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.

NIH…Turning Discovery Into Health®

Article

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

Immune system, bone marrow, anti-cancer, shark oil

marrowDr. Astrid Brohult, a Swedish oncologist, administered calves’ marrow to leukemia-stricken children in the 1950s, hoping it would replenish white blood cells destroyed by radiation therapy. After administering the marrow, some of the children improved immediately; many experienced increased energy and white blood cell normalization. After conducting a decade of research on the subject, she isolated a group of compounds called alkylglycerols (AKGs) in the calves’ marrow and discovered they were responsible for normalizing the white blood cell production.

Cindy Micleu, instructor at the Jade Institute complementary healing center, says bone marrow contains myeloid and lymphoid stem cells. The foundations for red and white blood cells, these cells build immunity, assist with blood clotting and help provide oxygen to cells. Collagen, the protein-rich substance that cooks down to gelatin, can also help repair the body. Collagen deficiency can lead to poor wound healing, easy bruising and bleeding gums. Collagen in bone marrow can help the body rebuild itself, says Micleu.

Bone marrow, in broth or in other forms, is a global wellness tool. Dr. Daniel Auer, a certified clinical nutritionist, says almost every culture claims some form of bone-based concoction. The Chinese use bone to support kidney and digestive function and to build blood. The Weston A. Price Foundation reports another example from a North Carolina mountain Indian population. Their diets rely heavily on wild game, and they value marrow to nourish their growing children.

The T helper cells (Th cells) are a type of T cell that play an important role in the immune system, particularly in the adaptive immune system. They help the activity of other immune cells by releasing T cell cytokines. These cells help suppress or regulate immune responses. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages.

Mature Th cells express the surface protein CD4 and are referred to as CD4+ T cells. Such CD4+ T cells are generally treated as having a pre-defined role as helper T cells within the immune system. For example, when an antigen-presenting cell expresses an antigen on MHC class II, a CD4+ cell will aid those cells through a combination of cell to cell interactions (e.g. CD40 (protein) and CD40L) and through cytokines.

CD154, also called CD40 ligand or CD40L, is a cell surface protein that mediates T cell helper function in a contact-dependent process[1] and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells (TFH cells).[2] On TFH cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication.[3] A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome.[4] Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.

The importance of helper T cells can be seen from HIV, a virus that primarily infects CD4+ T cells. In the advanced stages of HIV infection, loss of functional CD4+ T cells leads to the symptomatic stage of infection known as the acquired immunodeficiency syndrome (AIDS).

The mechanism that killer T cells use during auto-immunity is almost identical to their response against viruses, and some viruses have been accused of causing auto-immune diseases such as Type 1 Diabetes mellitus. Cellular auto-immune disease occurs because the host antigen recognition systems fail, and the immune system believes, by mistake, that a host antigen is foreign. As a result, the CD8+ T cells treat the host cell presenting that antigen as infected, and go on to destroy all host cells (or in the case of transplant rejection, transplant organ) that express that antigen.

According to an immunology textbook: “IL-2 is particularly important historically, as it is the first type I cytokine that was cloned, the first type I cytokine for which a receptor component was cloned, and was the first short-chain type I cytokine whose receptor structure was solved. Many general principles have been derived from studies of this cytokine including its being the first cytokine demonstrated to act in a growth factor–like fashion through specific high-affinity receptors, analogous to the growth factors being studied by endocrinologists and biochemists”.[18]:712

In the mid-1960s, studies reported “activities” in leukocyte-conditioned media that promoted lymphocyte proliferation.[19]:16 In the mid-1970s, it was discovered that T-cells could be selectively proliferated when normal human bone marrow cells were cultured in conditioned medium obtained from phytohemagglutinin-stimulated normal human lymphocytes.[18]:712 The key factor was isolated from cultured mouse cells in 1979 and from cultured human cells in 1980.[20] The gene for human IL-2 was cloned in 1982 after an intense competition.

The normal bone marrow architecture can be damaged or displaced by aplastic anemia, malignancies such as multiple myeloma, or infections such as tuberculosis, leading to a decrease in the production of blood cells and blood platelets. The bone marrow can also be affected by various forms of leukemia, which attacks its hematologic progenitor cells.[10] Furthermore, exposure to radiation or chemotherapy will kill many of the rapidly dividing cells of the bone marrow, and will therefore result in a depressed immune system. Many of the symptoms of radiation poisoning are due to damage sustained by the bone marrow cells.

Types of bone marrow

A femoral head with a cortex of bone and medulla of trabecular bone. Both red bone marrow and a central focus of yellow bone marrow are visible.

The two types of bone marrow are “red marrow” (Latin: medulla ossium rubra), which consists mainly of hematopoietic tissue, and “yellow marrow” (Latin: medulla ossium flava), which is mainly made up of fat cells. Red blood cells, platelets, and most white blood cells arise in red marrow. Both types of bone marrow contain numerous blood vessels and capillaries. At birth, all bone marrow is red. With age, more and more of it is converted to the yellow type; only around half of adult bone marrow is red. Red marrow is found mainly in the flat bones, such as the pelvis, sternum, cranium, ribs, vertebrae and scapulae, and in the cancellous (“spongy”) material at the epiphyseal ends of long bones such as the femur and humerus. Yellow marrow is found in the medullary cavity, the hollow interior of the middle portion of short bones. In cases of severe blood loss, the body can convert yellow marrow back to red marrow to increase blood cell production.

Stroma

The stroma of the bone marrow is all tissue not directly involved in the marrow’s primary function of hematopoiesis.[2] Yellow bone marrow makes up the majority of bone marrow stroma, in addition to smaller concentrations of stromal cells located in the red bone marrow. Though not as active as parenchymal red marrow, stroma is indirectly involved in hematopoiesis, since it provides the hematopoietic microenvironment that facilitates hematopoiesis by the parenchymal cells. For instance, they generate colony stimulating factors, which have a significant effect on hematopoiesis. Cell types that constitute the bone marrow stroma include:

Alkylglycerols are natural etherlipids abundant in shark liver oil (SLO) in a diacylated form. SLO is known to have antitumor properties and was recently described as an inhibitor of tumor neovascularization. However, most studies did not discriminate between the respective activities of alkylglycerols and of fatty acids, which both have potent biological properties. In this work, a mouse model was used to investigate the antitumor effects of SLO and of alkylglycerols purified from the same source, both administered orally. We demonstrated that either pure alkylglycerols or SLO reduced the tumor growth in a similar manner, suggesting that alkylglycerols were involved in this effect. In alkylglycerol-treated mice, metastasis dissemination was reduced by 64 ± 8%, whereas SLO effect was 30 ± 9% below control. Purified alkylglycerols also decreased significantly plasmalogen content in tumors, whereas SLO had no such effect. Finally, we demonstrated that a 5-day treatment with alkylglycerols curtailed the presence in tumors of von Willebrand factor, a marker of endothelial cells. This result suggested an anti-angiogenic effect of alkylglycerols. In summary, alkylglycerols were shown to decrease the growth, vascularization, and dissemination of Lewis lung carcinoma tumors in mice. These findings suggest that the antitumor activity of SLO is likely mediated by the presence of alkylglycerols.

Shark Oil contains alkylglycerols. Alkylglycerols act as immune system boosting agents.

As a natural bacteria fighter, alkylglycerols are able to stimulate the helper T-cells, which are highly sensitized to the bacteria-infected macrophage, and thus the body is able to destroy the bacteria.

Vagus nerve stimulation thru breathing, laughs and yoga

 

The benefits of vagus nerve stimulation (other than relaxing the body, mind, and soul – and really, isn’t that enough of a reason?):

  • It reduces the inflammatory response throughout our system.
  • It helps the brain emit new cells.
  • It decreases depression and anxiety and lifts our mood. Forty million Americans are affected by mood disorders. Enough said!
  • It assists in developing razor-sharp memory, and there are so many applications for increased memory capacity in our culture like Alzheimer’s work, traumatic brain injuries, and plain-and-simple everyday life.
  • It raises your immunity. How about staying healthy and taking vacations to beautiful faraway places instead of lying on the couch suffering through yet another bout of bronchitis?
  • It raises the level of endorphins, which bring about positive feelings in the body and reduce the sensation of pain.

Kundalini serpent tail whips the immune system into action

Have you ever seen the list “100 Benefits of Meditation“?  Of course, many of these benefits are psychological. You know, things like: helps control own thoughts (#39) and helps with focus & concentration (#40).  But many of the 100 benefits are rather physical, bodily, physiological, immunological and even biochemical benefits (such as #16- reduction of free radicals, less tissue damage).

These are awesome claims, and I’ve certainly found that mediation helps me feel more emotionally balanced and physically relaxed,  but I’m wondering – from a hard science point of view – how legit some of these claims might be.  For example, “#12 Enhances the immune system – REALLY?  How might yoga and mediation enhance my immune system?

In a previous post on the amazing vagus nerve – the only nerve in your body that, like the ancient Kundalini serpent, rises from the root of your gut to the brain – AND – a nerve that is a key to the cure of treatment resistant depression– it was suggested that much of the alleviation of suffering that comes from yoga comes from the stimulation of this amazing nerve during postures and breathing.

Somehow, the ancient yogis really got it right when they came up with the notion of Kundalini serpent – so strange, but so cool!

I happened to stumble on a paper that explored the possibility that the vagus nerve might also play a role in mediating communication of the immune system and the brain – and thus provide a mechanism for “#12- Enhances the immune system” Here’s a quote from the article entitled, “Neural concomitants of immunity—Focus on the vagus nerve” [doi:10.1016/j.neuroimage.2009.05.058] by Drs. Julian F. Thayer and Esther M. Sternberg (Ohio State University and National Institute of Mental Health).

By the nature of its “wandering” route through the body the vagus nerve may be uniquely structured to provide an effective early warning system for the detection of pathogens as well as a source of negative feedback to the immune system after the pathogens have been cleared. … Taken together these parasympathetic pathways form what has been termed “the cholinergic anti-inflammatory pathway

The scientists then investigate the evidence and possible mechanisms by which the vagus nerve sends immunological signals from the body to the brain and also back out to the immune system.  Its not a topic that is well understood, but the article describes several lines of evidence implicating the vagus nerve in immunological health.

So bend, twist, inhale and exhale deeply.  Stimulate your vagus nerve and, as cold and flu season arrives, awaken the serpent within!

What if you had magic fingers and could touch a place on a person’s body and make all their pain and anguish disappear?  This would be the stuff of legends, myths and miracles! Here’s a research review by Kerry J Ressler  and Helen S Mayberg on the modern ability to electrically “touch” the Vagus Nerve.

The article,  Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic discusses a number of “nerve stimulation therapies” wherein specific nerve fibers are electrically stimulated to relieve mental anguish associated with (drug) treatment-resistant depression.

Vagus nerve stimulation therapy (VNS) is approved by the FDA for treatment of medication-resistant depression and was approved earlier for the treatment of epilepsy20.  …  The initial reasoning behind the use of VNS followed from its apparent effects of elevating mood in patients with epilepsy20, combined with evidence that VNS affects limbic activity in neuroimaging studies21. Furthermore, VNS alters concentrations of serotonin, norepinephrine, GABA and glutamate within the brain2224, suggesting that VNS may help correct dysfunctional neurotransmitter modulatory circuits in patients with depression.

This stuff is miraculous in every sense of the word – to be able to reach in and “touch” the body and bring relief – if not bliss – to individuals who suffer with immense emotional pain.  So who is this Vagus nerve anyway?  Why does stimulating it impart so many emotional benefits?  How can I touch my own Vagus nerve?

The wikipedia page is a great place to explore – suggesting that this nerve fiber is central to the “rest and digest” functions of the parasympathetic nervous system.  As evidenced by the relief its stimulation brings from emotional pain, the Vagus nerve is central to mind-body connections and mental peace.

YOGA is a practice that also brings mental peace.  YOGA,  in so many ways (I hope to elaborate on in future posts),  aims to engage the parasympathetic nervous system (slowing down and resting responses) and disengage the sympathetic nervous system (fight or flight responses).  Since we all can’t have our very own (ahem) lululemon (ahem) vagal nerve stimulation device, we must rely on other ways to stimulate the Vagus nerve fiber.  Luckily, many such ways are actually known – so-called “Vagal maneuvers” – such as  holding your breath and bearing down (Valsalva maneuver), immersing your face in ice-cold water (diving reflex), putting pressure on your eyelids, & massage of the carotid sinus area – that have been shown to facilitate parasympathetic (relaxation & slowing down) responses.

But these “Vagal maneuvers” are not incorporated into yoga.  How might yoga engage and stimulate the Vagal nerve bundle? Check out these great resources on breathing and Vagal tone (here, here, here).  I’m not an expert by any means but I think the take home message is that when we breathe deep and exhale, Vagal tone increases.  So, any technique that allows us to increase the duration of our exhalation will increase Vagal tone. Now THAT sounds like yoga!

Even more yogic is the way the Vagus nerve is the only nerve in the parasympathetic system that reaches all the way from the colon to the brain.  The fiber is composed mainly of upward (to the brain) pulsing neurons – which sounds a lot like the mystical Kundalini Serpent that arises upwards from within (starting at the root – colon) and ending in the brain.  The picture above – of the Vagus nerve (bright green fiber) – might be what the ancient yogis had in mind?

 

  • Tips to stimulate the vagus nerve

  • Humming: The vagus nerve passes through by the vocal cords and the inner ear and the vibrations of humming is a free and easy way to influence your nervous system states. Simply pick your favorite tune and you’re ready to go. Or if yoga fits your lifestyle you can “OM” your way to wellbeing. Notice and enjoy the sensations in your chest, throat, and head.
  • Conscious Breathing: The breath is one of the fastest ways to influence our nervous system states. The aim is to move the belly and diaphragm with the breath and to slow down your breathing. Vagus nerve stimulation occurs when the breath is slowed from our typical 10-14 breaths per minute to 5-7 breaths per minute. You can achieve this by counting the inhalation to 5, hold briefly, and exhale to a count of 10. You can further stimulate the vagus nerve by creating a slight constriction at the back of the throat and creating an “hhh”. Breathe like you are trying to fog a mirror to create the feeling in the throat but inhale and exhale out of the nose sound (in yoga this is called Ujjayi pranayam).
  • Valsalva Maneuver: This complicated name refers to a process of attempting to exhale against a closed airway. You can do this by keeping your mouth closed and pinching your nose while trying to breathe out. This increases the pressure inside of your chest cavity increasing vagal tone.
  • Diving Reflex: Considered a first rate vagus nerve stimulation technique, splashing cold water on your face from your lips to your scalp line stimulates the diving reflex. You can also achieve the nervous system cooling effects by placing ice cubes in a ziplock and holding the ice against your face and a brief hold of your breath. The diving reflex slows your heart rate, increases blood flow to your brain, reduces anger and relaxes your body. An additional technique that stimulates the diving reflex is to submerge your tongue in liquid. Drink and hold lukewarm water in your mouth sensing the water with your tongue.
  • Connection: Reach out for relationship. Healthy connections to others, whether this occurs in person, over the phone, or even via texts or social media in our modern world, can initiate regulation of our body and mind. Relationships can evoke the spirit of playfulness and creativity or can relax us into a trusting bond into another. Perhaps you engage in a lighthearted texting exchange with a friend. If you are in proximity with another you can try relationship expert, David Snarch’s simple, yet powerful exercise called “hugging until relaxed.” The instructions are to simply “stand on your own two feet, place your arms around your partner, focus on yourself, and to quiet yourself down, way down.”


Because of the pathway of the vagus nerve, long deep breathing is the number one key to activating the vagus nerve.
Breathing can be involuntary (something the vagus nerve does for us when we aren’t paying attention), but it can also be something we do consciously. By bringing awareness to the breath, lengthening and deepening it, you turn on the vagus nerve, giving your body the opportunity to rejuvenate.

So, let’s stop and breathe with awareness for ten minutes:

As you inhale, lift your collarbone.

As you exhale, soften and relax.

As you inhale, expand your ribs out under your arms.

As you exhale, soften and relax.

As you inhale, expand your ribs across your back

As you exhale, soften and relax.

When you sit, close your eyes, and utilize your system’s own action, you enhance your health and wellness.

Here are a number of pathways to the vagus nerve. Choose your favorite:

  • Immerse your face (especially the forehead, eyes, and two-thirds of your cheeks) in cold water for three minutes.
  • Practice restorative yoga and include gentle backbends, forward bends, and twists.
  • Include inversions in your practice like downward dog or legs up the wall.
  • Chant and sing in low resonant tones.
  • Immerse your tongue in saliva while doing long deep breathing.
  • Practice Qigong.
  • Laugh with deep diaphragmatic laughs.

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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.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

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

Source: Robin Smith – Duke
Image Source: This NeuroscienceNews.com 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

CITE THIS NEUROSCIENCENEWS.COM ARTICLE
Duke. “Targeting the Gut-Brain Connection Can Impact Immunity.” NeuroscienceNews. NeuroscienceNews, 11 August 2016.
<http://neurosciencenews.com/immunity-gut-brain-connection-4829/&gt;.

Abstract

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

Highlights
•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

Summary
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

Know your gut microbiome, stop obesity and future infectious disease

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Sequence your microbiome and get a personalized diet plan

Order your gut DNA sequence test from us as we work with the lab by sending us an email at motherhealth@gmail.com to get a free personalized diet plan.

colon-health-3colon-health

 

And work with a genetic counselor.

Your gut microbiome controls production of cytokine.

Gut microbiome is affected by diet and medication.

Sequence your gut bacteria 3 times, $199. Before and after and another 6m later to see the effect of diet, lifestyle and stress/other factors in the bacteria diversity in your gut.

Not all bacteria are hereditable.

gut-swab-2gut-swab


About Cytokine

Cytokines (cyto, from Greek “κύτταρο” kyttaro “cell” + kines, from Greek “κίνηση” kinisi “movement”) are a broad and loose category of small proteins (~5–20 kDa) that are important in cell signaling. Their release has an effect on the behavior of cells around them. It can be said that cytokines are involved in autocrine signalling, paracrine signalling and endocrine signalling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factorsbut generally not hormones or growth factors (despite some overlap in the terminology). Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell.[1][2][3]

They act through receptors, and are especially important in the immune system; cytokines modulate the balance between humoral and cell-basedimmune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways.[3]

They are different from hormones, which are also important cell signaling molecules, in that hormones circulate in less variable concentrations and hormones tend to be made by specific kinds of cells.

They are important in health and disease, specifically in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction.


About PPI medication

Proton pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. Within the class of medications, there is no clear evidence that one agent works better than another.[1][2]

They are the most potent inhibitors of acid secretion available.[3] This group of drugs followed and largely superseded another group of medications with similar effects, but a different mode of action, called H2-receptor antagonists.

Skin sentry cells promote distinct immune responses

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A new study reveals that just as different soldiers in the field have different jobs, subsets of a type of immune cell that polices the barriers of the body can promote unique and opposite immune responses against the same type of infection. The research, published online on July 21st by Cell Press in the journal Immunity, enhances our understanding of the early stages of the immune response and may have important implications for vaccinations and treatment of autoimmune diseases.

Dendritic cells serve as sentries of the immune system and are stationed at the body’s “outposts,” like the skin, where they are likely to encounter invading pathogens. When dendritic cells encounter pathogen-associated antigens (molecules that trigger an immune response), they process the antigen and present it to other responding in an effort to inititate a cellular cascade resulting in clearance of the pathogen. This is a critical part of the immune response because many responding immune cells cannot “see” antigen and initiate the proper unless the antigen is properly presented by a dendritic cell.

“There are at least three different types of dendritic cells in the skin,” explains senior study author, Dr. Daniel Kaplan from the University of Minnesota. “Despite studies examining these cells, the basic question of whether skin resident dendritic cells have unique or redundant functions remains unresolved.” Dr. Kaplan and colleagues developed a model of that is limited to the superficial layer of the skin and studied antigen-specific immune responses in mice lacking specific subsets of skin dendritic cells.

The researchers discovered that direct presentation of antigen by one type of dendritic cell, Langerhans cells, was necessary and sufficient for the generation of antigen-specific T helper-17 (Th17) cells but not the generation of cytotoxic lymphocytes (CTL). T play a key role in orchestrating the , whereas CTLs can directly destroy infected cells. While Th17 cells play productive roles in indirectly eliminating pathogens when their response is dysregulated, they have been implicated in autoimmune disease, Meanwhile, another subset of dendritic cells was required for the generation of antigen-specific CTLs and inhibited the ability of other dendritic cells to promote Th17 cell responses.

“Our work demonstrates that in the skin promote distinct and opposing antigen-specific responses,” concludes Dr. Kaplan. “This has important implications for vaccination strategies that selectively target dendritic cell populations. In addition, the requirement for Langerhans cells in the development of Th17 cells suggests these cells may participate in the early pathogenesis of Th17 cell-mediated skin diseases such as psoriasis.”

How excess alcohol depresses immune function

 

Alcoholism suppresses the immune system, resulting in a high risk of serious, and even life-threatening infections. A new study shows that this effect stems largely from alcohol’s toxicity to immune system cells called dendritic cells. These cells play a critical role in immune function, responding to danger signals by searching for unfamiliar antigens within the body that would be coming from invading microbes, and presenting such antigens to T cells, thus activating them to seek and destroy cells containing these antigens. The research is published in the July 2011 issue of the journal Clinical and Vaccine Immunology.

Earlier studies in mice had shown that excessive drinking of impaired T cell function, and subsequently that this impairment could be reversed by exposure to dendritic (so named for their shape) from non-alcoholic mice, and that poor function in CD4 and CD8 T cells could be improved through exposure to cytokines produced by non-alcoholic dendritic cells. (Cytokines are immune regulatory cells.) In this study, Jack R. Wands and colleagues of Brown University, Providence, RI, compared dendritic cells produced by alcoholic and non-alcoholic mice, which they first removed from the mice.

The result: dendritic cells from the alcoholic mice had a poor ability to activate T cells, while the dendritic cells from mice on isocaloric diets containing no alcohol functioned normally. The researchers found further that the dendritic cells from alcohol-fed mice showed reduced antigen presentation compared to those from control mice, as well as less production of the regulatory cytokines. This research also confirmed earlier results showing that alcohol inhibits cytokine secretion by dendritic cells.

“This research helps us understand why alcoholics are predisposed to bacterial and viral infections, and why they do not respond well to vaccines,” says Wands. Understanding this, he says, will help in the development of ways to improve dendritic cell function in people with syndromes.

Explore further: Skin sentry cells promote distinct immune responses

More information: A. Eden, et al., 2011. Ethanol inhibits antigen presentation by dendritic cells. Clin. Vaccine Immunol. 18:1157-1166.)

Provided by: American Society for Microbiology