Category Archives: Minerals

DHA and Angiogenesis: The Bottom Line

So I thought I’d finish up the series on DHA and angiogenesis by discussing 2 issues:

1.      First, an assertion: The pathway by which oxidized DHA drives angiogenesis may be really important for human health.

2.      Second, the $64,000 question: Is there evidence that high levels of dietary DHA promotes diseases of pathological angiogenesis? What about other dietary factors bearing on DHA oxidation?

Significance of the Oxidized DHA Link to Angiogenesis

The papers discussed in Friday’s post about a major angiogenesis pathway stimulated by oxidized DHA (Omega-3s, Angiogenesis and Cancer: Part II, April 29, 2011) may not seem important to many readers. But to cancer researchers and pharmaceutical companies, this is blockbuster work.

A tumor is, in the words of Hal Dvorak, “a wound that never heals.” [1] To support growth, cancers invoke the wound healing process – especially, creation of new blood vessels, or angiogenesis. But the tumor prevents the wound healing process from completing. If it ever did complete, then the tumor itself would be healed. It would cease to grow and become benign.

It’s been recognized for decades that an ability to block angiogenesis would effectively constitute a cure for cancer. The William Li video explains why: nearly everyone gets microscopic tumors that never develop the ability to induce angiogenesis. Life-threatening cancer is the result of tumors that can induce angiogenesis. No angiogenesis, and no one would die of cancer.

But existing anti-angiogenic cancer therapies have produced disappointing results. Avastin, an anti-angiogenic drug targeting VEGF (vascular endothelial growth factor), has been estimated to extend colon cancer patient lifespan by only 6 weeks.  (Nevertheless, Avastin generated $7.3 billion in revenue last year. Imagine how much money there would be in an anti-angiogenic therapy that worked!)

The work I discussed last Friday suggests a reason for that failure. Recall these pictures:

If only the VEGF pathway is blocked (upper right), there is almost as much angiogenesis and wound healing as in a normal wound (upper left). But when both the VEGF and TLR-2 angiogenic pathways are blocked (lower right), there is no wound healing.

If these are the operative pathways in cancer also, then blocking the TLR-2 angiogenesis pathway might be the key to cancer therapy.

But cancer is not the only disease of pathological angiogenesis. Others include:

  • Age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity – three common causes of blindness.
  • Atherosclerosis, which often features angiogenic vessels in thickened arterial walls.
  • Vascular malformations and tumors.
  • Obesity. Adipose tissue utilizes angiogenic pathways, and angiogenesis inhibition prevents the deposition of fat.
  • Rosacea, psoriasis, and some other skin conditions.
  • Endometriosis, uterine fibroids, and some other causes of female infertility.
  • Rheumatoid arthritis.
  • Crohn’s disease.
  • Preeclampsia.

It may be that the TLR-2 pathway is key to these diseases as well, and that a treatment that inhibits this pathway can cure or improve all of these diseases.

Add up the size of these markets and a pharmaceutical company executive would swoon.

Luckily, we’re not pharmaceutical company executives. But we can still get excited over possibilities to improve these diseases through diet and anti-microbial medicine.

Infections as Contributing Causes of These Diseases

TLR-2 is stimulated by other things besides oxidized DHA. In particular, TLR-2 is an immune molecule which is stimulated by pathogen proteins. As Wikipedia notes:

TLR-2 recognizes many bacterial, fungal, viral, and certain endogenous substances.

This tells us that many pathogens may stimulate angiogenesis through the TLR-2 pathway. As a result, anti-microbial medicines might help treat some diseases of pathological angiogenesis.

Some antibiotics, including doxycycline and minocycline, are known to exercise anti-angiogenic effects independent of the antibiotic effects. [2]

Diet-Induced Angiogenesis

Many foods affect angiogenesis. In fact, cancer studies have identified dozens of plant foods, from garlic to tomatoes to leeks, that possess anti-angiogenic properties.

However, foods can also promote angiogenesis. Let’s stick to the oxidized DHA pathway and see if there’s evidence that foods drive it.

You’ll recall the recipe was:

DHA + oxidative stress + retinyl protein = TLR-2 driven angiogenesis

If this pathway is important in human disease, then we should expect diseases of angiogenesis to be worsened by adding the ingredients on the left.

Specifically, cancer, AMD, rosacea, and so forth should be worsened by high doses of DHA, high doses of vitamin A, and low doses of antioxidant minerals like zinc or selenium.

Is there any evidence for that pattern?

Cancer Studies

First, let me give my bottom line on the Brasky study that kicked off this series. High tissue levels of DHA were associated with increased risk of high-grade prostate cancer, and the oxidized DHA angiogenesis pathway provides a mechanism for this association. What’s not clear is why tissue DHA levels were high. EPA levels were also elevated in the high-grade prostate cancers, but not by nearly as much as DHA levels. EPA and DHA appear together in fish and fish oil, so this suggests that fish consumption contributed to but was not the primary cause of the elevated tissue DHA. The drug finasteride greatly raised risk of high-grade prostate cancer, but the paper did not break down the DHA-cancer association between the finasteride and placebo arms. The most likely explanation, in my view, is that finasteride increases conversion of EPA to DHA and creates artificially high tissue DHA levels. The high DHA levels combined with oxidative stress drive cancer through the TLR-2 angiogenesis pathway.

A clever but unlikely alternative explanation was suggested by Peter at Hyperlipid: perhaps extra dietary fish oil raises testosterone levels. Prostate cancer is a hormone-dependent cancer and can be promoted by testosterone, just as breast cancer is promoted by estrogen. Possible supporting evidence comes from a paper showing an inverse association between metabolic syndrome / diabetes and prostate cancer. The trouble with this idea is that (a) this effect should have been strongest in the low-grade cancers, since diabetes reduced the incidence of low-grade cancers, but in the Brasky study DHA had no association with low-grade cancers, (b) fish oil lowers testosterone levels in rats, (c) in the Brasky study high-grade prostate cancers were strongly associated with obesity and the obese generally have low testosterone levels, and (d) surprisingly, high-grade prostate cancers are associated with low testosterone, not high. So one could argue that fish oil might promote high-grade prostate cancer by lowering testosterone!

A unified explanation along this line would be: Finasteride raises DHA levels, and DHA lowers testosterone. Low testosterone reduces incidence of low-grade prostate cancers but makes it much more likely they will progress to high-grade. Thus, finasteride reduces prostate cancer incidence but increases high-grade prostate cancer incidence and overall prostate cancer mortality. Fits all the facts. Could be.

My bottom line: the Brasky study is weak evidence for anything, but it does raise a whiff of evidence that high dietary fish oil intake might encourage a transition from low-grade to high-grade cancer.

What about other ingredients in the recipe? Does increasing retinyl levels raise cancer risk?

Retinyl palmitate (vitamin A) has been tested in clinical trials for its effect on cancer risk. The trials had to be cut short when it was found that vitamin A increased cancer mortality:

The Carotene and Retinol Efficacy Trial (CARET) was a multicenter randomized, double-blind placebo-controlled chemoprevention trial testing whether daily supplementation with 30 mg β-carotene + 25,000 IU retinyl palmitate would reduce lung cancer risk among 18,314 heavy smokers, former heavy smokers and asbestos-exposed workers. The intervention ended 21 months early in January, 1996 when interim analysis found evidence that the supplements increased the risk of lung cancer and total mortality in this high-risk population by 28% and 17%, respectively (10). [3]

After the study ended participants were tracked for years afterward. Those who had received vitamin A during the trial, but especially those in the vitamin A arm who took additional supplements (mainly multivitamins which are rich in A, but possibly also fish oil), had more high-grade prostate cancers:

As a proportion of the total prostate cancer cases, more men who were randomized to the active arm developed high-grade prostate cancer (Gleason 7-10) than in the placebo arm (44.6% vs. 40.1%, respectively)….

For aggressive prostate cancer, men in the CARET intervention arm who used additional supplements had a relative risk for aggressive prostate cancer (Gleason >or=7 or stage III/IV) of 1.52 (95% CI, 1.03-2.24; P < 0.05), relative to all others. [3]

Interestingly, in the placebo arm taking multivitamins and other supplements reduced cancer risk.

Other studies have found similar results.

Men with higher retinol concentrations at baseline were more likely to develop prostate cancer (quintile 5 vs. quintile 1 hazard ratio = 1.19, 95% confidence interval: 1.03, 1.36; P(trend) = 0.009). The results were similar for aggressive disease. Joint categorization based on baseline and 3-year retinol levels showed that men who were in the highest quintile at both time points had the greatest increased risk (baseline/3-year quintile 5/quintile 5 vs. quintile 1/quintile 1 hazard ratio = 1.31, 95% confidence interval: 1.08, 1.59). In this largest study to date of vitamin A status and subsequent risk of prostate cancer, higher serum retinol was associated with elevated risk, with sustained high exposure conferring the greatest risk. [4]

Carotenoids, which can generally be converted to vitamin A, are also associated with higher cancer risk. There is one exception – lycopene:

Lycopene was inversely associated with prostate cancer risk (comparing highest with lowest quartiles, odds ratio (OR) = 0.65, 95% confidence interval (CI): 0.36, 1.15; test for trend, p = 0.09), particularly for aggressive disease (comparing extreme quartiles, OR = 0.37, 95% CI: 0.15, 0.94; test for trend, p = 0.04). Other carotenoids were positively associated with risk. [5]

What’s special about lycopene? Wikipedia explains:

Lycopene may be the most powerful carotenoid quencher of singlet oxygen,[18] being 100 times more efficient in test tube studies of singlet-oxygen quenching action than vitamin E … The absence of the beta-ionone ring structure for lycopene increases its antioxidant action….

Lycopene is not modified to vitamin A in the body

So lycopene does not increase retinyl levels, but does act as an extraordinarily powerful antioxidant, thus reducing oxidative stress! If you wanted a good food for stopping the DHA – angiogenesis pathway, you’ve found it: tomatoes.

Hmmm, tomatoes go well with salmon …

That gets us to the third part of the recipe, oxidative stress. If oxidized DHA drives angiogenesis, then antioxidants should be preventative for these diseases.

The evidence here is rather mixed, because with the exception of the negative effects of vitamin A, most antioxidants seem to have little effect on cancer. Nevertheless, I’ll give some studies. Selenium is a antioxidant mineral due to its role in glutathione peroxidase:

Serum selenium was inversely associated with risk of prostate cancer (comparing highest to lowest quartiles, OR = 0.71, 95% CI 0.39-1.28; p for trend = 0.11), with similar patterns seen in both blacks and whites. [6]

Zinc is an antioxidant due to its role in zinc-copper superoxide dismutase. Prostate cancer is associated with low tissue levels of zinc. [7, 8] High dietary intake of zinc is associated with lower rates of prostate cancer. [9]

N-acetylcysteine is an antioxidant supplement that is a precursor to glutathione. N-acetylcysteine has been shown to prevent angiogenesis and has been proposed as a likely cancer preventative, but this is as yet untested. [10]

Other Diseases of Angiogenesis

I’ll skip those for now, other than to note that fish oil is a well-known trigger of rosacea. Is it possible that the mechanism is via TLR-2 activation by oxidized DHA?


At the moment there’s some puffs of smoke but no fire. Observational studies weakly link high DHA, high vitamin A, and low antioxidant status to diseases of angiogenesis such as cancer.

This pattern would be consistent with the idea that the natural pathway used in wound healing to trigger angiogenesis – DHA oxidation and combination with retinyl protein to trigger TLR-2 pathways – is also important for cancer progression.

It suggests a strategy of reduced fish oil and vitamin A consumption and increased intake of certain antioxidants (such as lycopene, zinc, selenium, or NAC) may be helpful against cancer.

However, this idea needs testing. No study in animal cancer models has tested this dietary combination.

Given the many proven benefits of moderate amounts of fish oil, I don’t see a reason yet to alter our recommendation that healthy people should eat a pound of fish per week. That said, I do think very high intakes of fish or fish oil are ill advised. And I’m intrigued by the idea that dietary changes may have the potential to play a powerful role in recovery from diseases of angiogenesis such as cancer.


[1] Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986 Dec 25;315(26):1650-9.

[2] Yao JS et al. Comparison of doxycycline and minocycline in the inhibition of VEGF-induced smooth muscle cell migration. Neurochem Int. 2007 Feb;50(3):524-30.

[3] Neuhouser ML et al. Dietary supplement use and prostate cancer risk in the Carotene and Retinol Efficacy Trial. Cancer Epidemiol Biomarkers Prev. 2009 Aug;18(8):2202-6.

[4] Mondul AM et al. Serum retinol and risk of prostate cancer. Am J Epidemiol. 2011 Apr 1;173(7):813-21.

[5] Vogt TM et al. Serum lycopene, other serum carotenoids, and risk of prostate cancer in US Blacks and Whites. Am J Epidemiol. 2002 Jun 1;155(11):1023-32.

[6] Vogt TM et al. Serum selenium and risk of prostate cancer in U.S. blacks and whites. Int J Cancer. 2003 Feb 20;103(5):664-70.

[7] Sarafanov AG et al. Prostate cancer outcome and tissue levels of metal ions. Prostate. 2011 Jan 26. doi: 10.1002/pros.21339. [Epub ahead of print]

[8] Costello LC, Franklin RB. Zinc is decreased in prostate cancer: an established relationship of prostate cancer! J Biol Inorg Chem. 2011 Jan;16(1):3-8.

[9] Epstein MM et al. Dietary zinc and prostate cancer survival in a Swedish cohort. Am J Clin Nutr. 2011 Mar;93(3):586-93.

[10] Noonan DM et al. Angiogenesis and cancer prevention: a vision. Recent Results Cancer Res. 2007;174:219-24.

Bowel Disease, Part III: Healing Through Nutrition

[UPDATED August 2015 with updates in italic . – Paul]

Bowel diseases are characterized by chronic infection of the gut lining (and sometimes immune cells), wounded and inflamed gut tissue, and autoimmune attacks on the gut.

Malnutrition contributes to bowel disease by impairing immunity, impairing gut motility, and slowing intestinal healing.

Conversely, bowel diseases impair nutrient absorption along with the rest of digestion, exacerbating malnutrition.  To avoid a vicious spiral, bowel disease patients should be especially attentive to their nutritional needs.

The first step toward good nutrition is to eat the Perfect Health Diet, including all of our supplemental foods. For gut health, egg yolks are especially important. Also important are extracellular matrix components from bones and joints; vegetables, herbs, and spices; and healthy fats (which trigger bile production, bile being beneficial for the gut). See our Recommended Supplements page for more on the supplemental foods.

We no longer recommend taking a multivitamin. For various reasons multivitamin formulas are incomplete:

  • Some nutrients, such as magnesium and vitamin C, are too bulky to fit in a single pill.
  • Some, such as vitamin D and iodine, have no “one size fits all” dose that manufacturers can safely include.  They therefore include a low dose that is safe for all, meaning that most receive an insufficiency.
  • Others, like melatonin, may be unnecessary for the general population but are likely to benefit bowel disease patients.

Here, then, are a few supplements that bowel disease patients may find to be helpful additions to their multivitamin.

Vitamin D3 and Partners

Vitamin D has been called the “antibiotic vitamin” [1] because it triggers the body’s production of natural antibiotic compounds.

Vitamin D is needed for the production of the antimicrobial peptides cathelicidin and beta-defensin 2, which are produced mainly in immune cells and in epithelial cells lining the gut. [2, 3] These antimicrobial peptides normally saturate the mucosal barrier, where they kill most bacteria, enveloped viruses, fungi, and protozoa.

Evidence has accumulated that deficiencies in antimicrobial peptides are causal factors in bowel diseases:

  • In Crohn’s disease, a deficiency of antimicrobial peptides allows pathogens to invade. [4, 5, 6]
  • Reduced expression of intestinal defensins predicts diarrhea two months in advance. [7]
  • When antimicrobial peptides are induced therapeutically, intestinal infections are relieved. [8]
  • Mice with no vitamin D function due to knockout of the vitamin D receptor experience bacterial overgrowth of the intestine, and even mild injury to the colon results in the death of the mouse. [9]

There is increasing awareness that vitamin D is needed for defense against infections generally. [10]

Vitamin D has other benefits besides strengthening immunity. It also suppresses autoimmunity.  For instance, there is evidence for an inverse relationship between vitamin D levels and auto-antibody levels [11]. Some autoimmune patients have experienced a disappearance of auto-antibodies upon supplementation with vitamin D. [12]

Since bowel diseases are the result of infections and autoimmunity, normalization of vitamin D levels is probably extremely helpful.

Vitamin D is also associated with reduced risk of colorectal cancer. [13] Bowel disease patients are at elevated risk for colorectal cancer.

Sunshine should be sought regularly, and supplements added to bring serum 25-hydroxyvitamin D levels to at least 40 ng/ml. In addition, vitamin D should be accompanied by supplementation of two key partners:

  • Vitamin K2 is needed for proper vitamin D function.  Most inflammatory bowel disease patients are severely deficient in vitamin K2. [14] A good daily supplement should include 100 mcg of the MK-7 form, perhaps combined with some synthetic MK-4 and plant-derived vitamin K1.
  • Magnesium is needed for proper vitamin D function and many people are deficient.  200 mg/day magnesium citrate (which is better absorbed than magnesium oxide) is appropriate.


Melatonin is a crucial hormone which is evolutionarily conserved across all nearly all animals, indicating that it is essential to health. Most know that it is produced in the pineal gland of the brain during sleep, but it is less well known that it is abundantly produced by the gut. Much of the body’s melatonin gathers in the gut, where melatonin concentrations are 100-fold greater than in blood and 400-fold greater than in the pineal gland. [15]

In the gut melatonin reduces inflammation, stimulates immune function, fosters tissue repair and helps regenerate the epithelium. [15] Melatonin also has antimicrobial effects. [16]

Clinical trials have found that melatonin can be beneficial in treating bowel conditions. [17, 18, 19] Melatonin seems to be especially effective at reducing abdominal pain. [20, 21]

To maximize night-time melatonin levels, it is best to sleep in a totally darkened room; avoid eating food at night; and avoid exercising at night. Melatonin can also be supplemented.  Supplemental melatonin should be taken immediately before bed. Time-release tablets are best, otherwise fluctuating melatonin levels may cause waking in the middle of the night. If early waking does occur, reduce the dose.

Thyroid and Immune Minerals:  Selenium and Iodine

Selenium and iodine are critical for thyroid and immune function. Adequate thyroid hormone and a well-functioning immune system, in turn, are essential for gut health.

The thyroid hormone T4 is 65% iodine by weight, and the active thyroid hormone T3 is 59% iodine by weight.  Selenium-containing deiodinase enzymes are required to convert inactive thyroid hormone to its active form. Either iodine or selenium deficiency can cause hypothyroidism, or a deficiency of thyroid hormone.

Gut problems, especially constipation, are among the primary symptoms of hypothyroidism. Thyroid hormone is important for proper wound healing – and therefore for recovery from bowel disease.

Selenium and iodine are also essential for immune function.  Iodine along with the enzyme myeloperoxidase is needed to produce respiratory bursts – the burst of reactive oxygen species (ROS) that white blood cells use to kill pathogens.  Selenium is necessary both to strip iodine from thyroid hormone in the white blood cells, and to maintain (via the enzyme glutathione peroxidase) the function of the antioxidant glutathione which protects both white blood cells and gut cells from ROS.  Deficiency of either selenium or iodine leads to an immediate reduction in the killing activity of white blood cells.

Iodine was widely prescribed for infectious diseases in the 19th century. The Nobel laureate Dr. Albert Szent Györgyi, the discoverer of vitamin C, recounted this anecdote:

When I was a medical student, iodine in the form of KI was the universal medicine. Nobody knew what it did, but it did something and did something good. We students used to sum up the situation in this little rhyme:

If ye don’t know where, what, and why

Prescribe ye then K and I. [22]

Doses as large as 1 gram potassium iodide, containing 770 mg of iodine, were given. In practice, however, it’s highly desirable to start with a low dose of iodine, around 1 mg/day, and allow the thyroid to adapt before gradually increasing the dose.

The great danger of high doses of iodine is that it will make autoimmune attacks, as well as attacks on pathogens, more powerful. Therefore large supplemental doses of iodine should be taken only after grains and legumes have been eliminated from the diet for at least 3 months. Bowel disease patients should also be tested for the presence of thyroid auto-antibodies before beginning high-dose iodine.

Related minerals: 

  • Myeloperoxidase requires iron (heme), and unfortunately anemia due to iron deficiency is common in bowel disease patients, especially among menstruating women. [23] A good way to judge the need for iron is to measure blood ferritin levels, which should be 50 ng/ml or higher.

Thyroid hormone

If auto-antibodies are present, then hypothyroidism cannot be repaired by iodine supplementation. Yet thyroid hormone is necessary for gut healing.  In such cases, prescription thyroid hormone should be taken.

Hypothyroidism is widely undiagnosed, because the “normal” range of thyroid stimulating hormone (TSH) is far too wide. TSH levels over 1.5 mIU/L may indicate a subclinical hypothyroidism that is sufficient to measurably raise mortality. [24] Anyone with a TSH over 1.5 mIU/L and a basal body temperature below 98 F should consider obtaining prescription thyroid hormone to test whether it helps relieves hypothyroidism-associated symptoms such as constipation and improves general health. Generally, a good dose of thyroid hormone will eliminate symptoms of hypothyroidism and reduce TSH to 2.0 or so – still elevated, to stimulate thyroid healing.

Antioxidants and Bile Supports: Vitamin C, Glutathione, N-Acetylcysteine, Taurine, Glycine

Since the main immune defense (and autoimmune) mechanisms in the gut involve around ROS-producing respiratory bursts, the gut of any bowel disease patient is a ROS-rich environment.

It is therefore desirable to maximize the ability of both gut and immune cells to protect themselves against ROS with native antioxidants.

Foremost among the native antioxidants is glutathione, the primary immune and gut antioxidant. Glutathione may be supplemented directly, or its levels may be raised by supplementing with vitamin C and N-acetylcysteine.

Vitamin C has other important functions:  it is needed for wound healing and to maintain the collagen-based extracellular matrix which backs the gut and gives it integrity. One of the symptoms of scurvy (extreme vitamin C deficiency) is bleeding from the mucus membranes, including the gut lining.

A Japanese study found that vitamin C was highly protective against ulcerative colitis, reducing incidence by 55%. [25]

In rats, glutathione deficiency leads to elevated infection-induced bowel inflammation. [26] Glycine (the most abundant amino acid in extracellular matrix) and taurine both support glutathione synthesis.

Related minerals: 

  • Zinc and copper are both required for the function of another antioxidant, zinc-copper superoxide dismutase.  We recommend supplementing dietary intake with another 15 mg zinc and 2 mg copper. This can be achieved by taking a daily multivitamin plus eating occasional beef or lamb liver.
  • Magnesium is needed for glutathione synthesis. As noted before, 200 mg/day magnesium citrate is a highly desirable supplement for bowel disease patients.

Magnesium and copper deficiencies contribute to necrotizing enterocolitis [27], and probably worsen all bowel diseases.

Bile is an important aid to gut health, in part because it helps to clear the small intestine of bacteria. Bile needs vitamin C for its manufacture and needs to be conjugated with glycine or taurine. Glycine can be obtained from food as extracellular matrix material, or as a powder which you can sprinkle on food. Taurine is an excellent supplement for patients with gut disorders.


Although not a complete list of the vitamins and minerals which may be helpful to bowel disease patients, these are among the most important – and most often overlooked:

  • Vitamin D3 sufficient to raise serum 25-hydroxyvitamin D above 40 ng/ml.
  • Vitamin K2, at least 100 mcg/day.
  • Magnesium citrate or bis-glycinate, 200 mg/day.
  • Melatonin, if needed for deep restful sleep.
  • Selenium, 200 mcg/week.
  • Iodine, 225 mcg/day.
  • Thyroid hormone sufficient to bring TSH below 2.0.
  • Vitamin C, 1 g/day.
  • Glutathione, 500 mg/day, preferably in the reduced form, taken between meals on an empty stomach with a full glass of water (since it is destroyed by stomach acid).
  • N-acetylcysteine, 500 mg/day.
  • Iron, zinc, and copper sufficient to relieve deficiencies.
  • Taurine, 1 g/day.
  • Glycine (if insufficient extracellular matrix is eaten), up to 5 g/day.

Related Posts

Other posts in this series:

  1. Bowel Disorders, Part I: About Gut Disease July 14, 2010
  2. Bowel Disease, Part II: Healing the Gut By Eliminating Food Toxins m July 19, 2010
  3. Bowel Disease, Part IV: Restoring Healthful Gut Flora July 27, 2010


[1] “The antibiotic vitamin: deficiency in vitamin D may predispose people to infection,” Science News, Nov 11, 2006,

[2] Liu PT et al. Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol. 2007 Aug 15;179(4):2060-3.

[3] Lehrer RI, Ganz T. Defensins of vertebrate animals. Curr Opin Immunol. 2002 Feb;14(1):96-102.

[4] Rivas-Santiago B et al. Susceptibility to infectious diseases based on antimicrobial peptide production. Infect Immun. 2009 Nov;77(11):4690-5.

[5] Wehkamp J et al. Inducible and constitutive beta-defensins are differentially expressed in Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2003 Jul;9(4):215-23.

[6] Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn’s disease. Mucosal Immunol. 2008 Nov;1 Suppl 1:S67-74.

[7] Kelly P et al. Reduced gene expression of intestinal alpha-defensins predicts diarrhea in a cohort of African adults. J Infect Dis. 2006 May 15;193(10):1464-70.

[8] Wehkamp J et al. Defensins and cathelicidins in gastrointestinal infections. Curr Opin Gastroenterol. 2007 Jan;23(1):32-8.

[9] Froicu M, Cantorna MT. Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol. 2007 Mar 30;8:5.

[10] Yamshchikov AV et al. Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials. Endocr Pract. 2009 Jul-Aug;15(5):438-49.

[11] Goswami R et al. Prevalence of vitamin D deficiency and its relationship with thyroid autoimmunity in Asian Indians: a community-based survey. Br J Nutr. 2009 Aug;102(3):382-6.

[12] Dr. John Cannell, The Vitamin D Newsletter, March 9, 2009.

[13] Woolcott CG et al. Plasma 25-hydroxyvitamin D levels and the risk of colorectal cancer: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev. 2010 Jan;19(1):130-4.

[14] Kuwabara A et al. High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel disease. Osteoporos Int. 2009 Jun;20(6):935-42.

[15] Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci. 2002 Oct;47(10):2336-48.

[16] Tekbas OF et al. Melatonin as an antibiotic: new insights into the actions of this ubiquitous molecule. J Pineal Res. 2008 Mar;44(2):222-6.

[17] Sánchez-Barceló EJ et al. Clinical uses of melatonin: evaluation of human trials. Curr Med Chem. 2010;17(19):2070-95.

[18] Terry PD et al. Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research. Inflamm Bowel Dis. 2009 Jan;15(1):134-40.

[19] Chang FY, Lu CL.Treatment of irritable bowel syndrome using complementary and alternative medicine. J Chin Med Assoc. 2009 Jun;72(6):294-300.

[20] Lu WZ et al. Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2005 Nov 15;22(10):927-34.

[21] Song GH et al. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study.  Gut. 2005 Oct;54(10):1402-7.

[22] Szent-Györgyi, A. (1957) Bioenergetics. New York: Academic Press, p. 112.

[23] Gomollón F, Gisbert JP. Anemia and inflammatory bowel diseases. World J Gastroenterol. 2009 Oct 7;15(37):4659-65.

[24] Asvold BO et al. Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study. Arch Intern Med. 2008 Apr 28;168(8):855-60.

[25] Sakamoto N et al. Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in Japan. Inflamm Bowel Dis. 2005 Feb;11(2):154-63.

[26] van Ampting MT et al. Intestinal barrier function in response to abundant or depleted mucosal glutathione in Salmonella-infected rats. BMC Physiol. 2009 Apr 17;9:6.

[27] Caddell JL. A review of evidence for a role of magnesium and possibly copper deficiency in necrotizing enterocolitis. Magnes Res.1996 Mar;9(1):55-66.