Diet Induced Pro-inflammatory State


Vitamin and Mineral Deficiencies = Radiation Damage?
by David Seaman,DC,MS,DACBN

The Diet-Induced Pro-Inflammatory State

         Part 1 of 6: Vitamin and Mineral Deficiencies = Radiation Damage?

         Part 2 of 6: Give Your Patients a Nutritional Adjustment

         Part 3 of 6: Give Yourself a Nutritional Adjustment

         Part 4 of 6: The Diet-Induced Pro-Inflammatory State

         Part 5 of 6: Do You Frequently Get Tired After a Meal? You Need a Nutritional Adjustment!

         Part 6 of 6: Magnesium Defiency, Inflammation and Nervous System Hyperexcitability

I never thought I would write an article with such a title. At first glance, such a relationship seems a little hard to swallow. Nonetheless, such a connection appears to exist and was reviewed in a recent issue of Mutation Research,1 a journal that has been around for a long time, but not one DCs would commonly read. I came across this article during a Medline search for new studies on multivitamins.

I have been amazed at the new work on multivitamins that has been published in recent years. For example, Chandra performed a randomized, double blind, placebo-controlled trial to determine if one year of multivitamin supplementation could help cognitive function in men and women 65 years of age or older.2 Compared with controls, the supplement group showed a significant improvement in all cognitive tests (P<0.001 to 0.05) except long-term memory recall (P > 0.1). Consider Chandra's conclusion: "We recommend that such a supplement be provided to all elderly subjects because it should significantly improve cognition and thus quality of life and the ability to perform activities of daily living. Such a nutritional approach may delay the onset of Alzheimer's disease."2

Supplementation with a multivitamin/mineral also proved to lower homocysteine levels in a group of 50-87 year-olds who already consumed a folate-fortified diet.3 The mean homocysteine concentration decreased 9.6 percent in the supplemented group (P: < 0.001), and was unaffected in the placebo group. No significant changes in dietary intake were noted during the intervention. Based on this work, we can suggest that routine multivitamin supplementation might have a profound impact on preventing heart disease.

We can also protect vision with multivitamins. Compared with nonusers, the five-year risk for any cataract was 60 percent lower among persons who, at follow-up, reported the use of multivitamins, or any supplement containing vitamin C or E, for more than 10 years.4

Feeling a little stressed out? Multivitamin supplementation appears to help people better cope with stress. There were no statistically significant differences between the two study groups for demographics and baseline stress scores at a recent study's entry. Both groups (151 supplemented and 149 placebo) improved between baseline and the end of treatment as assessed. The degree of improvement was statistically significant and greatest in the supplemented group for all psychometric instruments, with this beneficial effect increasing over the course of the day. The multivitamin/mineral combination tested is well tolerated and can be used as part of a treatment program for stress-related symptoms at the recommended dose.5

Supplementation with multivitamins has even been shown to reduce birth deformities. Research found a 48 percent risk reduction for cleft lip (with or without cleft palate) among infants of mothers who used multivitamins during the periconceptional period, or who started multivitamin use during the first postconceptional month (after controlling for several covariates).6 With this study in mind, consider the title of this article. Most are well aware that radiation exposure can damage DNA and cause birth defects and cancer in children of exposed parents. However, very few of us would have considered that vitamin deficiencies can mimic radiation exposure. Ames1 explains: "A deficiency of any of the micronutrients: folic acid, vitamin B12, vitamin B6, niacin, vitamin C, vitamin E, iron, or zinc mimics radiation in damaging DNA by causing single and double-strand breaks, oxidative lesions, or both. Common micronutrient deficiencies are likely to damage DNA by the same mechanism as radiation and many chemicals, appear to be orders of magnitude more important, and should be compared for perspective. Remedying micronutrient deficiencies should lead to a major improvement in health and an increase in longevity at low cost."1

According to Ames,1 the RDA is mainly based on information on acute effects, and the optimum amount for long-term health is generally not known. Optimum intake of a micronutrient can vary with age and genetic constitution, state of well-being, and is also influenced by other aspects of diet. The optimum amount to protect against genomic (DNA) damage is generally thought to be higher than the current recommended daily allowance, and a sizeable percentage of the population is deficient relative to the RDAs.

In the recent past, many in mainstream medicine belittled multivitamin supplementation. However, recent research should dramatically change this view. Indeed, the June 19 issue of the Journal of the American Medical Association contained two articles devoted to the importance of multivitamin supplementation.7,8 In no uncertain terms, Fletcher and Fairfield state: "In the absence of specific predisposing conditions, a usual North American diet is sufficient to prevent overt vitamin deficiency diseases. ... However, insufficient vitamin intake is apparently a cause of chronic diseases. ... A large proportion of the general population is apparently at increased risk for this reason. ... We recommend that all adults take a multivitamin daily."8

Despite your background and approach to patient care, it is certainly reasonable to recommend supplementing with at least a multivitamin. As chiropractors, our philosophical orientation is to prevent the development of disease. Accordingly, the utilization of multivitamins in practice should be an easy addition if you are not already doing so. Multivitamin supplementation is a simple intervention that all patients need, and compliance is high if the importance of such supplementation is properly described.

1. Ames BN. DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mut Res 2001;475:7-20.
2. Chandra RK. Effect of vitamin and trace-element supplementation on cognitive function in elderly subjects. Nutrition 2001;17(9):709-12.
3. McKay DL, Perrone G, Rasmussen H, Dallal G, Blumberg JB. Multivitamin/mineral supplementation improves plasma B-vitamin status and homocysteine concentration in healthy older adults consuming a folate-fortified diet. J Nutr 2000;130(12):3090-96.
4. Mares-Perlman JA, Lyle BJ, Klein R, et al. Vitamin supplement use and incident cataracts in a population-based study. Arch Ophthalmol 2000; 118(11):1556-63.
5. Schlebusch L, Bosch BA, Polglase G, Kleinschmidt I, Pillay BJ, Cassimjee MH. A double-blind, placebo-controlled, double-centre study of the effects of an oral multivitamin-mineral combination on stress. S Afr Med J 2000;90(12):1216-23.
6. Itikala PR, Watkins ML, Mulinare J, Moore CA, Liu Y. Maternal multivitamin use and orofacial clefts in offspring. Teratology 2001;63(2):79-86.
7. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA 2002;287(23):3116-26.
8. Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: clinical applications. JAMA 2002;287 (23):3127-9.

About the author: Dr. Seaman is on the postgraduate faculties of several chiropractic colleges providing nutritional instruction, and is a clinical chiropractic consultant. He believes that chiropractors, when providing nutritional recommendations, view proper nutrition as a "nutritional adjustment" that complements the chiropractic adjustment. He is the author of Clinical Nutrition for Pain, Inflammation and Tissue Healing.

David Seaman, DC
Wilmington, North Carolina

[email protected]

Give Your Patients a Nutritional Adjustment

by David Seaman,DC,MS,DACBN

In my first article on the pro-inflammatory state ("Vitamin and Mineral Deficiencies = Radiation Damage?", I focused on fatty acids and their relationship to the pro-inflammatory state. Recall that grains contain an excessive amount of pro-inflammatory n(omega)6 fatty acids, and are essentially devoid of the anti-inflammatory n3 fatty acids. Unfortunately, there are additional problems with grains, flours, and related products (breads, pastas, cereals, muffins, desserts, and the like). For example, grains increase tissue acidity,1-4 which is a significant problem.

The human body possesses what is referred to as a "fixed acid production." Numerous metabolic reactions produce acids that must be buffered. We derive alkaline buffers from fruits and vegetables, and acidic end products from meats and grains.1-3

It is known that pain is augmented by tissue acidity, and that our musculoskeletal structures, particularly our bones and muscles, degenerate due to tissue acidity. Clearly, this subject has important implications for our patient population.

Spinal Pain and Inflammation

Most patients enter a chiropractic office with pain and inflammation. Although DCs think structurally, we must realize that it is the chemical mediators of inflammation that activate nociceptors, which result in pain and drive patients to our offices.

For many years it has been known that an acidic pH works synergistically with the chemical mediators of inflammation to activate and sensitize tissue nociceptors.5 Evidence existed regarding low back pain and pH at least as early as the 1960s. At the time of surgery, Nachemson discovered that the pH of lumbar discs ranged from 5.7 to 7.5. The lower the pH, the greater the pain, disc degeneration, and fibrous tissue deposition.6

Hambly and Mooney state that "sick" discs, as reflected by pain on discography, have consistently demonstrated an acidic pH.7 Additionally, an acidic pH will reduce proteoglycan synthesis.8

An acidic pH is also known to reduce bone mineral density and promote osteoporosis.9,10 Researchers also believe that an acidic environment will promote the muscle wasting that occurs with aging.11,12

Clearly, an acidic biochemical environment is capable of promoting inflammation; pain; histopathology; bone pathology; and myopathology. When this series of events occurs in the spine, we call it subluxation.

Causes of Acid-Induced Subluxation

Researchers who study pH explain that with advancing age we develop a low-grade metabolic acidosis. Kidney function normally declines as we age, such that we develop renal insufficiency and a compromised acid-base regulatory capacity.12

Presumably, if we take care of ourselves and adopt a healthy lifestyle, we might be able to delay the inevitable decline in body pH that will occur in all of us. In fact, we can profoundly influence body pH by eating more fruits and vegetables and by not smoking. As mentioned above, it has been known for many years that fruits and vegetables are alkaline, while grains and meat are acidic. Additionally, it is known that smoking lowers pH,7 so why not quit if you are a smoker. Drinking soda can also provide an unnecessary acid load, and this should be avoided.

New Study on pH and Back Pain

As described above, increased tissue acidity can cause inflammation; nociception; pain; bone loss; and muscle wasting. Accordingly, researchers recently hypothesized that a latent chronic acidosis might contribute to the symptoms of back pain, and sought to see if supplementation with alkaline minerals might reduce overacidity and pain.13 For four weeks, 82 patients with chronic low back pain took a supplement containing calcium; potassium; sodium; magnesium as citrates; and a number of trace elements. Seventy-six patients reported a reduction in pain, while blood buffering capacity and venous blood pH both increased.

As this was an open trial, a more rigorous placebo-controlled trial is needed. Certainly the research departments at one of our chiropractic colleges could perform such a trial, which may help to elucidate the interactions between mechanical and chemical causes of low back pain.


Latent chronic tissue acidity is thought to be a cause of skeletal degeneration and pain. While the specific details have yet to be elucidated, there is no reason to wait before implementing corrective nutritional measures. Eat more vegetables and fruits and minimize the consumption of grains and sodas, and add a multiple vitamin, supplemental minerals, and an omega-3 fatty acid supplement. These are simple modifications anyone can make, which may have a profound health outcome for your patients. Don't wait any longer, give your patients a nutritional adjustment.

9.       Kleiner I, Orten J. Human Biochemistry 5th ed. St. Louis: CV Mosby 1961: p. 355.
10.    Orten J, Neuhaus O. Biochemistry 8th ed. St. Louis: CV Mosby 1970: p. 861.
11.    Carney A. Internal exchanges of hydrogen ions: Gastrointestinal tract. In: Seldin & Giebisch. eds. The Regulation of Acid Base Balance. New York: Raven Press 1989: p. 89-105.
12.    Cordain L. Cereal grains: humanity is double edge sword. World Rev Nutr Diet 1999;84:19-73.
13.    Handwerker H. Chemosensitivity and sensitization by chemical agents. In Willis W. ed. Hyperalgesia and Allodynia. New York: Raven Press 1992: p. 107-15.
14.    Nachemson A. Intradiscal measurements of pH in patients with lumbar rhizopathies. Acta Ortho Scand 1969;40:23-42.
15.    Hambly MF, Mooney V. Effect of smoking and pulsed electromagnetic fields on intradiscal pH in rabbits. Spine 1992;17(6 Suppl):S83-5.
16.    Oshima H, Urban JPG. The effect of lactate and pH on proteoglycan and protein synthesis rates in the intervertebral disc. Spine 1992;17(9):1079-82.
17.    Hegsted DM. Fractures, calcium and the modern diet. Am J Clin Nutr 2001; 74:571-73.
18.    New SA, et al. Dietary influences on bone mass and bone metabolism: further evidence of a positive link between fruit and vegetable consumption and bone health? Am J Clin Nutr 2000; 71:142-51.
19.    Frasetto LA, Morris RC, Sebastian A. Potassium bicarbonate reduces urinary nitrogen excretion in postmenopausal women. J Clin Endocrinol Metab 1997;82:254-259.
20.    Frasetto LA, Todd KM, Morris RC, Sebastian A. Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents. Am J Clin Nutr 1998; 68:576-83.
21.    Vormann J, Worlitschek M, Goedecke T, Silver B. Supplementation with alkaline minerals reduces symptoms in patients with chronic low back pain. J Trace Elem Med Biol 2001;15:179-83.

David Seaman,DC,MS,DACBN

Give Yourself a Nutritional Adjustment

by David Seaman,DC

In the March/April issue of JMPT,1 I published an article that described how we "eat ourselves into an inflamed state," that is, a condition which promotes chronic pain and such inflammatory conditions as cancer, heart disease, and Alzheimer's. Readers need to appreciate that the inflammation that drives these conditions is subclinical and chronic, unlike what you see after an acute injury. Atherosclerosis is now viewed as a chronic, smoldering inflammatory state that develops slowly and unnoticed - until one has a sudden heart attack. (The most recent and easy-to-read review of this subject is "A Fire Within: Inflammation's Link to Heart Disease," published in the May 2002 edition of Scientific American.)

We need to appreciate that the chronic, subclinical inflammation that drives atherosclerosis is not limited to blood vessels. It is the body that is subclinically inflamed, and the area of primary manifest-ation just happens to be in the coronary vessels. Depending on one's genetic predisposition, some may develop atherosclerosis; others may get cancer; still others develop Alzheimer's or osteoporosis. Some may just suffer with back pain, headaches or a sensitive gut.

Respective of the location of the tissue dysfunction or disease, it seems reasonably clear that a poor diet is responsible for driving the subclinical chronic inflammatory state. In short, a diet that is deficient in fruits and vegetables will ultimately promote inflammation. How might this be? First, the phytonutrients and fatty acids in fruits and vegetables are anti-inflammatory. And second, consider what people who avoid fruits and vegetables eat. They eat copious amounts of pro-inflammatory grains in the form of bread; muffins; pasta; cereal; chips; pretzels; and dessert foods.

Americans are bread-eaters trying to hasten their deaths. (I use the word "bread" to refer to all of the grain products mentioned above.) They are so convicted in their bread-eating efforts that most get nervous and wonder what they might eat if they stop eating bread in all its forms. Understand that bread is a new food from an evolutionary perspective, so it is kind of shocking to consider that we have no idea about what to eat if we can't reach for a piece of bread.

Consider that humans existed as noncereal-eating hunter-gatherers since the emergence of Homo erectus some 1.7 million years ago.2 The sum of evidence indicates that the human genetic constitution has changed little over the past 40,000 years. The addition of cereal grains some 5,000 to 10,000 years ago represents a dramatic departure from those foods to which we are genetically adapted - wild game, fruits and vegetables.2 Today, the absurd level of grains consumed by most people is truly an assault on our genes. We feed bread to our cattle and other animals; we even raise fish in farms where they are fed bread. In contrast, consider that game animals either eat foliage, fruit or smaller animals that have also fed on foliage and/or fruit.

What Makes Grains Pro-Inflammatory?

Many people make the mistake of thinking that whole grains are healthy, while refined grains represent the problem. This is an incorrect notion. Grains, in general, are problematic, and here is why. Grains and bread contain excessive amounts of pro-inflammatory omega-6 fatty acids, gluten (to which many are sensitive) and lectins that inflame the gut and promote systemic disease. They are deficient in such key nutrients as vitamins C, A, B12 and beta-carotene.1 The pH of grains is acidic. Lowering body pH can promote inflammation, pain and osteoporosis. A small amount of grains is not a problem for most, but they become problematic when they are relied upon extensively. The "food pyramid" guide, for example, suggests that we get 6-11 servings of grains per day. There is no good evidence for this quantity of grain consumption. Most of us would do much better if we were to replace pro-inflammatory breads with anti-inflammatory fruits and vegetables.

Omega-6 Fatty Acid Imbalances

While grains harbor many problematic substances, I will focus herein on the omega-6 fatty acids. We are genetically accustomed to a 1:1 ratio of omega-6 (n6) to omega-3 (n3) fatty acids. Under 4:1 is an acceptable ratio, however, as the ratio increases, so does inflammation. The average American's ratio range is from 10:1 to 30:1, reflecting an extreme aberration that creates a pro-inflammatory state, which is thought to promote pain; inflammation; cancer; heart disease; Alzheimer's disease; inflammatory gut disease; depression; osteoporosis; and most of the other chronic diseases from which we suffer. In general, n6 fatty acids result in the production of eicosanoids (prostaglandins, leukotrienes, and thromb-oxanes) and cytokines that are pro-inflammatory. Omega-3 fatty acids, on the other hand, have the opposite effect on eicosanoids and cytokines.

Linoleic acid is an n6 fatty acid in great abundance in grains, while alpha-linolenic acid (ALA) is an n3 fatty acid in green vegetables. Grains contain only miniscule amounts of ALA, the anti-inflammatory n3 fatty acid.

Consider oatmeal, a very common breakfast food, for example. In one quarter of a cup of rolled oats, we are treated to .44 mg of linoleic acid (n6) and .02 mg of linolenic acid (n3), which reflects a 21:1 ratio of n6 to n3.3 White bread provides a 21:1 ratio, while whole wheat contains a 27:1 ratio.3 Potato chips boast a 60:1 ratio, and corn chips provide a 12:1 ratio.3 I suggest throwing away all of these foods, and avoid consuming grains, such as those in bread, for at least three months. Thereafter, have one serving per day, if you wish.

What about vegetables? Broccoli provides an impressive 1:3 ratio of n6 to n3, and kale offers a 1:1.3 ratio, while most lettuces give a 1:2 ratio.3 Fish ranges from 1:1 to 1:7, which represents the most significant source of n3 fatty acids. Obviously, this reflects the values found in fresh fish that is baked, broiled or steamed, and not packaged fish found in the frozen food section of the store, or deep-fried at your local fast-food restaurant.

The ratio of n6 to n3 in fruits generally ranges from 2:1 to 1:1. For example, blueberries are noted for their heavy concentration of bioflavonoids; they produce a 4:3 ratio of n6:n3. Cherries are also rich in flavonoids and provide a 1:1 ratio. The banana, one of the more commonly eaten fruits, possesses a 2:1 ratio.3

Clearly, the mainstay of our diet should be fruits, vegetables and fish. You can also buy special n3-rich eggs from your supermarket or health food store. Grass-fed beef rich in n3s is also available; however, you need to order it on line.

Omega-3 Supplements

At this point, it should be clear that we gorge ourselves with n6 fatty acids and create a pro-inflammatory state that drives inflammation, pain and chronic disease. Regretfully, it is nearly impossible to ensure a proper ratio of n6:n3 if you plan to do anything but shop and prepare meals. I strongly suggest that you immediately begin a lifelong supplementation program involving n3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA). We find these in fresh fish and wild game to varying degrees. However, they are most commonly associated with fish, so EPA and DHA supplements are typically referred to as fish oil.

The standard fish oil capsule contains 180 mg of EPA and 120 mg of DHA - a total of 300 mg of n3 fatty acids - an amount that reflects what is normally found in fish. It is not known exactly how much EPA or DHA we should take. Some experts suggest one gram daily, which amounts to 3-4 capsules per day.4 I suggest anywhere from 1-3 grams daily, depending upon a patient's size, diet history and overall condition.

I also suggest taking flaxseed oil, which contains ALA. Each flaxseed oil capsule contains 500 mg of ALA. The standard recommendation is two grams of ALA per day, a total of four capsules.4

These fatty acids do not represent pharmacologic amounts, and are designed to provide the level that we would normally get in the pre-grain period of history. They are without side effects, and there are only a select handful of patients who need to be careful with n3 supplements. Simopoulos,4 the leading expert in n3 fatty acids, explains that people with asthma should take them only under close supervision by their doctors. While n3s have been highly beneficial for some asthmatics, they have increased bronchial sensitivity in others. People with diabetes should take no more than three grams per day, because higher amounts might disrupt glucose regulation. People with clotting disorders, or who are taking very potent blood thinners, should not take n3 fatty acids unless prescribed by a physician. Omega-3 fatty acids slow clotting time, and there is no way of predicting the net effect.


This article represents an introduction to the subject of fatty acids and the diet-induced pro-inflammatory state. There are numerous articles that cover this subject in great detail. My recent paper in JMPT contains a long list of references that are clinically relevant.

As a clinician, you should consider n6:n3 imbalances to be perhaps the most important nutritional issue for you and your patients. Fortunately, it is relatively easy to shift the balance back to normal. The essential goal is to avoid the bread family, which loads our cells with inflammatory n6 fatty acids. We need to consume liberal amounts of fresh fruits and vegetables, and focus particularly on the green leafy veggies. Try to eat fresh fish as often as possible, and make sure to take at least one gram of EPA or DHA and two grams of ALA per day.

It is not uncommon to see a significant reduction in pain complaints within one to two weeks. I recently presented a seminar in Jacksonville, Florida, at the FCA spring convention. One of the attending doctors later told me that within 10 days of following this prescription, he lost five pounds, and 50 percent of his chronic athletic pains had disappeared. This outcome is quite common. I receive many communications from fellow chiropractors stating that chronic back pain, foot pain, and headaches are resolving within a month.

Please realize that such testimonials are coming from chiropractors that already got adjusted and understood the importance of the adjustment. However, they were all missing an important element of care. The adjustment primarily addresses the mechanical problem associated with a painful musculo-skeletal condition, however, mechanical adjustments cannot influence tissue concentrations of pro-inflammatory fatty acids. Only with nutrition can we change the balance of fatty acids in our cells. Accordingly, we should view the addition of n3 supplements as a nutritional adjustment. I personally view an adjustment to be incomplete without nutrition.

22.    Seaman DR. The diet-induced proinflammatory state: A cause of chronic pain and other degenerative diseases? J Manipulative Physiol Ther 2002 Mar-Apr;25(3):168-79.
23.    Cordain L. Cereal grains: humanity's double-edge sword. World Rev Nutr Diet 1999;84:19-73.
24.    Hands ES. Nutrients in Food. Philadelphia: Lippincott Williams and Wilkins, 2000.
25.    Simopoulos A. The Omega Diet. NY: HarperCollins; 1999: p.124-131

David Seaman,DC
The Diet-Induced Pro-Inflammatory State (Part 4 of 6)

Fight the Flu with a Nutritional Adjustment

by David Seaman, DC

This article greets you during the height of flu season. As I drove by a local retailer last fall, I noticed it displayed a large advertisement for free flu shots. (The only time the thought of a flu shot enters my mind is when I drive by such signs, or hear about them on the news. Like many people, I have never received a flu shot, and have no future plans to drop by the "retail giant" and get one.)

Flu Symptoms

Each fall, masses of people believe that the flu virus will once again be set loose and wreak havoc on those who happen to get in its path. Accordingly, many flock to get flu shots for the purpose of "preventing" the flu. All this really means is that they want to avoid being plagued for a week by high fever, coughing, nasal congestion, fatigue, malaise and headaches - symptoms we associate with the flu. Diagnosis is typically rendered by symptoms alone. So, if you have these symptoms, you supposedly have the flu.

The serious flaw with the classic tale of flu prevention is that we hear nothing about the nature of the host unlucky enough to develop the flu symptoms. We typically hear about the host who is "susceptible" because of a weakened immune system, one that supposedly allows for the flu to develop. I'm referring to the type of person, and immune-weakening, that we think enters the chiropractic office. Personally, I have a hard time believing in this type of "immune inhibition," and suggest that it has probably never existed.

My view obviously runs contrary to the standard treatment. Most people sincerely believe that colds and the flu develop because of some type of immune-inhibiting encounter, which renders us susceptible to a virus or bacteria; or a direct encounter with a virus that simply overwhelms our system. The latter is a common perception as it relates to the flu, which is why so many run to get their flu shots.

The Missing Flu Link - Overactive Immune System Causes Flu Symptoms

It seems that flu symptoms may actually develop because of an "overactive" immune system, not one that is depressed. All flu symptoms can be related to immune system stimulation, rather than inhibition. To understand this connection, we need to know a little about cytokine biology.

Cytokines are defined as molecules of cell communication. The term "interleukin" is used to describe one of the subfamilies of cytokines. Interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor (TNF) are examples of cytokines that are pro-inflammatory and are thought to play a role in immune stimulation. These cytokines are released from immune cells, such as macrophages, in response to injury; infection; poisons; immune complexes; and other cytokines.1

IL-1 and TNF stimulate:

         an increase in production of IL-l, TNF and other cytokines from macrophages and other immune cells;

         white cells to release pro-inflammatory free radicals;

         atherogenic process in endothelial cells;

         fibrogenic activity in fibroblasts; and

         the acute-phase response.1

What is the acute-phase response? Biochemically, it is associated with an increase in the production of acute-phase proteins, such as C-reactive protein, serum amyloid, complement and coagulation proteins. With respect to signs and symptoms, it is characterized by general hyperalgesia and allodynia; fever; increased sleep; decreased appetite; shivering; chills; malaise; somnolence; depression; memory loss; reduced social interactions; reduced aggressive behavior; and reduced sexual activity.1,2 Are these not the exact signs and symptoms one has when diagnosed with the flu?

Clearly, the flu is nothing more than an acute-phase response. And remember, a "flu" diagnosis is done by symptoms alone. So, we need to consider that perhaps the acute-phase response may not be caused by the influenza virus, and that there may be other inducers of the response. One thing is certain: We are suffering from immune activation, not inhibition.

Research on the Acute-Phase Response

Maier and Watkins published perhaps the most readable paper on the acute-phase response.2 IL-1 is particularly potent at generating the acute-phase response, and research has demonstrated that peripheral administration of IL-1 leads to all features of the acute-phase response. Additionally, this results in the induction of IL-1 production in the hypothalamus and hippocampus. It is this central induction of IL-1 (and TNF and IL-6) that leads to the acute-phase response.

To understand the physiological process that generates the acute-phase response, it is important to first know that modern anatomical studies have revealed that about 70% of vagal fibers are afferent - quite different than what is presented in standard neuroanatomy books. With this in mind, consider that, upon stimulation (injury, infection, etc.), peripheral macrophages release cytokines that activate vagal afferents (located in the gut, liver and spleen), which terminate in the nucleus tractus solitarius (NTS) located in the medulla. The NTS then projects to the hypothalamus and hippocampus, and this results in CNS production of IL-1, which leads to the induction of the acute-phase response or flu-like symptoms.2

Research has demonstrated that the acute-phase response induced by peripheral IL-1 administration could be abolished by cutting the vagus nerve,2 so there is no question that the sickness response is neurologically generated. Research has also demonstrated that afferent input from laminae I, IV-VII and X project to regions of the NTS very close to vagal afferents. This means that somatic nociceptive afferents will ultimately lead to activation of the NTS-hypothalamus-IL1 cascade, resulting in an acute-phase response. Consider, for example, that flu-like symptoms can develop if you are out of shape and decide to engage in heavy exercise.

Acute-Phase Foods and the Holiday Nutritional Nightmare

Nutritional research is clear when it comes to cytokine generation. It is known that omega-6 (n6) fatty acids (linoleic acid and arachidonic acid) increase macrophage release of IL-l and TNF, while omega-3 (n3) fatty acids have the opposite effect.3,4 James, et al., state that supplementation of fish oil (which contains the n3 fatty acids EPA and DHA) in healthy controls and rheumatoid arthritis patients has resulted in up to 90% inhibition of IL-1 and TNF.3

Future articles will discuss additional nutritional considerations in relation to cytokine modulation, but suffice it to say that antioxidants and bioflavonoids can also inhibit cytokine activity. So, lots of fruits and vegetables, green tea, olive oil, and anti oxidant supplements such as lipoic acid; coenzyme Q10; vitamin E; curcumin; and resveratrol can help reduce cytokine induction.

For the time being, let's consider our holiday dietary issues. There is really no better way to put it: Holidays are basically an "omega-6 fatty-acid fest." From Halloween to Easter, we literally gorge ourselves on bread, pastries, cakes, grains and the n6 seed oils (corn, sunflower, safflower) present in these and other packaged foods. Compare, for example, your own ingestion of the above foods to n3-rich, leafy green vegetables during the period extending from Halloween to Easter. Is this not the time of year that many of us gain 5-10 additional pounds? We certainly don't pack on these pounds because we eat too much salad and broccoli; instead, we gorge ourselves with "acute-phase foods."

Some might argue that we gain weight and get sick from too much sugar, and this certainly plays a role, for a reason you may be unaware of. Consider that sweets can also be considered "acute-phase foods." A recent study indicated that hyperglycemia acutely increases circulating cytokine concentrations; in particular, IL-6, IL-18 and TNF.5

There is no escaping the fact that the holiday stretch of months is an inflammatory bonanza. "Acute-phase foods," rich in omega-6 fatty acids and with high glycemic indices, are the rule during this time of year.

Experts believe that we need a one-to-one ratio of n6:n3 fatty acids in our diet, and the average American boasts a 20-30:1 ratio, which is exceedingly inflammatory. There is no question that holiday eating helps to drive this imbalance and the related acute-phase response.


Numerous insults can stimulate our immune cells into action. Trauma, toxins and even autosuggestion (although not mentioned here) can stimulate cytokine release and the acute phase response. The flu is nothing more than an acute-phase response, and without appropriate testing, we cannot state that the presence of an acute phase response confirms a flu virus infection. The holidays are stressful in many ways, and any number of stressors are capable of inducing an acute-phase response. We only augment this possibility by ingesting enormous amounts of "acute-phase foods" during this time of year.

During this holiday season, try avoiding the "acute-phase foods," increase your intake of fruits and vegetables and increase your supplementation with n3 fatty acids and antioxidants.

26.  Contran RS, Kumar V, Collins T. Robbins Pathologic Basis of Disease, 6th ed. Philadelphia: WB Saunders, 1999:74,86.
27.  Maier SF, Watkins LR. Cytokines for psychologists: implications of a bidirectional immune-to-brain communication for understanding behavior, mood, and cognitions. Psychol Rev 1998;105(1):83-107.
28.  James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 2000;71(suppl):343S-48S.
29.  Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999;70(suppl):560S-69S.
30.  Esposito K, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans. Circulation 2002;106:2067-72.

David Seaman, DC

Do You Frequently Get Tired After a Meal? You Need a Nutritional Adjustment!

by David Seaman, DC

When I began practice back in 1987, the study of candida and its relation to food allergies was all the rage. Accordingly, most of us who utilized nutrition as a component of chiropractic practice were taught that the majority of our patients' symptoms were caused by candida, food allergies, or liver or bowel toxicity. I embraced many of these concepts until the early 90s, when I began to learn more about inflammation and nociception. The more I learned about inflammation in particular, the more it became clear that candida, allergies and toxicity cannot be involved in most patients we see on a daily basis, contrary to what many continue to believe.

To a surprising degree, many still strongly defend the notion that food allergies, yeast, and toxic livers are the problem. Simply put, no data support this notion. Today, as most of you probably know, liver toxicity is the most popular of the purported causes of most symptoms; shockingly enough, absolutely no data suggest that patients walking into a chiropractor's office are suffering from the variety of liver toxicities promoted by many nutritional companies and specialty laboratories.

Fatigue and sleepiness are two symptoms routinely associated with liver toxicity. We hear terms such as "sluggish liver," which supposedly can be correlated to feeling sluggish and tired. And, if you get tired immediately after a meal - watch out - you definitely have candida growing out of control, severe food allergies, or a brutally toxic liver. At least this is what many teach. However, as this article explores, there is also a viable physiological explanation for postmeal fatigue.

Why Do We Get Tired After a Meal?

I don't know if anyone has the complete answer to this question; however, rest assured that in the great majority of cases, postmeal fatigue has absolutely nothing to do with food allergies, candida, or a toxic liver. The most plausible explanation involves cytokine-induction of sleep.

In part IV of this series I discussed how cytokines induce the acute-phase response, which includes signs and symptoms such as general hyperalgesia and allodynia; fever; depression; memory loss; reduced social interactions; malaise; feeling sleepy; and increased sleep. Although it is known that cytokines drive these symptoms, many still argue that a toxic liver is at fault. In fact, it is known that eating too much food generally makes us tired, in that overeating increases cytokine production, which induces fatigue or sleep.

Background on Cytokines and Sleep

IL-1 and TNF are two of the pro-inflammatory cytokines discussed in Part IV. It is known that injections of either IL-1 or TNF into experimental animals increase sleep. For example, when rabbits are given IL-1 at the onset of darkness, they sleep three extra hours during the first 12 hours after injection. These cytokines promote sleep whether administered directly into the brain, or following intraperitoneal or intravenous injections. It turns out that IL-1 and TNF promote sleep in every species tested thus far, including rats; mice; monkeys; cats; and rabbits.1 In humans, it is thought that IL-1 and TNF promote sleep, although the details are not as clear. Research also suggests that IL-6 promotes sleep in humans.2 So, when we think of sleepiness, we need to consider cytokines.

"Pigging Out" and Sleep

I have known that overeating promotes sleep since my first reading of "Jack and the Beanstalk." When you "pig out," you go to sleep; it's that simple. In research terms, Hansen, et al., state it clearly: "Food intake is one of the determining factors of the daily amount of sleep; an excess of sleep occurs when there is increased feeding."2

Hansen, et al., discovered that IL-1 levels rise in rats that "pigged out" on cafeteria food, compared with those that ate regular chow.4 Consider the title of another paper written by the team: "Cafeteria Diet-Induced Sleep Is Blocked by Subdiaphragmatic Vagotomy." Both articles were published in the American Journal of Physiology, one of the most prestigious physiology journals in the world.

What is the cafeteria diet? Bread, chocolate and shortbread cookies!3 The researchers found that both vagotomized and control rats pigged-out on the sweets (which is what rats do when presented with these foods); however, only the control rats slept after overeating.

The vagus nerve has an enormous sensory component, and it innervates the liver, spleen, and intestines, so it is extremely sensitive to cytokine production in these organs. As it turns out, bread, chocolate and cookies stimulate IL-1 production, which is known to activate vagal sensory fibers that end in the nucleus tractus solitarious, which ultimately results in increased CNS production of IL-1, which is known to produce acute-phase symptoms, such as sleep. When the researchers cut the vagus, they eliminated the sleep-inducing signals from the cytokines produced after over consumption of bread, chocolate, and cookies.


At present, over 50 percent of adults in the U.S. are overweight or obese. We know we are a nation of overeaters, so it should not be a surprise that postmeal fatigue is a common symptom. The most likely explanation for postmeal fatigue involves the cytokine mechanisms described above. Get your patients to eat less, and see how quickly their postmeal fatigue disappears. As pro-inflammatory cytokines drive sleep and the acute-phase response, it is important to adopt the anti-inflammatory diet and supplement recommendations described in the first four articles in this series.

31.    Krueger JM, Obal F, Fang J, Kubota T, Taishi P. The role of cytokines in physiological sleep regulation. Ann NY Acad Sci 2001;933:211-21.
32.    Mullington JM, Hinze-Selch D, Pollmacher T. Mediators of inflammation and their interaction with sleep. Relevance for chronic fatigue syndrome and related conditions. Ann NY Acad Sci 2001;933;201-210.
33.    Hansen MK, Kapas L, Fang J, Krueger JM. Cafeteria diet-induced sleep is blocked by subdiaphragmatic vagotomy. Am J Physiol 1998;274:R168-74.
34.    Hansen MK, Taishi P, Chen Z, Krueger JM. Cafeteria feeding induces interleukin-1 mRNA expression in rat liver and brain. Am J Physiol 1998;274:R1734-39.

David Seaman, DC

Magnesium Deficiency, Inflammation and Nervous System Hyperexcitability

by David Seaman, DC

The first five parts in this series detailed several factors contributing to the diet-induced pro-inflammatory state. In review, it should be clear that grains are pro-inflammatory on many levels. Among other things, they are acidic and contain omega-6 fatty acids that promote the production of inflammatory eicosanoids and cytokines. Fruits and vegetables are alkaline, and green vegetables, in particular, contain anti-inflammatory omega-3 fatty acids.

While fatty acids play the most obvious role in the inflammatory process, numerous other nutritional factors can promote inflammation. Magnesium is an example, and few of us understand its connection to inflammation. A 1994 R.J.Elin article, "Magnesium: The Fifth but Forgotten Electrolyte,"1 emphasized our lack of focus on this potential problem.

Approximately 300 bodily enzymes require magnesium, which suggests that magnesium is vital for most cells and tissues of the body. As a consequence, magnesium deficiency can have far-reaching effects on many different tissues, to the point that a leading researcher wrote an article on the subject: "Magnesium Deficiency: A Cause of Heterogeneous Disease in Humans."2 Numerous conditions and symptoms can be promoted by magnesium deficiency, including osteoporosis; muscle dysfunction; depression; apathy; cardiac arrythmia; hypertension; atherosclerosis; and even stress and aging.2,3

No bodily system can escape without being insulted by magnesium; in fact, it is thought to promote genomic stability. It turns out that nearly all DNA synthetic and repair enzymes require magnesium.4

Inflammation and Nervous System Hyperexcitability

A recent article in Magnesium Research discusses inflammation and nervous system hyperexcitability in detail.7 (As it turns out, Magnesium Research is found in only 10 libraries in the United States, so it is not easy to acquire. I think every chiropractic college library should have it.)

Nervous system hyperexcitability caused by magnesium deficiency can manifest differently in different species, and even in the same species, as a result of strain, gender and age. With this in mind, consider what has been discovered about magnesium deficiency.

From previous articles, the terms "pro-inflammatory eicosanoids" and "cytokines" should be familiar. Magnesium deficiency has been shown to increase eicosanoid synthesis and cytokine release. Substance-P release from nociceptors also can occur, which helps to reinforce nociceptive and inflammatory responses. Cellular production of free radicals also occurs with magnesium deficiency. Clearly, numerous inflammatory responses have the potential to develop in the wake of magnesium deficiency.7

Concerning the nervous system, magnesium deficiency is known to increase sodium conductance, which results in an overactive nervous system, affecting both the peripheral and central nervous systems. Rude explains that muscles become hyperexcitable with magnesium insufficiency,2 allowing them to become much more responsive to noxious stimuli. In the central nervous system, there is increased activity of excitatory transmitters, including acetylcholine, dopamine, norepinephrine, aspartate, and glutamate; and there is a simultaneous decrease in activity of inhibitory neuromediators including serotonin, GABA, taurine and melatonin.7 Concerning melatonin, it appears that magnesium adequacy is required for appropriate regulation,8 which has far-reaching implications concerning sleep issues, such as daytime fatigue.

Durlach explains that the body has numerous compensatory mechanisms that allow magnesium deficiency to go undetected, leading to the development of what he calls "latent nervous system hyperexcitability."7 In other words, a patient will already be deficient in magnesium prior to the development of symptoms. The exact manner in which nervous system hyperexcitability will manifest in a patient is not known, although as chiropractors, hyperexcitable muscles would be a likely finding.

So, we should not be surprised that Rude described magnesium deficiency as a cause of heterogenous disease in humans.2 What should we do? Eat more fruits, veggies, and healthy meat, chicken, and fish, and take supplements.

Supplementation with Magnesium

Intakes below the recommended daily allowance (RDA) are common, if not the norm, in many countries, including the United States.4,5 The U.S. RDA for magnesium is 320 mg for women and 420 milligrams (mg) for men. At the turn of the century (1900), magnesium intake was estimated to be 475-500 mg per day,5 which suggests our intake has declined substantially.

Researchers suggest that for every 2.2 pounds (one kilogram) of body weight, we should ingest six mg of magnesium. Accordingly, a 150-pound man (70 kg) requires 420 mg/day, while a 200-pound man (90 kg) requires 540 mg/day. As most people in the U.S. are deficient in magnesium, it is suggested that we supplement five mg per kg of body weight to replenish what has been lost.4 Researchers have observed that between 950-1,020 mg of magnesium per day is required to create a positive magnesium balance.5

If you are presently taking a calcium supplement, it is important to add a magnesium supplement to your regimen. The current accepted balance of calcium/magnesium intake is 2:1. At present, the average intake of calcium in the U.S. is thought to be about 1,000 mg/day or greater (including supplements and fortified foods), but only about 250-350 mg of magnesium. This imbalance (i.e., about a 4:1 ratio of calcium/magnesium) is thought to reduce magnesium absorption and further enhance magnesium deficiency.6 So, for overall health, the nervous system, and to help reduce inflammation, consider adding a magnesium supplement to your diet. A nutritional adjustment with magnesium works best when taken about 30 minutes before eating a meal. If you are taking more than 300 mg per day, divide your supplementation dosage throughout the day; this will help prevent loose stools, the primary side-effect of magnesium ingestion.

35.  Elin RJ. Magnesium: the fifth but forgotten electrolyte. Am J Clin Path 1994;102:616-22.
36.  Rude RE. Magnesium deficiency: a cause of heterogeneous disease in humans. J Bone Mineral Res 1998;13:74-958.
37.  Durlach J, Bac P, Durlach V, Rayssiguier Y, Bara M, Guiet-Bara A. Magnesium status and ageing: an update. Mag Res 1997;11:25-42.
38.  Hartwig A. Role of magnesium in genomic stability. Mutation Res 2001; 475:113-21.
39.  Saris NL, Mervaala E, Karppanen H, Khawaja JA, Lewenstam A. Magnesium: an update on physiological, clinical and analytical concepts. Clin Chim Acta 2000;294:1-26.
40.  Dreosti IE. Magnesium status and health. Nutr Rev 1995;53(9):S23-S27.
41.  Durlach J, Bac P, Bara M, Guiet-Bara A. Physiopathology of symptomatic and latent forms of central nervous system hyperexcitability due to magnesium deficiency: a current general scheme. Magnes Res 2000;13:293-302.
42.  Durlach J, Pages N, Bac P, Bara M, Guiet-Bara A. Biorhythms and possible central regulation of magnesium status, phototherapy, darkness therapy and chronopathological forms of magnesium depletion. Magnes Res 2002;15:49-66.

David Seaman, DC

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