SEE BELOW IN THIS SECTION ON CHOLINE:
DO YOU INGEST ENOUGH CHOLINE?
Are You One of the 92% of the Population
THE VAGUS NERVE, WITH ITS MAJOR NEUROTRANSMITTER BEING ACETYLCHOLINE,
WHEN ACTIVATED IN WOMEN CAN PRODUCE O R G A S M!
That Does Not Consume the Adequate Intake of
Choline Recommended by the Institute of Medicine?
CHOLINE is an Essential Nutrient But Much More
An article in a food industry trade journal (Hutt. "Choline: the Silent Deficiency," Prepared Foods, Jan. 2015) warns that Choline is the “Silent Deficiency” and cites Institute of Medicine data from 2007 to 2010 showing that 92% of Americans are not getting the recommended AI (adequate intake) of choline, 550 mg/day for men and 425 mg/day for women (more is recommended in the case of pregnant and lactating women). The article points out the opportunity for the food industry to “do well by doing good” (our words, not the article’s) by fortifying foods with choline. As they explain, the FDA allows a claim of a “good” source of choline for a product containing 75 mg of choline chloride or 137.5 mg of choline bitartrate per serving. To be permitted to say your product is an “excellent” source of choline, the FDA requires that the product contains twice this much per serving. The article goes on from there to discuss a number of health benefits from taking choline, typically (as in most trade publications) providing no references to the scientific literature on choline! Incredibly, the article claims that choline sales are not reported by companies that track the supplement market other than Nielsen/SPINS, which reported the combined sales of choline and inositol in 2012, with these sales in natural/mass channels reported to reach an unbelievably tiny $428,000. What gives? How can a nutrient as important as choline and ingested at such an officially estimated meager level by most Americans have escaped notice?
The Institute of Medicine
Chances are that you are not getting enough choline in your diet and, unless you take a choline supplement, you are not ingesting the AI recommended by the Institute of Medicine, an amount that (on the basis of the scientific literature) is on the low side of what would be optimal. Here are a few of the important health benefits provided by choline, some of which you have undoubtedly read about but others you are likely to have never heard of. You should know about these if you are not yet taking a choline supplement.
NOTE TO OUR READERS: In order to keep this newsletter from expanding beyond the bounds of a reader’s reasonable time to spare, we have not included much of what we had written up on beneficial effects of choline. More on that in a later newsletter!
CHOLINE FOR MEMORY AND LEARNING
One of the oldest known and studied effects of the cholinergic nervous system is its relation to learning and memory, with one early influential paper from 1974. A later paper showed that acetylcholine in the forebrain regulates adult hippocampal neurogenesis and learning. A recent paper reported that in a community-based population of nondemented individuals, participants in the Framingham Offspring Cohort (744 women and 647 men aged 36–83), higher concurrent dietary choline intake was related to better cognitive performance.
- Drachman and Leavitt. Human memory and the cholinergic system. Arch Neurol. 30:113–21 (1974).
- Mohapel, Leanza, et al. Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging. 26:939–46 (2005).
- Poly, Massaro, et al. The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort. Am J Clin Nutr. 94:1584–91 (2011).
THE CHOLINERGIC NERVOUS SYSTEM IS THE MAJOR ANTIINFLAMMATORY PATHWAY
A MAJOR REGULATOR OF INFLAMMATION
INFLAMMATION, A RECOGNIZED CAUSE OF
CANCER, CARDIOVASCULAR DISEASE, AGE-
ASSOCIATED DISEASES, AND
An early (2007) review paper on the cholinergic antiinflammatory pathway quoted Claude Bernard who thought that health was due to equilibrium in the “milieu interieur” by a “continuous and delicate compensation, established with the most sensitive of balances” (“Lessons on the phenomena of life common to animals and vegetables”). This early view foresaw in a simple sketch the new understanding of health that we have today and in which the cholinergic antiinflammatory pathway plays a major role in maintaining that “balance” of which Claude Bernard wrote.
The review then discussed the emergence of the “cytokine theory of disease” in which defensive molecules, the inflammatory cytokines, produced by the immune system can cause the signs, symptoms, and damaging after effects of disease. The cholinergic antiinflammatory pathway is important in preventing the damage that can be caused by massive releases of these cytokines in response to various diseases. In one example, a major cytokine, TNF-alpha (tumor necrosis factor alpha) is released in response to gram-negative bacteria but excessive amounts of that release can cause septic shock. With the problem of antibiotic resistance increasingly making it difficult to treat septic shock, this condition has a high mortality rate.
The Vagus Nerve
An early discovery was that the vagus nerve served as a conduit for signals from the cholinergic nervous system to modulate the production of inflammatory cytokines. For example, the review notes that, “an accidental discovery revealed that intracerebral administration of a molecule that inhibited TNF production also increased efferent vagus nerve activity and inhibited inflammation outside the CNS.” The mechanism responsible for this effect was found to be acetylcholine, the major vagus nerve neurotransmitter. Acetylcholine signals the inhibition of cytokine synthesis via the vagus nerve.
Keep in mind that this was an early review on a research area about to explode, and it continues to expand at a dramatic pace today. The review points to scientific evidence suggesting that signaling via the vagus nerve can affect many aspects of human health, noting specifically that sudden death, increased morbidity and mortality following cardiac surgery in hostile or depressed patients, and increased death rates in patients with sepsis or organ failure have been linked (as of the date this paper was published and supported by new evidence since then) to decreased vagus nerve activity. These are just three examples out of many medical conditions in which deficient vagus nerve activity plays an important role.
One of those mysteries that remains unexplained is noted at the end of the review, where it is mentioned that clinical antiinflammatory responses may be linked to the fat induced stimulation of the cholinergic antiinflammatory pathway as in the case of rats, using fish oil, soy oil, olive oil or other fats. And, now (to the review, “now” is 2007), the review says, a major source of systemic TNF during lethal challenges is the spleen, the source of Galen’s black bile. The review finishes by asking: How did the ancient Greeks know? (It may have simply been that the ancients noticed that when people had this black gunk emerging from the spleen, they were unlikely to survive.)
1. Tracey. Physiology and immunology of the cholinergic aniinflammatory pathway. J Clin Invest. 117(2):289–96 (2007).
Choline Attenuates Immune Inflammation in Patients with Asthma
A 2010 paper reported that, in a randomized study, 76 asthma patients were treated with 1500 mg of choline chloride twice daily + pharmacotherapy or with pharmacotherapy alone (pharmacotherapy was inhaled steroids and long-acting beta adrenergic agonist), with short acting beta adrenergic agonist given as needed. There was a significant decrease in symptom/drug use score of patients receiving choline from baseline, but no significant change in the symptom/drug use score from baseline in the standard pharmacotherapy alone group patients. Choline was also reported to significantly decrease peripheral eosinophil counts and Th2 response (the immune system activity that occurs during active disease) such as lower IL-4 levels and reduced TNF-alpha levels in the choline treated patients.
These results indicate activation of the cholinergic antiinflammatory pathway by treatment with choline in human asthma patients.
2. Mehta, Singh, et al. Choline attenuates immune inflammation and suppresses oxidative stress in patients with asthma. Immunobiology. 215:527–34 (2010).
Dietary Choline and Betaine Intake Associated with Reduced Levels of Inflammatory Markers in Healthy Adults
In an early study (2008) in the runup of research following the discovery of the cholinergic antiinflammatory pathway, a cross sectional survey of 1514 men and 1528 women with no history of cardiovascular disease was carried out (the ATTICA Study). Compared with the lowest tertile of choline intake (<250 mg/d), participants who consumed >310 mg/d had, on average, 22% lower concentrations of C-reactive protein [with high levels linked to poor cardiovascular health], a commonly used measure of inflammation, 26% lower concentration of IL-6 (an inflammatory cytokine), and 6% lower concentration of tumor necrosis factor alpha, another inflammatory cytokine. (Similarly, those who consumed >360 mg/d of betaine had an average of 10% lower homocysteine levels, 19% lower C-reactive protein, and 12% lower concentrations of TNFalpha than did those who consumed <260 mg/day.)
This was an associational study, thus did not provide evidence for cause and effect. But it was an early study and much more was to come in later research to support these findings as having causal implications.
3. Detopoulou et al. Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr. 87:424–30 (2008).
A 2014 paper reported that chronic stimulation of the vagus nerve improved left ventricular function in a canine model of chronic mitral valve regurgitation. As the authors explain, autonomic dysregulation, failure of the systems regulating (for example) respiration and heart function, is characterized by activation of the sympathetic nervous system (adrenergic) and declining activity of the vagus (cholinergic) nerve and is an important contributor to the progression of heart failure. “One of the key features of chronic heart failure (CHF) is the autonomic sympathetic/parasympathetic (adrenergic/cholinergic) imbalance, which is usually characterized by excessive sympathetic drive accompanied by parasympathetic withdrawal.” They further explain that the use of inhibitors of sympathetic activity (such as beta adrenergic receptor blockers) is one of the ways that has been used to treat this problem but, “[o]n the other hand, reversing the sympathetic/parasympathetic imbalance by enhancing parasympathetic activity through vagal nerve stimulation (VNS) becomes an obvious potential therapeutic approach.”
In this study, dogs had mitral valve regurgitation induced experimentally and were treated with electrodes that stimulated the vagus nerve. The results showed improved contractile function and significant improvement (that is, reduced expression) of inflammatory markers such as C-reactive protein.
4. Yu, Tang, et al. Chronic vagus nerve stimulation improves left ventricular function in a canine model of chronic mitral regurgitation. J Transl Med. 12:302 (2014).
YOU MAY NEED MORE CHOLINE THAN THE AMOUNT RECOMMENDED BY THE INSTITUTE OF MEDICINE
New Study Reports Genetic Differences Between Ethnic and Racial Groups in Amount of Choline Required
The Institute of Medicine of the National Institute of Health defines the “adequate intake” (AI) for choline as 550 mg/day for men and 425 mg/day for women. Many Americans are said not to ingest the AI for choline, which can result in fatty liver, liver damage, muscle damage, and may promote eventual dementia. In this new paper, scientists report that genetic differences (identified as single nucleotide polymorphisms, SNPs) between ethnic and racial groups indicate that the amount of choline required will differ between these groups. Seventy-nine humans were fed a low choline diet and 200 SNPs in 10 genes related to choline metabolism examined to determine associations with organ dysfunction. Some people on low choline diets presented with muscle damage, others with liver damage.
As the researchers note, the setting of dietary recommendations has not (or has rarely) considered genetic diversity in the need for daily intake of nutrients. They suggest that the simplest and safest way to deal with this is to set dietary recommendations at a level high enough to meet the needs of those with the greatest requirements. That may indeed be the simplest and safest way, but what these researchers probably have not considered is that dietary programs (school lunches, food stamps, etc.) are based upon these dietary recommendations and setting the level high enough to meet the needs of those with the greatest requirements would be quite a bit more expensive for these government programs than setting it at a level that would meet the requirements of the average American. Moreover, when you think of the case of choline, the foods that can supply it (eggs, dairy, and fish, for example) tend to be on the expensive side or perhaps on the yucky side (liver).
Add to the genetic variation the decreasing ability of older persons to transport choline into the brain and it appears likely that a significant fraction of the populace may require a higher intake of choline than that recommended by the Institute of Medicine of the National Institute of Health, where experiments on nutrition are usually done on college students. A recent paper showed that a donor of peroxynitrite, a potent oxidant, as well as other oxidants, caused rapid dose-dependent inhibition of the sodium-coupled high-affinity choline transporters, suggesting one possible mechanism for the decreased choline transport in older persons.
It has also been reported that choline acetyltransferase, the enzyme needed to convert choline to acetylcholine, is inhibited by exposure to excitatory amino acids. Taurine and the antiinflamatory compounds naturally formed from it, taurine bromamine and taurine chloramine, are able to provide protection against these inflammatory excitatory amino acids and, hence, are likely to help prevent the suppression of choline acetyltransferase formation resulting from exposure to excitatory amino acids.
- da Costa, Corbin, Niculescu, et al. Identification of new genetic polymorphisms that alter the dietary requirement for choline and vary in their distribution across ethnic and racial groups. FASEB J. 28:2970–8 (2014).
- Cohen, Renshaw, Stoll, Wurtman, et al. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. JAMA.274(11):902–7 (1995).
- Louzada et al. Taurine prevents the neurotoxicity of beta-amyloid and glutamate receptor agonists; activation of GABA receptors and possible implications for Alzheimer’s disease and other neurological disorders. FASEB J. 18:511–8 (2004).
- Cuddy, Gordon, et al. Peroxynitrite donor SIN-1 alters high affinity choline transporter activity by modifying its intracellular trafficking. J Neurosci.32(16):5573-84 (2012).
Central Fatigue May Be Associated with Low Activity of the Vagus Nerve and Hence of Low Parasympathetic (Cholinergic) Nervous System Activity
For example, the authors explain that glucocorticoids, stress hormones, play an important role in the regulation of the sympathetic nervous system (SNS), restraining SNS responses after stress and under resting conditions. The paper suggests that although glucocorticoids are often considered immunosuppressive, it may be more accurate to call them immune modulators and that they can have important antiinflammatory effects via negative feedback to the immune system’s production of inflammatory cytokines. Thus, like the cholinergic antiinflammatory pathway, glucocorticoids help to keep the sympathetic nervous system under control.Central fatigue is chronic fatigue, lasting six months or more, characterized by a persistent sense of tiredness, has been reported to generally correlate poorly with traditional markers of disease. “In general, hypoactivity of the hypothalamic-pituitary-adrenal axis, autonomic nervous system alterations characterized by sympathetic overactivity and low vagal tone, as well as immune abnormalities, may contribute to the expression of CF [chronic fatigue].” “Central fatigue generally correlates poorly with traditional markers of disease and is frequently associated with other psychosocial factors, such as depression, sleep disorder, anxiety, and coping styles, which suggests that dysregulation of the body’s stress systems may serve as an underlying mechanism of CF.”
Despite many attempts to pin down CF to specific immune abnormalities, to hypercortisolism or hypocortisolism, results have been inconsistent. However, the paper reports that a recent and robustly designed study showed that “fatigue not only in its severe and chronic form, as in CFS [chronic fatigue syndrome], but also in its milder forms, is associated with increased inflammation, as indexed by elevated plasma C-reactive protein levels and white blood cell counts, even after adjusting for depressive status. This study further supports the notion that the symptom of fatigue, rather than a diagnosis of CFS itself, may be what is clinically associated with inflammation.”
- Silverman, Helm, et al. Neuroendocrine and immune contributors to fatigue. PM R. 2(5):338–346 (2010).
- Raison, Lin, Reeves. Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun. 23:327–337 (2009) PubMed: 19111923.
A 2005 paper reported a study by fMRI of the brain regions activated during orgasm by vaginal cervical mechanical self-stimulation in women with spinal cord injury. A number of areas of the brain were activated during orgasm, with the authors concluding that, “the Vagus nerves provide a spinal cord-bypass pathway for vaginal-cervical sensibility and that activation of this pathway can produce analgesia and orgasm.” The authors comment that some patients, both men and women, who have spinal cord injury described an intensely sensitive to the touch area of skin near their injury and which when stimulated in the right way, can produce orgasm. Just an interesting little tidbit here. Too bad they didn’t try choline supplementation in some of these patients.
- Komisaruk, Whipple. Functional MRI of the brain during orgasm in women. Annu Rev Sex Res. 16:62–86 (2005).
BEST FOOD SOURCES FOR CHOLINE IF YOU CHOOSE TO GET IT FROM YOUR DIET
The March 2004 USDA Database for the Choline Content of Common Foods tells you that the highest food sources for choline include egg yolk, raw, fresh (682.4 mg choline moiety/100 g of food), chicken liver, all classes, cooked, pan-fried (308.5 mg choline moiety/100 g of food), veal, variety meats and by-products, liver, cooked, pan-fried (411.0 mg choline moiety/100 g of food). Perhaps a more palatable source is one egg, whole, cooked, fried (272.6 mg choline moiety/100 g of food), while a hardboiled egg contained 225.2 mg choline moiety/100 g of food.
Your brain on choline.
“Choline moiety” is choline contributed by free choline, phosphatidylcholine, phosphocholine, glycerophosphocholine, and sphingomyelin.