine. Many of these molecules are pleiotropic mediators exerting effects on various tissues and organs. This review is focused on the functional roles of gaseous molecules that perform neuromediator and/or endocrine functions. The molecular mechanisms that underlie the effects of microbial fermentation-derived gaseous metabolites are not well understood. It is possible that these metabolites produce their effects via immunological, biochemical, and neuroendocrine mechanisms that involve endogenous and microbial modulators and transmitters; of considerable importance are also changes in epigenetic transcriptional factors, protein post-translational modification, lipid and mitochondrial metabolism, redox signaling, and ion channel/gap junction/transporter regulation. Recent findings have revealed that interactivity among such modulators/transmitters is a prerequisite for the ongoing dialog between microbial cells and host cells, including neurons. Using simple reliable methods for the detection and measurement of short-chain fatty acids (SCFAs) and small gaseous molecules in eukaryotic tissues and prokaryotic cells, selective inhibitors of enzymes that participate in their synthesis, as well as safe chemical and microbial donors of pleiotropic mediators and modulators of host intestinal microbial ecology, should enable us to apply these chemicals as novel therapeutics and medical research tools.

“Neuromodulatory effects and targets of the SCFAs and gasotransmitters produced by the human symbiotic microbiota” by Alexander V. Oleskin and Boris A. Shenderov in Microbial Ecology in Health and Disease. Published online July 5 2016 doi:10.3402/mehd.v27.30971

Targeting the Gut-Brain Connection Can Impact Immunity

Summary: Researchers report that manipulating dopamine signaling in the nervous system of C. elegans can control inflammation in the gut.

Source: Duke.

Drugs aimed at nervous system act on immune system as well.

There’s a reason it’s called a gut feeling. The brain and the gut are connected by intricate neural networks that signal hunger and satiety, love and fear, even safety and danger. These networks employ myriad chemical signals that include dopamine, a powerful neurotransmitter most famous for its role in reward and addiction.

Duke University researchers have shown that manipulating dopamine signaling in the nervous system of the nematode worm C. elegans can control inflammation in the gut.

The study, which appears Aug. 12 in Current Biology, provides a proof of principle that the immune system can be controlled using drugs originally designed to target the nervous system, such as antipsychotics.

“We are talking about an existing set of drugs and drug targets that could open up the spectrum of potential therapeutic applications by targeting pathways that fine-tune the inflammatory response,” said Alejandro Aballay, Ph.D., a professor of molecular genetics and microbiology at Duke School of Medicine.

“It is a big leap from worms to humans, but the idea of targeting the nervous system to control the immune system could potentially be used to treat conditions such as rheumatoid arthritis, autoimmune disease, cancer, inflammatory bowel disease, and Crohn’s disease,” Aballay said.

Recent research suggests that the wiring between the gut and the brain is involved in many other maladies, including autism, anxiety, depression, Alzheimer’s disease, and Parkinson’s disease.

Aballay believes that C. elegans provides an excellent model for dissecting this complex cross-talk between the nervous system and the immune system. This tiny, transparent worm has a simple nervous system, consisting of only 302 neurons compared to the roughly 100 billion neurons in the human brain. Yet the worm also has a very basic, rudimentary immune system.

Aballay and his team first stumbled upon the gut-brain connection a few years ago when they were studying the immune system of C. elegans. The worms were subjected to a barrage of chemicals in search of immune activators that could protect against bacterial infections. Out of more than a thousand different chemical compounds, they identified 45 that turned on an immune pathway. Curiously, half of those were involved in the nervous system, and a handful blocked the activity of dopamine.

In this study, Aballay decided to examine the effects of dopamine and dopamine signaling pathways on immunity.

Image shows a C. elegans.

Graduate student Xiou Cao blocked dopamine by treating animals with chlorpromazine, a dopamine antagonist drug used to treat schizophrenia and manic depression in humans. He found that these worms were more resistant to infection by the common pathogen Pseudomonas aeruginosa than counterparts that hadn’t received the drug.

When Cao then treated the animals with dopamine, it generated the opposite effect, rendering them more susceptible to infection.

The researchers believe their findings indicate that dopamine signaling acts by putting the brakes on the body’s inflammatory response so it doesn’t go too far.

“Worms have evolved mechanisms to deal with colonizing bacteria,” Aballay said. “That is true for us as well. Humans have trillions of microorganisms in our guts, and we have to be careful when activating antimicrobial defenses so that we mainly target potentially harmful microbes, without damaging our good bacteria — or even our own cells — in the process.”

“The nervous system appears to be the perfect system for integrating all these different physiological cues to keep the amount of damage in check,” Aballay said.

Aballay plans continue his studies in C. elegans to identify the different cues involved in fine-tuning the immune response. He also thinks it is worth looking at different analogues or different doses of dopamine antagonists to see if their effects on psychosis can be separated from their effects on immunity.


Funding: The research was supported by the National Institutes of Health (GM0709077 and AI117911).

Source: Robin Smith – Duke
Image Source: This image is credited to Alejandro Aballay Lab, Duke University.
Original Research: Abstract for “Neural Inhibition of Dopaminergic Signaling Enhances Immunity in a Cell-Non-autonomous Manner” by Xiou Cao and Alejandro Aballay in Current Biology. Published online August 11 2016 doi:10.1016/j.cub.2016.06.036

Duke. “Targeting the Gut-Brain Connection Can Impact Immunity.” NeuroscienceNews. NeuroscienceNews, 11 August 2016.


Neural Inhibition of Dopaminergic Signaling Enhances Immunity in a Cell-Non-autonomous Manner

•Inhibition of dopamine signaling protects against bacterial infections
•Chlorpromazine enhances immunity by inhibiting a D1-like dopamine receptor
•Dopamine signaling regulates p38 MAP kinase activity
•Dopaminergic neurons control immunity in the C. elegans intestine

The innate immune system is the front line of host defense against microbial infections, but its rapid and uncontrolled activation elicits microbicidal mechanisms that have deleterious effects. Increasing evidence indicates that the metazoan nervous system, which responds to stimuli originating from both the internal and the external environment, functions as a modulatory apparatus that controls not only microbial killing pathways but also cellular homeostatic mechanisms. Here we report that dopamine signaling controls innate immune responses through a D1-like dopamine receptor, DOP-4, in Caenorhabditis elegans. Chlorpromazine inhibition of DOP-4 in the nervous system activates a microbicidal PMK-1/p38 mitogen-activated protein kinase signaling pathway that enhances host resistance against bacterial infections. The immune inhibitory function of dopamine originates in CEP neurons and requires active DOP-4 in downstream ASG neurons. Our findings indicate that dopamine signaling from the nervous system controls immunity in a cell-non-autonomous manner and identifies the dopaminergic system as a potential therapeutic target for not only infectious diseases but also a range of conditions that arise as a consequence of malfunctioning immune responses.

“Neural Inhibition of Dopaminergic Signaling Enhances Immunity in a Cell-Non-autonomous Manner” by Xiou Cao and Alejandro Aballay in Current Biology. Published online August 11 2016 doi:10.1016/j.cub.2016.06.036

Parkinson’s Disease Linked to Gut Microbiome

Summary: A new study reports a link between the deterioration of motor skills in Parkinson’s disease and alterations in the composition of populations of gut bacteria.

Source: California Institute of Technology.

Caltech scientists have discovered for the first time a functional link between bacteria in the intestines and Parkinson’s disease (PD). The researchers show that changes in the composition of gut bacterial populations–or possibly gut bacteria themselves–are actively contributing to and may even cause the deterioration of motor skills that is the hallmark of this disease.

The work–which has profound implications for the treatment of PD–was performed in the laboratory of Sarkis Mazmanian, the Luis B. and Nelly Soux Professor of Microbiology and Heritage Medical Research Institute Investigator, and appears in the December 1 issue of Cell.

PD affects 1 million people in the US and up to 10 million worldwide, making it the second most common neurodegenerative disease. Characteristic features of PD include symptoms such as tremors and difficulty walking, aggregation of a protein called alpha-synuclein (αSyn) within cells in the brain and gut, and the presence of inflammatory molecules called cytokines within the brain. In addition, 75 percent of people with PD have gastrointestinal (GI) abnormalities, primarily constipation.

“The gut is a permanent home to a diverse community of beneficial and sometimes harmful bacteria, known as the microbiome, that is important for the development and function of the immune and nervous systems,” Mazmanian says. “Remarkably, 70 percent of all neurons in the peripheral nervous system–that is, not the brain or spinal cord–are in the intestines, and the gut’s nervous system is directly connected to the central nervous system through the vagus nerve. Because GI problems often precede the motor symptoms by many years, and because most PD cases are caused by environmental factors, we hypothesized that bacteria in the gut may contribute to PD.”

To test this, the researchers utilized mice that overproduce αSyn and display symptoms of Parkinson’s. One group of mice had a complex consortium of gut bacteria; the others, called germ-free mice, were bred in a completely sterile environment at Caltech and thus lacked gut bacteria. The researchers had both groups of mice perform several tasks to measure their motor skills, such as running on treadmills, crossing a beam, and descending from a pole. The germ-free mice performed significantly better than the mice with a complete microbiome.

“This was the ‘eureka’ moment,” says Timothy Sampson, a postdoctoral scholar in biology and biological engineering and first author on the paper. “The mice were genetically identical; both groups were making too much αSyn. The only difference was the presence or absence of gut microbiota. Once you remove the microbiome, the mice have normal motor skills even with the overproduction of αSyn.”

“All three of the hallmark traits of Parkinson’s were gone in the germ-free models,” Sampson says. “Now we were quite confident that gut bacteria regulate, and are even required for, the symptoms of PD. So, we wanted to know how this happens.”

Image shows the outline of a person and a drawing of bacteria.

When gut bacteria break down dietary fiber, they produce molecules called short-chain fatty acids (SCFAs), such as acetate and butyrate. Previous research has shown that these molecules also can activate immune responses in the brain. Thus, Mazmanian’s group hypothesized that an imbalance in the levels of SCFAs regulates brain inflammation and other symptoms of PD. Indeed, when germ-free mice were fed SCFAs, cells called microglia–which are immune cells residing in the brain–became activated. Such inflammatory processes can cause neurons to malfunction or even die. In fact, germ-free mice fed SCFAs now showed motor disabilities and αSyn aggregation in regions of the brain linked to PD.

In a final set of experiments, Mazmanian and his group collaborated with Ali Keshavarzian, a gastroenterologist at Rush University in Chicago, to obtain fecal samples from patients with PD and from healthy controls. The human microbiome samples were transplanted into germ-free mice, which then remarkably began to exhibit symptoms of PD. These mice also showed higher levels of SCFAs in their feces. Transplanted fecal samples from healthy individuals, in contrast, did not trigger PD symptoms, unlike mice harboring gut bacteria from PD patients.

“This really closed the loop for us,” Mazmanian says. “The data suggest that changes to the gut microbiome are likely more than just a consequence of PD. It’s a provocative finding that needs to be further studied, but the fact that you can transplant the microbiome from humans to mice and transfer symptoms suggests that bacteria are a major contributor to disease.”

The findings have important implications for the treatment of Parkinson’s, the researchers say.

“For many neurological conditions, the conventional treatment approach is to get a drug into the brain. However, if PD is indeed not solely caused by changes in the brain but instead by changes in the microbiome, then you may just have to get drugs into the gut to help patients, which is much easier to do,” Mazmanian says. Such drugs could be designed to modulate SCFA levels, deliver beneficial probiotics, or remove harmful organisms. “This new concept may lead to safer therapies with fewer side effects compared to current treatments.”


The paper is titled “Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease.” Other Caltech coauthors include Taren Thron, Gnotobiotic Facility manager and research technician for the Mazmanian laboratory; undergraduate Gauri G. Shastri; postdoctoral scholar Collin Challis; graduate student Catherine E. Schretter; and Viviana Gradinaru, assistant professor of biology and biological engineering and Heritage Medical Research Institute Investigator.

Funding: The work was funded by the Larry L. Hillblom Foundation, the Knut and Alice Wallenberg Foundation, the Swedish Research Council, Mr. and Mrs. Larry Field, the Heritage Medical Research Institute, and the National Institutes of Health.

Source: Lori Dajose – California Institute of Technology
Image Source: This image is adapted from the California Institute of Technology press release.
Video Source: The video is credited to CalTech.
Original Research: Full open access research for “Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease” by Timothy R. Sampson, Justine W. Debelius, Taren Thron, Stefan Janssen, Gauri G. Shastri, Zehra Esra Ilhan, Collin Challis, Catherine E. Schretter, Sandra Rocha, Viviana Gradinaru, Marie-Francoise Chesselet, Ali Keshavarzian, Kathleen M. Shannon9, Rosa Krajmalnik-Brown, Pernilla Wittung-Stafshede, Rob Knight, and Sarkis K. Mazmanian in Cell. Published online December 1 2016 doi:10.1016/j.cell.2016.11.018

California Institute of Technology. “Parkinson’s Disease Linked to Gut Microbiome.” NeuroscienceNews. NeuroscienceNews, 1 December 2016.


Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease

•Gut microbes promote α-synuclein-mediated motor deficits and brain pathology
•Depletion of gut bacteria reduces microglia activation
•SCFAs modulate microglia and enhance PD pathophysiology
•Human gut microbiota from PD patients induce enhanced motor dysfunction in mice

The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson’s disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.

“Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease” by Timothy R. Sampson, Justine W. Debelius, Taren Thron, Stefan Janssen, Gauri G. Shastri, Zehra Esra Ilhan, Collin Challis, Catherine E. Schretter, Sandra Rocha, Viviana Gradinaru, Marie-Francoise Chesselet, Ali Keshavarzian, Kathleen M. Shannon9, Rosa Krajmalnik-Brown, Pernilla Wittung-Stafshede, Rob Knight, and Sarkis K. Mazmanian in Cell. Published online December 1 2016 doi:10.1016/j.cell.2016.11.018