Category Archives: Hypothyroidism - Page 4

Intermittent Fasting as a Therapy for Hypothyroidism

Posted by on December 1, 2010 128 comments

Reader Adam Kadela has begun intermittent fasting and wonders how it might affect his hypothyroidism:

I have a question pertaining to the section at the end of the book covering extended fasts. I regularly practice the 16-8 fast/feast protocol (breakfast at noon, last meal before eight), and plan to throw in a 36 hour fast once a month per your book. However, I am hypothyroid (hashimoto’s) and take synthetic T4 and T3 (unithroid and cytomel), so I’m wondering if an extended fast could affect my thyroid function negatively.

This is a great question. I think the daily 16-hour fast should be therapeutic for hypothyroidism, but I’m not sure about the 36-hour fast.

In today’s post I want to talk about why daily intermittent fasting may be therapeutic for Hashimoto’s, which is an autoimmune hypothyroidism.

Food Sets The Circadian Clock

The circadian clock is strongly influenced by diet: indeed, food intake dominates light in setting the circadian clock. If you regularly eat at night and fast during the day, the body will start treating night as day and day as night. [1]

(Alcohol consumption at night will also tend to reset the clock, which may explain why college students are often night owls!)

This suggests that controlling the timing of food consumption can help to maintain circadian rhythms.

The Circadian Clock and Hypothyroidism

The thyroid follows circadian rhythms. There is a circadian pattern to TSH levels:  high at night, low during the day.

The thyroid’s circadian pattern is diminished in autoimmune hypothyroidism. In a study of hypothyroid children, the night-time surge of TSH averaged 22%, compared to 124% in normal children. Only one of 13 hypothyroid children had a night-time TSH surge in the normal range. [2]

The study authors concluded:

We suggest that the nocturnal surge of TSH is important for maintenance of thyroid function and conclude that the nocturnal TSH surge is a much more sensitive test than the TSH response to TRH for the diagnosis of central hypothyroidism. [2]

Shift Work and Hypothyroidism

If circadian rhythms are important for thyroid function, we would expect shift workers to have high rates of hypothyroidism. Shift workers sleep during the day and eat at night, which disrupts circadian rhythms.

It turns out that shift work doubles the risk of autoimmune hypothyroidism:

Stress induces autoimmune disorders by affecting the immune response modulation. Recent studies have shown that shift work stress may enhance the onset of the autoimmune Graves hyperthyroidism. On the other hand, the possible association between occupational stress and autoimmune hypothyroidism has not yet been investigated…. Subclinical autoimmune hypothyroidism was diagnosed in 7.7 percent shift workers and in 3.8 percent day-time workers with a statistically significant difference: Odds Ratio (OR) 2.12, 95 percent Confidence Interval (CI) 1.05 to 4.29; p=0.03…. Our data show a significant association between shift work and autoimmune hypothyroidism. This finding may have implications in the health surveillance programs. [3]

Shift Work Affected Adam Too

In a follow up email, Adam told me that night shift work may have helped cause his hypothyroidism:

[T]he paper about thyroid and fasting … is particularly interesting to me due to my experience with night shift work for 10 months last year. My circadian rhythm was all out of whack due to experimenting with different sleep schedules and trying to workout around midnight before going into work at two a.m. I also played around with different diet strategies (grazing method w/ small meals, warrior diet, and ultimately settling on the 16-8, which is by far superior imo). My thyroid, along with other hormones, did not enjoy these trials.

Intermittent Fasting May Be Therapeutic

Since the circadian rhythm is affected by both food and light exposure, lifestyle practices can enhance natural circadian rhythms. These practices should optimize the circadian cycle:

  • Light entrainment:  Get daytime sun exposure, and sleep in a totally darkened room.
  • Daytime feeding: Eat during daylight hours, so that food rhythms and light rhythms are in synch.
  • Intermittent fasting: Concentrate food intake during an 8-hour window during daylight hours, preferably the afternoon. A 16-hour fast leading to lower blood sugar and insulin levels, and the more intense hormonal response to food that results from concentration of daily calories into a short 8-hour time window, will accentuate the diurnal rhythm.
  • Adequate carb intake:  Eat at least 400 “safe starch” carbohydrate calories daily during the afternoon feeding window. Relative to a very low-carb diet, this will increase daytime insulin release and, by increasing insulin sensitivity, may reduce fasting insulin levels. It will thus enhance diurnal insulin rhythm.

Adam tells me that intermittent fasting seems to be improving his hypothyroidism:

I think you’re correct in that I’ve experienced some curative effects. However, with the improved nutrient absorption and gut health from healthier eating and fasting, I think I fluctuate a lot b/w slightly hypo, normal, and hyper, since my medication is constant. I’m still in the process of finding a balance, but it’s a bigger improvement than my past state.

Conclusion

Many doctors mistakenly assume that little can be done to cure autoimmune disorders. In fact, however, autoimmune conditions commonly disappear once the chronic infections, food toxins, or poor health practices that cause them are eliminated.

Circadian rhythms have powerful influences on many biological processes, and disrupted circadian rhythms are a common feature of disease. Without clinical trials it’s impossible to be sure, but efforts to enhance circadian rhythms may be therapeutic for diseases such as hypothyroidism.

Intermittent fasting, daytime light exposure, excluding light from the bedroom, night fasting and daytime feeding are simple practices. But they may be underappreciated keys to good health.

References

[1] Fuller PM et al. Differential rescue of light- and food-entrainable circadian rhythms. Science. 2008 May 23;320(5879):1074-7. http://pmid.us/18497298.

[2] Rose SR et al. Hypothyroidism and deficiency of the nocturnal thyrotropin surge in children with hypothalamic-pituitary disorders. J Clin Endocrinol Metab. 1990 Jun;70(6):1750-5. http://pmid.us/2112153.

[3] Magrini A et al. Shift work and autoimmune thyroid disorders. Int J Immunopathol Pharmacol. 2006 Oct-Dec;19(4 Suppl):31-6. http://pmid.us/17291404.

Thyroid: More Evidence That “Normal” is Unhealthy

Posted by on July 30, 2010 114 comments

Two inexpensive blood tests should be done routinely, but often aren’t: Vitamin D levels (by serum 25-hydroxyvitamin D) and thyroid stimulating hormone levels (TSH). There are few easier ways to substantially improve health than to normalize levels of these hormones.

One difficulty, however, is disagreement over what “normal” levels are. The standard “normal” range for TSH on lab tests is about 0.5 to 4.6 mIU/L. This range originally encompassed two standard deviations about the US mean, meaning that 95% of the population fell in the “normal” range. Unfortunately, evidence that TSH values in this range were healthy has always been lacking.  In fact, many people with “normal” TSH live with symptoms of hypothyroidism.

As awareness has grown of the biological significance of thyroid hormone, researchers have looked more closely into the correlation of TSH levels with health.  This research is revealing is that many people are thyroid-deficient and that improving thyroid status can dramatically improve health.

The best research has been conducted in Europe:

  • The HUNT study of 25,000 healthy Norwegians found that their prospects were substantially affected by thyroid function. Those with a TSH level of 1.5 to 2.4 were 41% more likely to die over the next 8 years than those with TSH below 1.5; those with TSH 2.5-3.4 were 69% more likely to die. [1]
  • An Italian study showed that pregnant women with TSH between 2.5 and 5.0 had a miscarriage rate 70% higher than women with TSH below 2.5. [2]

Now, a Dutch study shows that the likelihood of breech birth rises monotonically with the mother’s TSH levels at gestational week 36. [3] Breech birth is a significant hazard:  it commonly requires a Caesarean section delivery, and both mother and infant are more likely to die or otherwise suffer damaged health if the baby presents in the breech position. The Dutch study found that:

  • Pregnant women with a TSH of 0.5 or less had NO breech births at all, and those between 0.51 and 0.71 had only a 1% chance of a breech birth.
  • Pregnant women with a TSH between 0.71 and 2.49 had about a 5% chance of breech birth.
  • Pregnant women with TSH of 2.50 to 2.89 had an 11% chance of breech birth, while those with TSH above 2.89 had a 14% chance of breech birth.

The authors didn’t provide a detailed breakdown of breech rates for TSH levels in the middle range, but it is a safe bet that TSH levels of 1.5 to 2.49 were much more dangerous than TSH levels of 0.72 to 1.0.

What these studies are telling us is that:

  1. People with the healthiest thyroid status have very low TSH. A TSH level below 0.5 can indicate either hyperthyroidism (too much thyroid hormone) or perfect health. Any TSH above 0.5 is suggestive of, at a minimum, a slight deficiency of either iodine or selenium.
  2. You can have impaired thyroid status with normal free T4 hormone levels. This study and others have found that TSH levels, not free thyroid hormone levels, are the best indicator of health.
  3. Health becomes significantly impaired above TSH levels of about 1.5. Any TSH above 1.5 should be addressed, if only through iodine and selenium supplementation (or abundant seaweed consumption with ~3 Brazil nuts per day.) Since a TSH of 1.5 is about the population mean, it’s a fair inference that most Americans are needlessly suffering impaired health due to impaired thyroid status.
  4. Especially during pregnancy, thyroid and iodine status are critical. Breech birth and miscarriage are far from the only negative consequences of impaired thyroid status. An elevated TSH usually indicates an iodine deficiency, and “even a mild iodine deficiency during pregnancy and during the first years of life adversely affects brain development.” [4] Iodine deficiency is the most common worldwide cause of mental retardation (cretinism), and elevated TSH during pregnancy can be expected to reduce the IQ of the child by up to 10 points and to produce other neurological deficits, including “visuomotor, memory, attention and posture” deficits. [5]

So, if your doctor doesn’t do it routinely, ask for TSH and vitamin D measurements at your next physical. There are few easier ways to improve your health than fixing thyroid and vitamin D status.

[1] 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. http://pmid.us/18443261.

[2] Negro R et al. Increased Pregnancy Loss Rate in Thyroid Antibody Negative Women with TSH Levels between 2.5 and 5.0 in the First Trimester of Pregnancy. J Clin Endocrinol Metab. 2010 Jun 9. [Epub ahead of print] http://pmid.us/20534758.

[3] Kuppens SM et al. Maternal thyroid function during gestation is related to breech presentation at term. Clin Endocrinol (Oxf). 2010 Jun;72(6):820-4. http://pmid.us/19832853.

[4] Remer T et al. Iodine deficiency in infancy – a risk for cognitive development. Dtsch Med Wochenschr. 2010 Aug;135(31/32):1551-1556. http://pmid.us/20665419.

[5] Joseph R. Neuro-developmental deficits in early-treated congenital hypothyroidism. Ann Acad Med Singapore. 2008 Dec;37(12 Suppl):42-3. http://pmid.us/19904446.

Bowel Disease, Part III: Healing Through Nutrition

Posted by on July 22, 2010 113 comments

[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

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.

Summary

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

References

[1] “The antibiotic vitamin: deficiency in vitamin D may predispose people to infection,” Science News, Nov 11, 2006, http://findarticles.com/p/articles/mi_m1200/is_20_170/ai_n16865477/.

[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. http://pmid.us/17675463.

[3] Lehrer RI, Ganz T. Defensins of vertebrate animals. Curr Opin Immunol. 2002 Feb;14(1):96-102. http://pmid.us/11790538.

[4] Rivas-Santiago B et al. Susceptibility to infectious diseases based on antimicrobial peptide production. Infect Immun. 2009 Nov;77(11):4690-5. http://pmid.us/19703980.

[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. http://pmid.us/12902844.

[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. http://pmid.us/19079235. 

[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. http://pmid.us/16619196.

[8] Wehkamp J et al. Defensins and cathelicidins in gastrointestinal infections. Curr Opin Gastroenterol. 2007 Jan;23(1):32-8. http://pmid.us/17133082.

[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. http://pmid.us/17397543.

[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. http://pmid.us/19491064.

[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. http://pmid.us/19203420.

[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. http://pmid.us/20056631.

[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. http://pmid.us/18825300.

[15] Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci. 2002 Oct;47(10):2336-48. http://pmid.us/12395907.

[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. http://pmid.us/18289175.

[17] Sánchez-Barceló EJ et al. Clinical uses of melatonin: evaluation of human trials. Curr Med Chem. 2010;17(19):2070-95. http://pmid.us/20423309.

[18] Terry PD et al. Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research. Inflamm Bowel Dis. 2009 Jan;15(1):134-40. http://pmid.us/18626968.

[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. http://pmid.us/19541564.

[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. http://pmid.us/16268966.

[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. http://pmid.us/15914575.

[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. http://pmid.us/19787829.

[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. http://pmid.us/18443261.

[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. http://pmid.us/15677909.

[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. http://pmid.us/19374741.

[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. http://pmid.us/8819095.