Acetylcholine/Choline Deficiency in Chronic Illness – mental, liver, kidney, heart and hormones

Acetylcholine/Choline Deficiency in Chronic Illness – The Hunt for the Missing Egg.

Those who lack choline are prone to mental illness, heart disease, fatty liver and/or hemorrhagic kidney necrosis and chronic illness as choline is oxidized to betaine which acts as an important methyl donor and osmolyte. With fatty liver, a person can be prone to diabetes and other chronic illness.  Eggs are rich in choline.  Choline is also found in a wide range of plant foods in small amounts. Eating a well-balanced vegan diet with plenty of whole foods should ensure you are getting enough choline. Soymilk, tofu, quinoa, and broccoli are particularly rich sources.

Eggs are an excellent source of choline and selenium, and a good source of high-quality protein, vitamin D, vitamin B12, phosphorus andriboflavin. In addition, eggs are rich in the essential amino acid leucine(one large egg provides 600 milligrams), which plays a unique role in stimulating muscle protein synthesis.

ucm278430We hear a lot about vitamins and minerals such as B12, folate, magnesium, vitamin C, and so on, but there seems very little talk these days on the importance of dietary lecithin and choline. Are you consuming an adequate amount of acetylcholine, or other phospholipids? The odds are that you are not.

A little bit about choline

The human body produces choline by methylation of phosphatidylethanolamine (from dietary sources such as lecithin and others) to form phosphatidylcholine in the liver by the PEMT enzyme. Phosphatidylcholine may also be consumed in the diet or by supplementation. Choline is oxidized to betaine which acts as an important methyl donor and osmolyte.

For those wanting to see how this relates to the methylation cycle, below is a nice graphic (courtesy of Wikipedia).

Choline metabolism

It is well known that magnesium deficiency is widespread (57% of the population does not meet the U.S. RDA according to the USDA), but the numbers for choline deficiency are even more shocking.

According the National Health and Nutrition Examination Survey (NHANES) in 2003-2004, only about 10% of the population have an adequate intake of choline. This means about 90% of the population consumes a diet deficient in choline. Furthermore, those without an adequate intake of choline may not have symptoms.

Along with folate and B12 deficiency, inadequate consumption of choline can lead to high homocysteine and all the risks associated with hyperhomocysteinaemia, such as cardiovascular disease, neuropsychiatric illness (Alzheimer’s disease, schizophrenia) and osteoporosis. Inadequate choline intake can also lead to fatty liver or non-alcoholic fatty liver disease (NAFLD).

The most common symptoms of choline deficiency are fatty liver and/or hemorrhagic kidney necrosis. Consuming choline rich foods usually relieve these deficiency symptoms. Diagnosing fatty liver isn’t as simple as running  ALT and AST since nearly 80% of people with fatty liver have normal levels of these enzymes according to a population study published in the journal Hepatology. In fact, in an experiment, 10 women were fed a diet low in choline. Nine developed fatty liver and only one had elevated liver enzymes.


Estrogen and Choline Deficiency

Given the connection between low lipids and choline deficiency, it would be tempting to think that as long as someone has enough cholesterol and TG that they will be protected from choline deficiency.  Unfortunately this is not the case.  Having adequate lipids does indeed help support healthy choline levels, but it does not guarantee a person will avoid choline deficiency.  The truth is that choline deficiency can come from more than one source.  Both sex hormone levels and genetic SNPs may lead to a choline deficiency by influencing the PEMT enzyme – the enzyme responsible for synthesis of choline inside the body.  Recent research now confirms how hormones and genetic polymorphisms play a major role in choline deficiency.

The body can make choline only one way; that is by methylating a molecule of phosphatidylethanolamine (PE) into a molecule of phosphatidylcholine (PC).  The body’s only method for accomplishing this is via the enzyme PEMT (phosphatidylethanolamine N-methyltransferase) which is found in the liver, brain, muscle, fat and other tissues.1,2    As with other well-known methylation enzymes like MTHFR and COMT, the PEMT enzyme can have genetic SNPs that slow it down.  When this enzyme slows down the body cannot make choline in high amounts and choline deficiency is more likely.  But there is more to the story of PEMT than just polymorphisms.  In addition to being slowed by SNPs, PEMT is also dependent upon the hormone estrogen for activation. 1, 3  What this means is that the PEMT enzyme, the body’s only method of synthesizing choline, has not one but two Achilles heals.  The PEMT pathway and how it relates to phosphatidylcholine production is shown in Figure 1.3 below.

Communicating Vessels4-PEMT

Figure 1.3 – PEMT is shown as the rate-limiting reaction in the production of phosphatidylcholine inside the human body.  Due to genetic and hormonal variances, most people have a PEMT enzyme working too slow and are susceptible to choline deficiency when there is not enough choline in the diet.  ACoA – Acetyl-CoA; TG – Triglycerides; PE – phosphatidylethanolamine; PC – phosphatidylecholine; PEMT – phosphatidylethanolamine N-methyltransferase.

As mentioned above, the sex hormone estrogen is intimately linked with the production of choline.  Women have a biological advantage here as the premenopausal female body has much higher levels of estrogen than does the male body.  When a woman becomes pregnant this advantage is taken to an extreme, as pregnancy increases estrogen levels over 30 times normal.4  A successful pregnancy requires high amounts of nutrients delivered to the growing baby, esp. choline.  Since the mother’s body is building a human being from scratch, there is an added burden on her biology to provide enough nutrition to her growing baby.  Viewed from this perspective, the high estrogen levels during pregnancy can be seen to act like a biochemical insurance policy.  Since the PEMT enzyme requires estrogen to function, pregnancy allows a woman to make extra choline for her developing child.  Furthermore, the nervous system is the first system to form in utero and is a tissue that requires high levels of choline for proper development.5, 6  Choline plays such an important role in cell membranes, myelin sheaths, and nervous system tissue that the high estrogen levels during pregnancy help make sure the growing brain and nervous system is nourished.  It is a genius system that assures the health and survival of the child.

Even though Nature has conferred an advantage to females by providing them with higher estrogen levels, esp. during pregnancy, this alone cannot protect against a lack of choline in the diet.  All the estrogen in the world will not save a woman from choline deficiency if the gene responsible for producing choline is slowed down by a polymorphism.  Genetic research has shown that the gene responsible for synthesizing choline, the PEMT gene, is susceptible to common polymorphisms which alter its function by slowing it down.  In a recent study looking at a population in North Carolina, men and women of various ages were placed on a choline-deficient diet.  They were followed closely for up to 42 days on a low choline diet consisting of less than 50mg choline per day.  Throughout the study, the participants’ liver function was continuously assessed for any sign of fatty liver and damage.  After eating a choline deficient diet for just six weeks, 63% of participants developed liver dysfunction and choline blood levels dropped 30% in every single participant, including premenopausal females.7  During this six week trial of low dietary choline the odds of developing liver dysfunction were 77% for men, 80% for postmenopausal women and just 44% for premenopausal women.7  Based on what has been discussed so far about estrogen and choline, it makes sense that men and postmenopausal women would be more susceptible to developing fatty liver since they don’t have high estrogen levels.  And based on the fact that estrogen levels drive choline production, premenopausal women should have been protected from fatty liver since they make higher amounts of choline – but that was not the case.

With dietary choline restricted to just 50 mg/day, approximately half of the premenopausal group also suffered liver dysfunction, suggesting that a choline deficient diet can even harm women with higher estrogen levels.  In addition, blood tests revealed that premenopausal female experienced a 30% loss of choline on a low choline diet right along with everyone else.   Despite the fact that higher estrogen levels allow fertile women to make more choline, many were not able to make enough to avoid problems.  A PEMT gene polymorphism is the only mechanism that can explain how women with high estrogen levels are still susceptible to choline deficiency when placed on a low choline diet.

Just like many individuals in the population, some of the premenopausal women inherited one or two copies of the PEMT gene which slows down the production of choline.   This study showed that fatty liver occurred in 80% of the premenopausal women with two copies of PEMT and in 43% with only one copy of PEMT.8  What this means is that a premenopausal woman with two copies of the slowed PEMT gene has exactly the same risk of fatty liver as a postmenopausal woman.  It is as if inheriting two copies of the PEMT gene effectively shuts off all estrogen-related choline production in the body.  If a woman only has a single copy of the slowed PEMT gene, she will still have a roughly 50% chance of liver dysfunction on a low choline diet.  Thus a single copy of the gene is only slightly better than two copies, as at least some estrogen-related choline production is preserved.

If having a PEMT gene can put one at risk for choline-related diseases like fatty liver, then it is important to know how common these genes are in population.  We know that 74% of all women in the study had a SNP in the PEMT that made their PEMT enzyme unresponsive to estrogen.9  This means that only 26% of women can make enough choline on a low choline diet; and that ability depends on whether the woman is still fertile or has entered menopause.  In this way genetics can take away the biological advantage that high estrogen levels usually offer to premenopausal females.  Women with these PEMT genes will be at risk for choline deficiency and liver damage just like all men and post-menopausal women – two groups who don’t have enough estrogen to make choline regardless of their genes.  Due to all the interference from the PEMT gene, dietary choline levels must be optimized for the vast majority of our population.

Summary of PEMT and Choline Deficiency:

  • In humans, choline is only made by the PEMT enzyme
  • Estrogen is required for the PEMT enzyme to activate and function normally
  • Men and postmenopausal women have an elevated risk of choline deficiency due to low estrogen levels.
  • The PEMT enzyme is commonly slowed down by polymorphisms, making it unresponsive to estrogen levels
    • 74% of women have at least one copy of a slowed PEMT
    • Homozygous carriers of PEMT have much higher risk of choline deficiency
    • Men, postmenopausal women, and premenopausal women with PEMT SNPs need to increase choline intake in the diet to offset elevated risk of liver dysfunction

The take away here is that studies have recently shown that because of common genetic polymorphisms, choline deficiency is a widespread problem.  Normally the hormone estrogen allows the body to make choline from scratch.  However, genetic variation in the PEMT enzyme, estrogen levels and gender differences prevent most people from making adequate choline.  Realistically then the only group in our population who is protected from choline deficiency are premenopausal females without a single copy of the slowed PEMT gene.   Every single male, every single postmenopausal woman, and 74% of premenopausal woman all require daily intake of approx. 500 mg of choline to prevent fatty liver, organ damage, and the associated health problems.7  If the body is already depleted, then levels that simply prevent deficiency won’t be enough to replete the body.  In these cases, higher daily doses of at least 1 gram or more are needed to replenish the tissues.  Choline it seems must be absorbed from the diet in just about everyone except for the few young women who have a normal PEMT gene and can synthesize choline regardless of dietary intake.

References

1 Resseguie ME, da Costa KA, Galanko JA, et al. Aberrant estrogen regulation of PEMT results in choline deficiency-associated liver dysfunction. J Biol Chem. 2011 Jan 14;286(2):1649-58.

2 Tehlivets O. Homocysteine as a risk factor for atherosclerosis: is its conversion to s-adenosyl-L-homocysteine the key to deregulated lipid metabolism? J Lipids. 2011;2011:702853. Epub 2011 Aug 1.

3 Wallace JM, McCormack JM, McNulty H, et al. Choline supplementation and measures of choline and betaine status: a randomised, controlled trial in postmenopausal women. Br J Nutr. 2012 Oct;108(7):1264-71. Epub 2011 Dec 15.

4 Guyton AC, Hall JE. Textbook of Medical Physiology, 11th ed.  Philadelphia, PA: Elsevier, 2006, p. 1033.

5 Sadler, TW. Medical Embryology, 10th ed. Baltimore, MD: Lippincott Williams & Wilkins, 2006, p. 86.

6 Steinfeld R, Grapp M, Kraetzner R, et al. Folate Receptor Alpha Defect Causes Cerebral Folate Transport Deficiency: A Treatable Neurodegenerative Disorder Associated with Disturbed Myelin Metabolism. Am J Hum Genet. 2009 September 11; 85(3): 354–363.

7 da Costa KA, Kozyreva OG, Song J, et al. Common genetic polymorphisms affect the human requirement for the nutrient choline. FASEB J. 2006 Jul;20(9):1336-44.

8 Fischer LM, da Costa KA, Kwock L, et al. Dietary choline requirements of women: effects of estrogen and genetic variation. Am J Clin Nutr. 2010 Nov;92(5):1113-9. Epub 2010 Sep 22.

9 Zeisel SH. Nutritional genomics: defining the dietary requirement and effects of choline. J N

New evidence that chronic stress predisposes brain to mental illness

By Robert Sanders

University of California, Berkeley, researchers have shown that chronic stress generates long-term changes in the brain that may explain why people suffering chronic stress are prone to mental problems such as anxiety and mood disorders later in life.

myelin

Myelin is stained blue in this cross section of a rat hippocampus. Myelin, which speeds electrical signals flowing through axons, is produced by oligodendrocytes, which increase in number as a result of chronic stress. New oligodendrocytes are shown in yellow. Image by Aaron Friedman and Daniela Kaufer.

Their findings could lead to new therapies to reduce the risk of developing mental illness after stressful events.

Doctors know that people with stress-related illnesses, such as post-traumatic stress disorder (PTSD), have abnormalities in the brain, including differences in the amount of gray matter versus white matter. Gray matter consists mostly of cells – neurons, which store and process information, and support cells called glia – while white matter is comprised of axons, which create a network of fibers that interconnect neurons. White matter gets its name from the white, fatty myelin sheath that surrounds the axons and speeds the flow of electrical signals from cell to cell.

How chronic stress creates these long-lasting changes in brain structure is a mystery that researchers are only now beginning to unravel.

In a series of experiments, Daniela Kaufer, UC Berkeley associate professor of integrative biology, and her colleagues, including graduate students Sundari Chetty and Aaron Freidman, discovered that chronic stress generates more myelin-producing cells and fewer neurons than normal. This results in an excess of myelin – and thus, white matter – in some areas of the brain, which disrupts the delicate balance and timing of communication within the brain.

“We studied only one part of the brain, the hippocampus, but our findings could provide insight into how white matter is changing in conditions such as schizophrenia, autism, depression, suicide, ADHD and PTSD,” she said.

The hippocampus regulates memory and emotions, and plays a role in various emotional disorders.

Kaufer and her colleagues published their findings in the Feb. 11 issue of the journal Molecular Psychiatry.

Does stress affect brain connectivity?

Kaufer’s findings suggest a mechanism that may explain some changes in brain connectivity in people with PTSD, for example. One can imagine, she said, that PTSD patients could develop a stronger connectivity between the hippocampus and the amygdala – the seat of the brain’s fight or flight response – and lower than normal connectivity between the hippocampus and prefrontal cortex, which moderates our responses.

“You can imagine that if your amygdala and hippocampus are better connected, that could mean that your fear responses are much quicker, which is something you see in stress survivors,” she said. “On the other hand, if your connections are not so good to the prefrontal cortex, your ability to shut down responses is impaired. So, when you are in a stressful situation, the inhibitory pathways from the prefrontal cortex telling you not to get stressed don’t work as well as the amygdala shouting to the hippocampus, ‘This is terrible!’ You have a much bigger response than you should.”

white-m

 

 

She is involved in a study to test this hypothesis in PTSD patients, and continues to study brain changes in rodents subjected to chronic stress or to adverse environments in early life.

Stress tweaks stem cells

Kaufer’s lab, which conducts research on the molecular and cellular effects of acute and chronic stress, focused in this study on neural stem cells in the hippocampus of the brains of adult rats. These stem cells were previously thought to mature only into neurons or a type of glial cell called an astrocyte. The researchers found, however, that chronic stress also made stem cells in the hippocampus mature into another type of glial cell called an oligodendrocyte, which produces the myelin that sheaths nerve cells.

The finding, which they demonstrated in rats and cultured rat brain cells, suggests a key role for oligodendrocytes in long-term and perhaps permanent changes in the brain that could set the stage for later mental problems. Oligodendrocytes also help form synapses – sites where one cell talks to another – and help control the growth pathway of axons, which make those synapse connections.

The fact that chronic stress also decreases the number of stem cells that mature into neurons could provide an explanation for how chronic stress also affects learning and memory, she said.

Kaufer is now conducting experiments to determine how stress in infancy affects the brain’s white matter, and whether chronic early-life stress decreases resilience later in life. She also is looking at the effects of therapies, ranging from exercise to antidepressant drugs, that reduce the impact of stress and stress hormones.

Kaufer’s coauthors include Chetty, formerly from UC Berkeley’s Helen Wills Neuroscience Institute and now at Harvard University; Friedman and K. Taravosh-Lahn at UC Berkeley’s Department of Integrative Biology; additional colleagues from UC Berkeley and others from Stanford University and UC Davis.

The work was supported by a BRAINS (Biobehavioral Research Awards for Innovative New Scientists) award from the National Institute of Mental Health of the National Institutes of Health (R01 MH087495), a Berkeley Stem Cell Center Seed Grant, the Hellman Family Foundation and the National Alliance for Research on Schizophrenia and Depression.

RELATED INFORMATION

Genes Affecting Communication Skills Linked to Genes Related to Psychiatric Disorders

Summary: A new study links genes that pose as a risk factor for autism and schizophrenia with genes that influence the ability to communicate during development.

Source: Max Planck Institute.

Genetic links depend on stages in a child’s development.

By screening thousands of individuals, an international team led by researchers of the Max Planck Institute for Psycholinguistics in Nijmegen, the University of Bristol, the Broad Institute and the iPSYCH consortium has provided new insights into the relationship between genes that confer risk for autism or schizophrenia and genes that influence our ability to communicate during the course of development.

The researchers studied the genetic overlap between the risk of having these psychiatric disorders and measures of social communicative competence – the ability to socially engage with other people successfully – during middle childhood to adolescence. They showed that genes influencing social communication problems during childhood overlap with genes conferring risk for autism, but that this relationship wanes during adolescence. In contrast, genes influencing risk for schizophrenia were most strongly interrelated with genes affecting social competence during later adolescence, in line with the natural history of the disorder.

“The findings suggest that the risk of developing these contrasting psychiatric conditions is strongly related to distinct sets of genes, both of which influence social communication skills, but which exert their maximum influence during different periods of development”, explained Beate St Pourcain, senior investigator at the Max Planck Institute and lead author of the study.

Timing makes the difference

People with autism and with schizophrenia both have problems interacting and communicating with other people, because they cannot easily initiate social interactions or give appropriate responses in return. On the other hand, the disorders of autism and schizophrenia develop in very different ways. The first signs of ASD typically occur during infancy or early childhood, whereas the symptoms of schizophrenia usually do not appear before early adulthood.

People with autism can have difficulties in engaging socially with others and in understanding social cues, as well as frequently being rigid, concrete thinkers with occasionally obsessive interests. In contrast, schizophrenia is characterised by hallucinations, delusions, and disorganized thought processes. Yet recent research has shown that many of these characteristics and experiences can be found, to a mild degree, in typically developing children and adults. In other words, there is an underlying continuum between normal and abnormal behaviour.

Thousands of genetic differences

Recent advances in genome-wide analyses have helped drawing a more precise picture of the genetic architecture underlying psychiatric disorders and their related symptoms in unaffected people. A large proportion of risk to disorder, but also variation in milder symptoms, stems from combined small effects of many thousands of genetic differences across the genome, known as polygenic effects. For social communication behaviour, these genetic factors are not constant, but change during childhood and adolescence. This is because genes exert their effects consistent with their biological programming.

Disentangling psychiatric disorders

“A developmentally sensitive analysis of genetic relationships between traits and disorders may help disentangling apparent behavioural overlap between psychiatric conditions”, St Pourcain commented.

Image shows dna.

George Davey Smith, Professor of Clinical Epidemiology at the University of Bristol and senior author of the study, said “The emergence of associations between genetic predictors for different psychiatric conditions and social communication differences, around the ages the particular conditions reveal themselves, provides a window into the specific causes of these conditions”.

David Skuse, Professor of Behavioural and Brain Sciences at University College London said “this study has shown convincingly how the measurement of social communicative competence in childhood is a sensitive indicator of genetic risk. Our greatest challenge now is to identify how genetic variation influences the development of the social brain”.

ABOUT THIS GENETICS RESEARCH ARTICLE

The data on unaffected individuals for this study came from a general population cohort, the Avon Longitudinal Study of Parents and Children, hosted by the University of Bristol. ASD and schizophrenia collections included several large, international autism genetic studies: the Psychiatric Genomics Consortium Autism group, the Psychiatric Genomics Consortium Schizophrenia group and the iPSYCH autism project in Denmark.

Source: Beate St Pourcain – Max Planck Institute
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: The study will appear in Molecular Psychiatry during the week of January 2 2017.

A Possible Link Between Gut Bacteria and PTSD

Could bacteria in your gut be used to cure or prevent neurological conditions such as post-traumatic stress disorder (PTSD), anxiety or even depression? Two researchers sponsored by the Office of Naval Research (ONR) think that’s a strong possibility.

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

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

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

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

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

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

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

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

Image shows microbiota.

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

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

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

ABOUT THIS PTSD RESEARCH

Source: Bob Freeman – Office of Naval Research
Image Source: The image is credited to Nicola Fawcett and is licensed CC BY-SA 4.0.
Original Research: Abstract for “Posttraumatic Stress Disorder: Does the Gut Microbiome Hold the Key?” by Sophie Leclercq, Paul Forsythe, and John Bienenstock in Canadian Journal of Psychiatry. Published online February 24 2016 doi:10.1177/0706743716635535


Abstract

Posttraumatic Stress Disorder: Does the Gut Microbiome Hold the Key?

Gut bacteria strongly influence our metabolic, endocrine, immune, and both peripheral and central nervous systems. Microbiota do this directly and indirectly through their components, shed and secreted, ranging from fermented and digested dietary and host products to functionally active neurotransmitters including serotonin, dopamine, and γ-aminobutyric acid. Depression has been associated with enhanced levels of proinflammatory biomarkers and abnormal responses to stress. Posttraumatic stress disorder (PTSD) appears to be marked in addition by low cortisol responses, and these factors seem to predict and predispose individuals to develop PTSD after a traumatic event. Dysregulation of the immune system and of the hypothalamic-pituitary-adrenal axis observed in PTSD may reflect prior trauma exposure, especially early in life. Early life, including the prenatal period, is a critical time in rodents, and may well be for humans, for the functional and structural development of the immune and nervous systems. These, in turn, are likely shaped and programmed by gut and possibly other bacteria. Recent experimental and clinical data converge on the hypothesis that imbalanced gut microbiota in early life may have long-lasting immune and other physiologic effects that make individuals more susceptible to develop PTSD after a traumatic event and contribute to the disorder. This suggests that it may be possible to target abnormalities in these systems by manipulation of certain gut bacterial communities directly through supplementation or indirectly by dietary and other novel approaches.

“Posttraumatic Stress Disorder: Does the Gut Microbiome Hold the Key?” by Sophie Leclercq, Paul Forsythe, and John Bienenstock in Canadian Journal of Psychiatry. Published online February 24 2016 doi:10.1177/0706743716635535

A Link Between Gut Bacteria and Neurogenesis: Mouse Study

Summary: According to a new mouse study, antibotics that are strong enough to kill gut bacteria can also halt the growth of hippocampal neurons.

Source: Cell Press.

Antibiotics strong enough to kill off gut bacteria can also stop the growth of new brain cells in the hippocampus, a section of the brain associated with memory, reports a study in mice published May 19 in Cell Reports. Researchers also uncovered a clue to why– a type of white blood cell seems to act as a communicator between the brain, the immune system, and the gut.

“We found prolonged antibiotic treatment might impact brain function,” says senior author Susanne Asu Wolf of the Max-Delbrueck-Center for Molecular Medicine in Berlin, Germany. “But probiotics and exercise can balance brain plasticity and should be considered as a real treatment option.”

Wolf first saw clues that the immune system could influence the health and growth of brain cells through research into T cells nearly 10 years ago. But there were few studies that found a link from the brain to the immune system and back to the gut.

In the new study, the researchers gave a group of mice enough antibiotics for them to become nearly free of intestinal microbes. Compared to untreated mice, the mice who lost their healthy gut bacteria performed worse in memory tests and showed a loss of neurogenesis (new brain cells) in a section of their hippocampus that typically produces new brain cells throughout an individual’s lifetime. At the same time that the mice experienced memory and neurogenesis loss, the research team detected a lower level of white blood cells (specifically monocytes) marked with Ly6Chi in the brain, blood, and bone marrow. So researchers tested whether it was indeed the Ly6Chi monocytes behind the changes in neurogenesis and memory.

In another experiment, the research team compared untreated mice to mice that had healthy gut bacteria levels but low levels of Ly6Chi either due to genetics or due to treatment with antibodies that target Ly6Chi cells. In both cases, mice with low Ly6Chi levels showed the same memory and neurogenesis deficits as mice in the other experiment who had lost gut bacteria. Furthermore, if the researchers replaced the Ly6Chi levels in mice treated with antibiotics, then memory and neurogenesis improved.

“For us it was impressive to find these Ly6Chi cells that travel from the periphery to the brain, and if there’s something wrong in the microbiome, Ly6Chi acts as a communicating cell,” says Wolf.

Luckily, the adverse side effects of the antibiotics could be reversed. Mice who received probiotics or who exercised on a wheel after receiving antibiotics regained memory and neurogenesis. “The magnitude of the action of probiotics on Ly6Chi cells, neurogenesis, and cognition impressed me,” she says.

But one result in the experiment raised more questions about the gut’s bacteria and the link between Ly6Chi and the brain. While probiotics helped the mice regain memory, fecal transplants to restore a healthy gut bacteria did not have an effect.

Image show the impact of prolonged antibiotic treatment on brain cell plasticity and cognitive function.

“It was surprising that the normal fecal transplant recovered the broad gut bacteria, but did not recover neurogenesis,” says Wolf. “This might be a hint towards direct effects of antibiotics on neurogenesis without using the detour through the gut. To decipher this we might treat germ free mice without gut flora with antibiotics and see what is different.”

In the future, researchers also hope to see more clinical trials investigating whether probiotic treatments will improve symptoms in patients with neurodegenerative and psychiatric disorders.”We could measure the outcome in mood, psychiatric symptoms, microbiome composition and immune cell function before and after probiotic treatment,” says Wolf.

ABOUT THIS NEUROPHARMACOLOGY RESEARCH ARTICLE

Funding: This project was funded by the German Research Council.

Source: Joseph Caputo – Cell Press
Image Source: This NeuroscienceNews.com image is credited to Möhle et al./Cell Reports 2016.
Original Research: Full open access research for “Ly6Chi Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis” by Luisa Möhle, Daniele Mattei, Markus M. Heimesaat, Stefan Bereswill, André Fischer, Marie Alutis, Timothy French, Dolores Hambardzumyan, Polly Matzinger, Ildiko R. Dunay, and Susanne A. Wolf in Cell Reports. Published online May 19 2016 doi:10.1016/j.celrep.2016.04.074

CITE THIS NEUROSCIENCENEWS.COM ARTICLE
Cell Press. “A Link Between Gut Bacteria and Neurogenesis: Mouse Study.” NeuroscienceNews. NeuroscienceNews, 19 May 2016.
<http://neurosciencenews.com/neurogenesis-gut-bacteria-4253/&gt;.

Abstract

Ly6Chi Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis

Highlights
•Antibiotics decrease neurogenesis and cognitive function
•Probiotics or exercise rescues neurogenesis and cognitive function
•Ly6Chi monocytes are crucial for brain homeostasis

Summary
Antibiotics, though remarkably useful, can also cause certain adverse effects. We detected that treatment of adult mice with antibiotics decreases hippocampal neurogenesis and memory retention. Reconstitution with normal gut flora (SPF) did not completely reverse the deficits in neurogenesis unless the mice also had access to a running wheel or received probiotics. In parallel to an increase in neurogenesis and memory retention, both SPF-reconstituted mice that ran and mice supplemented with probiotics exhibited higher numbers of Ly6Chi monocytes in the brain than antibiotic-treated mice. Elimination of Ly6Chi monocytes by antibody depletion or the use of knockout mice resulted in decreased neurogenesis, whereas adoptive transfer of Ly6Chi monocytes rescued neurogenesis after antibiotic treatment. We propose that the rescue of neurogenesis and behavior deficits in antibiotic-treated mice by exercise and probiotics is partially mediated by Ly6Chi monocytes.

“Ly6Chi Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis” by Luisa Möhle, Daniele Mattei, Markus M. Heimesaat, Stefan Bereswill, André Fischer, Marie Alutis, Timothy French, Dolores Hambardzumyan, Polly Matzinger, Ildiko R. Dunay, and Susanne A. Wolf in Cell Reports. Published online May 19 2016 doi:10.1016/j.celrep.2016.04.074

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.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Source: Vladimir Koryagin – Lomonosov Moscow State University
Image Source: This NeuroscienceNews.com 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

CITE THIS NEUROSCIENCENEWS.COM ARTICLE
Lomonosov Moscow State University. “Gut Busting: How Gaseous Substances in the Body Affect Psyche and Behavior.” NeuroscienceNews. NeuroscienceNews, 26 July 2016.
<http://neurosciencenews.com/gaseous-substances-behavior-4739/&gt;.

Abstract

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

Missing link between gut and brain discovered with big implications for disease

Summary: Researchers have identified immune cells in the membranes around the brain that could be a ‘missing link’ in the gut-brain axis. The immune cells also appear to have a positive impact on recovery following spinal cord injury.

Source: University of Virginia.

A rare and powerful type of immune cell has been discovered in the meninges around the brain, suggesting the cells may play a critical but previously unappreciated role in battling Alzheimer’s, multiple sclerosis, meningitis and other neurological diseases, in addition to supporting our healthy mental functioning. By harnessing the cells’ power, doctors may be able to develop new treatments for neurological diseases, traumatic brain injury and spinal cord injuries – even migraines.

Further, University of Virginia School of Medicine researchers suspect the cells may be the missing link connecting the brain and the microbiota in our guts, a relationship already shown important in the development of Parkinson’s disease.

Unexpected Presence

The cells, known as “type 2 innate lymphocytes,” previously have been found in the gut, lung and skin – the body’s barriers to disease. Their discovery in the meninges, the membranes surrounding the brain, comes as a surprise. They were found as UVA researcher Jonathan Kipnis, PhD, explored the implications of his lab’s game-changing discovery last year that the brain and the immune system are directly connected via vessels long thought not to exist.

“This all comes down to immune system and brain interaction,” said Kipnis, chairman of UVA’s Department of Neuroscience. “The two were believed to be completely not communicating, but now we’re slowly, slowly filling in this puzzle. Not only are these [immune] cells present in the areas near the brain, they are integral to its function. When the brain is injured, when the spinal cord is injured, without them, the recovery is much, much worse.”

Curiously, the immune cells were found along the vessels discovered by Kipnis’ team. “They’re right on the lymphatics, which is really weird,” noted researcher Sachin Gadani. “You have the lymphatics and they’re stacked right on top. They’re not inside of them – they’re around them.”

Image shows immune cells.

Important Immune Role

The immune cells play several important roles within the body, including guarding against pathogens and triggering allergic reactions. In exploring their role in protecting the brain, the Kipnis team has determined they are vital in the body’s response to spinal cord injuries. But it’s their role in the gut that makes Kipnis suspect they may be serving as a vital communicator between the brain’s immune response and our microbiomes. That could be of great importance, because our intestinal flora is critical for maintaining our health and wellbeing.

“These cells are potentially the mediator between the gut and the brain. They are the main responder to microbiota changes in the gut. They may go from the gut to the brain, or they may just produce something that will impact those cells. But you see them in the gut and now you see them also in the brain,” Kipnis said. “We know the brain responds to things happening in the gut. Is it logical that these will be the cells that connect the two? Potentially. We don’t know that, but it very well could be.”

Image shows immune cells.

While much more research needs to be done to understand the role of these cells in the meninges, Gadani noted that it’s almost certain that the cells are important in a variety of neurological conditions. “It would be inconceivable they’re not playing a role in migraines and certain conditions like that,” he said. “The long-term goal of this would be developing drugs for targeting these cells. I think it could be highly efficacious in migraine, multiple sclerosis and possibly other conditions.”

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

The article is by Gadani, of UVA’s Medical Scientist Training Program; Igor Smirnov; Ashtyn T. Smith; Christopher C. Overall; and Kipnis, who, in addition to being department chairman, is the director of UVA’s Center for Brain Immunology and Glia (BIG).

Funding: The work was supported by the National Institutes of Health, grant NS081026.

Source: Josh Barney – University of Virginia
Image Source: NeuroscienceNews.com images are credited to Sachin Gadani | University of Virginia School of Medicine.
Original Research: Abstract for “Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury” by Sachin P. Gadani, Igor Smirnov, Ashtyn T. Smith, Christopher C. Overall, and Jonathan Kipnis in Journal of Experimental Medicine. Published online December 19 20166 doi:10.1084/jem.20161982


Abstract

Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury

The meningeal space is occupied by a diverse repertoire of immune cells. Central nervous system (CNS) injury elicits a rapid immune response that affects neuronal survival and recovery, but the role of meningeal inflammation remains poorly understood. Here, we describe type 2 innate lymphocytes (ILC2s) as a novel cell type resident in the healthy meninges that are activated after CNS injury. ILC2s are present throughout the naive mouse meninges, though are concentrated around the dural sinuses, and have a unique transcriptional profile. After spinal cord injury (SCI), meningeal ILC2s are activated in an IL-33–dependent manner, producing type 2 cytokines. Using RNAseq, we characterized the gene programs that underlie the ILC2 activation state. Finally, addition of wild-type lung-derived ILC2s into the meningeal space of IL-33R−/− animals partially improves recovery after SCI. These data characterize ILC2s as a novel meningeal cell type that responds to SCI and could lead to new therapeutic insights for neuroinflammatory conditions.

“Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury” by Sachin P. Gadani, Igor Smirnov, Ashtyn T. Smith, Christopher C. Overall, and Jonathan Kipnis in Journal of Experimental Medicine. Published online December 19 20166 doi:10.1084/jem.20161982


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