2014

Clostridia Detection and Comparison of Organic Acid Detection Versus Stool Testing

William Shaw, Ph.D.

Continued research at The Great Plains Laboratory has resulted in new information on Clostridia bacteria markers that will soon be available for the urine organic acid test. New information will soon be available for the organic acid interpretations of 3 (3 hydroxyphenyl)-3 hydroxypropionic acid (HPHPA), 4-hydroxyphenylacetic acid, phenyllactic acid, and 3-indoleacetic acid at the beginning of 2015.

In addition, this article will help to clarify information about the increased value of organic acid testing compared to stool testing for assessing Clostridia species.

HPHPA

First, the species that are the major producers of the precursors of HPHPA have been identified and include C. botulinum, C. sporogenes, and C.caloritolerans. (It is common to use the abbreviation for the Clostridia genus "C" when giving the genus and species designation.)

C. botulinum is a gram-positive, rod-shaped, anaerobic, spore-forming, motile bacterium with the ability to produce the neurotoxin botulinum. The botulinum toxin can cause a severe flaccid paralytic disease in humans and animals and is the most potent toxin known to humankind (natural or synthetic) with a lethal dose of less than 1 μg (microgram) in humans. Symptoms of botulism include weakness, trouble seeing, feeling tired, and trouble speaking. This may then be followed by weakness of the arms, chest muscles, and legs. In food borne botulism, symptoms generally begin 18 to 36 hours after eating a contaminated food, but they can occur as early as 6 hours or as late as 10 days after eating the food.

It is interesting that the symptoms of botulism vary widely from a mild illness for which the patient may seek no medical treatment to a fulminant disease, killing within 24 hours (1). Since laboratory testing for this organism is only available at state health departments, it seems likely that many cases of botulism, especially the mild cases, may be undiagnosed. I suspect that some children with autistic behavior,with extremely high urine HPHPA, little or no speech, and extremely severe low muscle tone might actually have undiagnosed botulism, and further research on this possibility is warranted.

C. sporogenes is virtually identical to C. botulinum except it is lacking the gene for the botulinum neurotoxin. Like C. botulinum, it is an anaerobic gram-positive, rod-shaped bacterium that produces oval, subterminal endospores, and is commonly found in soil.

C. caloritolerans is named after its extreme heat (calor) resistance (tolerans). It can survive at the boiling point for 8 hours (2); its ability to resist heat may allow transmission even in well-cooked food. No scientific papers on any disease associations (other than my own articles dealing with its production of HPHPA) were found, which means there is still a great deal of research opportunity for microbiologists in the future.

 

4-Hydroxyphenylacetic Acid

High 4-hydroxyphenylacetic acid is associated with small intestinal bacteria overgrowth due to its production by the following Clostridia bacteria: C. diificile, C. stricklandii, C. lituseburense, C. subterminale, C. putrefaciens, and C. propionicum. C. difficile can be distinguished from the other species by its production of 4-cresol; none of the other species produce 4-cresol. No information on the pathogenicity of the other species producing 4-hydroxyphenylacetic acid is available. However, it is likely that 4-hydroxyphenylacetic is also an inhibitor of dopamine-beta-hydroxylase and appropriate treatment with probiotics or antibiotics may be clinically useful. 4-hydroxyphenylacetic acid is associated with bacterial overgrowth of the small intestine (3). Elevated values are common in celiac disease and cystic fibrosis, and have also been reported in jejuna web, transient lactose intolerance, Giardia infection, ileal resection, ileo-colic intersusseception, septicemia, and projectile vomiting. The elevations of 4-hydroxyphenylacetic acid in celiac disease and cystic fibrosis are so prevalent that involvement of these Clostridia bacteria may play a role in these illnesses. In C. difficileinfections 4-hydroxyphenylacetic acid is utilized by this bacteria to produce 4-cresol.

 

Phenyllactic Acid

Very high amounts of phenyllactic acid are found in the rare genetic disease phenylketonuria (PKU). Moderate amounts of phenyllactic acid may be due to gastrointestinal overgrowth of the intestine of the following Clostridia bacteria: C. sordellii, C. stricklandii, C. mangenoti, C. ghoni, and C. bifermentans. C sordellii is usually considered a nonpathogen except in immunocompromised people, but has been implicated in catastrophic infectious gynecologic illnesses among women of childbearing age. The other species have rarely or never been reported to be pathogenic.

 

3-Indoleacetic Acid

High 3-indoleacetic acid in urine is a byproduct of C. stricklandii, C. lituseburense, C. subterminale, and C. putrefaciens. No information on the pathogenicity of these species producing indoleacetic acid is available. However, very high amounts of this metabolite derived from tryptophan might indicate a depletion of tryptophan needed for other physiological functions.

 

4-Cresol

4-cresol is predominantly produced by C. difficile, a pathogenic bacteria, that is one of the most common pathogens spread in hospitals. Toxin-producing strains of C. difficile can cause illness ranging from mild or moderate diarrhea to pseudomembranous colitis, which can lead to toxic dilatation of the colon (megacolon), sepsis, and death (4). 4-cresol (para-cresol) has been used as a specific marker for Clostridium difficile (5). 4-Cresol, a phenolic compound, is classified as a type-B toxic agent and can cause rapid circulatory collapse and death in humans (6). Yokoyama et al. (7) have recently proposed that intestinal production of 4-cresol may be responsible for a growth-depressing effect on animals. Signs of acute toxicity in animals typically include hypoactivity, salivation, tremors and convulsions. High amounts of 4-cresol have been found in autism (8); the amount of 4- cresol in the urine has been found elevated in baseline samples and in replica samples of autistic children. Higher values of 4-cresol are found in girls with autism compared to boys with autism and higher values are associated with greater clinical severity of autistic symptoms and history of behavioral regression. 4-cresol is apparently produced by Clostridia difficile as an antimicrobial compound that kills other species of bacteria in the gastrointestinal tract, allowing the Clostridia difficile to proliferate and predominate.

 

Organic acid test superior to stool testing for Clostridia testing

C. difficile is the only species of 100 species of Clostridia from the gastrointestinal tract to be commonly tested in hospital laboratories throughout the world. However, this species is not commonly cultured, but rather is detected by its toxin formation. The gastrointestinal damage caused by C. difficile is thought to be due to exposure to two toxins produced by C. difficile, toxin A and toxin B, with toxin B considered to be more toxic (4). The toxins can be tested by immunoassay of stool samples which is a fairly rapid test. Toxigenic stool culture, which requires growing the bacteria in a culture and detecting the presence of the toxins, is the most sensitive test for C. difficile, and it is still considered to be the gold standard (4). However, it can take 2 to 3 days for results. Polymerase chain reaction (PCR) evaluation of the C. difficile toxins is also becoming more available. Virtually all of the research on C. difficile is related to the effects of this species of bacteria on the intestinal tract. Toxin-negative C. difficile strains are considered nonpathogenic for the infection of the intestine (4) but cresol producing strains that don't produce toxins and B may be pathogenic due to their effects on brain metabolism and for the inherent toxicity of 4-cresol itself.

In addition, urinary 4-cresol elevations associated with C. difficileovergrowth are much less common than urinary HPHPA elevations associated with other Clostridia species. In a survey of 1000 consecutive samples submitted for urine organic acids tests, The Great Plains Laboratory found that 15.2% were abnormally elevated for HPHPA, 6.8% were abnormally elevated for 4-cresol, and 1.6% were abnormally elevated for both HPHPA and 4-cresol for a total positive percentage of 23.6%. Thus, if only stool testing for Clostridium difficile is performed on a patient, at least 15.2/23.6 or 64.4% (nearly two-thirds) of patients with clinically significant infections with other types of Clostridia might be missed.

Sometimes total Clostridia are tested using culture methods or PCR (polymerase chain reaction) technology. In one case, a parent showed me the stool test results of their child with autism. They had done a stool test with a laboratory using PCR technology to determine both C. difficile and total Clostridia. The total Clostridia was reported as extremely low and the C. difficile negative, but The Great Plains Laboratory organic acid test found high levels of the HPHPA marker. If the parent had relied on the stool test alone, their child might have missed an important therapeutic intervention that can restore normal neurotransmitter balance. The advantage of The Great Plains Laboratory organic acid test is that it is not necessary to determine particular species of Clostridia because it is the HPHPA and/or 4-cresol that are neurotoxic.

People sometimes assume that a test using DNA is more accurate than other types of testing. However, DNA testing is fraught with complexities. The nucleic acids of Clostridia are extremely diverse. The content of the nucleic acid bases guanosine and cytosine (G+C) is used to classify bacteria species. The G+C content of DNA of Clostridia species ranges from 21-54 % (9). The majority of intestinal species have G+C contents in the lower half of this range. Ribosomal RNA cataloging confirms that Clostridia occupy six independent sublines with multiple branches including non-Clostridia species. The failure to offer documentation on which species are being detected and how validation was performed should lead to caution by the user of such testing, especially when such tests may be labeled "experimental". Similar complexities exist with traditional culture methods for Clostridia since results are commonly reported from 0 to 4+. Since many Clostridia are not pathogenic, what does a high Clostridia level of 4+ indicate since beneficial, neutral, and harmful species are lumped together in one category? In reality, the results of stool tests for total Clostridia are virtually meaningless and may lead to inappropriate patient treatment.

It is estimated that there are about 10 billion cells of Clostridia per gram of stool. Clostridium ramosum is the most common (53% of all subjects tested) with a mean count of about one billion per gram of stool (9). The prevalence of some Clostridia species is highly dependent on diet. Stool samples of vegetarians did not contain Clostridium perfringens whereas meat and fish eaters had high amounts (10).

Since HPHPA is associated with multiple species of Clostridia but not Clostridium difficile, there is really no available confirmation test for determining the specific species of Clostridium producing HPHPA. As mentioned above, stool testing for total Clostridia is useless since it cannot currently differentiate between harmful or beneficial species. Since HPHPA, in my experience, disappears after treatment with vancomycin or metronidazole, I always recommend treatment based on the HPHPA value with a follow-up test 30 days after completion of treatment.

Confirmation testing of Clostridium difficile could be performed when 4-cresol is elevated. However, the prevalent testing for Clostridium difficile toxins A and B are focused on strains that cause gastrointestinal damage. Strains that produce 4-cresol but not toxins A or B may still cause significant psychiatric disease, so performing these toxin tests may muddy the interpretation of the clinical situation if these tests are negative. I think that it is easier to treat based on the 4-cresol results and then do follow-up testing of the 4-cresol on the organic acid test 30 days after completion of treatment.

Clinical References

  • Beatty, H. Botulism. In: Harrison's Principles of Internal Medicine, 10th edition, ed. R. Petersdorf, et al. McGraw Hill. New York. 1983. Pages 1009-1013.
  • Meyer, K.F. and Lang, O.W. A highly heat-resistant sporulating anaerobic bacterium: Clostridium caloritolerans, N. SP. The Journal of Infectious Diseases Vol. 39, No. 4 (Oct., 1926), pp. 321-327
  • Chalmers, R.A., Valman. H.B., and Liberman, M.M., Measurement of 4-hydroxyphenylacetic aciduria as a screening test for small-bowel disease. Clin Chem 25:1791, 1979
  • Carrico, R.M. Association for Professionals in Infection Control and Epidemiology (APIC) Implementation Guide to Preventing Clostridium difficile Infections http://apic.org/Resource_/EliminationGuideForm/59397fc6-3f90-43d1-9325-e8be75d86888/File/2013CDiffFinal.pdf (accessed Oct 30,2014)
  • Sivsammye, G. and Sims, H.V. Presumptive identification of Clostridium difficile by detection of p-cresol (4-cresol) in prepared peptone yeast glucose broth supplemented with p-hydroxyphenylacetic acid. J Clin Microbiol. Aug 1990; 28(8): 1851–1853.
  • Phua, T.J., Rogers, T.R., and Pallett, A.P. Prospective study of Clostridium difficile colonization and paracresol detection in the stools of babies on a special care unit. J. Hyg., Camb. (1984). 93. 17-25 17
  • Yokoyama, M. T., Tabori, C., Miller, E. R. and Hogberg, M. G. (1982). The effects of antibiotics in the weanling pig diet on growth and the excretion of volatile phenolic and aromatic bacterial metabolites. The American Journal of Clinical Nutrition 35, 1417-1424.
  • Persico, A.M. and Napolioni, V. Urinary p-cresol (4-cresol) in autism spectrum disorder. Neurotoxicology and Teratology 36 (2012) 82–90
  • Wells, J.M. and Allison, C. Molecular genetics of intestinal anaerobes. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Page28
  • 10. Conway, P. Microbial ecology of the human large intestine. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Pages 1-24

 

The Little Lauded Benefits of Lithium

Heather Getz

While most know lithium as a drug (or the title of a popular song by 90's grunge band, Nirvana), it's also an element (a salt) that occurs naturally and is present in our drinking water here in the United States in varying amounts, depending on where you live. While it seems it's not being talked about much, there is a great deal of evidence in the scientific community that even very small doses of lithium may be beneficial to mental health. Several studies have shown it to be effective in many areas, from reducing rates of suicide and dementia to treating bipolar disorder (see below for a list of studies).

Dr. Nassir Ghaemi, professor of psychiatry at Tufts University School of Medicine said, "Lithium is, by far the most proven drug to keep neurons alive, in animals and in humans, consistently and with many replicated studies". So why aren't more people in the mainstream or even integrative and alternative medicine groups giving it serious consideration? Dr. Peter D. Kramer, clinical professor of psychiatry at Brown University suggested that mainstream doctors may "distrust low-dose supplements as somehow ineffective or like homeopathy" and that the alternative medicine crowd "may shun it because – though it's a salt found in groundwater – lithium already has an identity as a powerful, marketed medication for mental illness".

There has been a considerable amount of research done on the effects of both naturally occurring lithium (in tap water) and on dietary supplementation on a variety of mental health disorders. You may review some of that research and decide whether lithium supplementation is a possible treatment for any of your patients.

Clinical References

  • Schrauzer GN. Lithium: occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr (2002) 21(1):14-21.
  • Dawson EB. The relationship of tap water and physiological levels of lithium to mental hospital admission and homicide in Texas, in Schrauzer & Klippel, Eds. Lithium in Biology and Medicine. Cambridge, VCH, 1991:169-188.
  • Schrauzer GN, Shrestha KP. Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biol Trace Elem Res (1990) 25(2):105-113.
  • Schrauzer GN, de Vroey E. Effects of nutritional lithium supplementation on mood: A placebo-controlled study with former drug users. Biol Trace Elem Res (1994) 40(1):89-101.
  • Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease. Curr Alzheimer Res (2013) 10(1):104-107.
  • Forlenza OV, Diniz BS, Radanovic M, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial.Br J Psychiatry (2011) 198(5):351-356.
  • Straten G, Saur R, Laske C, et al. Influence of lithium treatment on GDNF serum and CSF concentrations in patients with early Alzheimer's disease. Curr Alzheimer Res (2011) 8(8):853-859.
  • Leyhe T, Eschweiler GW, Stransky E, et al. Increase of BDNF serum concentration in lithium treated patients with early Alzheimer's disease. J Alzheimers Dis (2009) 16(3):649-656.
  • Nierenberg A, Friedman E, Bowden C, et al. Lithium treatment moderate-dose study (LiTMUS) for bipolar disorder: A randomized comparative effectiveness trial for optimized personalized treatment with and without lithium. The American Journal of Psychiatry (2013) 170(1):102-110
  • Geddes, J, Miklowitz D. Treating of bipolar disorder. The Lancet (2013) 381(9878):1672 – 1682 doi:10.1016/S0140-6736(13)60857-0
  • Cipriani A, Hawton K, Stockton S, Geddes J. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ (2013) 346:f3646 doi: http://dx.doi.org/10.1136/bmj.f3646
  • Other reference for article:

    Fels, Anna (2014 September 14). Should We All Take a Bit of Lithium? The New York Times. Retrieved from http://www.nytimes.com/2014/09/14/opinion/sunday/should-we-all-take-a-bit-of-lithium.html?_r=0

The Role of Diet and the Gut in Mental Health

Terri Hirning

While the traditional mental health model focuses on brain function, neurotransmitters and potentially pharmaceutical medications, the ever burgeoning integrative mental health field understands there is more to it than that. Even mainstream media is starting to get the hint. Our gut influences our mind, emotions, cognition and mental health more than we've given it credit for in recent history. Whether we want to focus on the role food allergies play on mental health (1), (2) or how the gut-brain axis impacts our mental health (3), or even how the microbiome shapes our mental functioning (4) we can see the trend in research confirming what many integrative physicians and clinicians know: the gut matters

When we talk about the gut, we must cover diet. Some literature even suggests that a debilitating mental health disorder like Alzheimer's now be called "Type 3 Diabetes" (5) because of its links to certain kinds of foods and a generally poor diet. What is causing the alarming trend of food allergies, food sensitivities and the increase in auto-immune conditions? Is it GMO's? Is it Glyphosate (the herbicide used in products like Monsanto's Roundup)? Is it the prevalence of processed grains in our diets now? It may be all of thesethings, or none of these things, but as physicians and clinicians, the data suggests we take a closer look at our patients' diets and here are some things to consider:

Is there an underlying food allergy or multiple allergies? This can be an easy and yet very powerful place to start. Research shows that food allergies can indeed cause manifestations of mental health disorders. Running a simple IgG food allergy test from the Great Plains Laboratory, which also includes markers for Candida (harmful fungus in the gut) can be a great first step. More mainstream information on the treatment of Celiac disease can be also helpful in finding its connections to many mental health disorders like dementia, seizures, schizophrenia, etc.(6), and one does not have to be diagnosed with Celiac disease to be sensitive and reactive to gluten.

What about healthy gut function and microbiome population? Our microbiome is sensitive to our diets, and quickly reactive to changes. Looking at potential gut dysbiosis and the levels of beneficial flora in the gut is very important. An organic acids test will show you a wide range of metabolic markers, including several for bacteria (like Clostridia) and fungus (like Candida albicans) in the gut. If a patient has high levels of these, a course of treatment can be started to rid them of these invaders, possibly including dietary restrictions (like a low sugar, low carb diet) and adding helpful antibacterial or antifungal supplements. Then, to assess the beneficial bacteria in the gut, you may want to run a comprehensive stool analysis. This will help determine whether a patient needs to add a high-quality probiotic supplement to their diet and possibly increase his/her intake of probiotic-rich and fermented foods like kefir and sauerkraut.

Today's mental health disorders are very complex. Their treatment requires a well-rounded look at the many factors impacting the body and brain, including diet, lifestyle, the microbiome, and more. When an integrative approach is used and these many factors considered when creating a treatment plan, time and time again we see improvements in functioning and a reduction in clinical symptoms.

Clinical References:

  • Jackson J1, Eaton W2, Cascella N3, Fasano A4, Santora D5, Sullivan K6, Feldman S6, Raley H7, McMahon RP6, Carpenter WT Jr6, Demyanovich H6, Kelly DL8.Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia Schizophr Res. (2014) Oct 10. pii: S0920-9964(14)00511-8. doi: 10.1016/j.schres.2014.09.023.
  • Genuis SJ1, Lobo RA2. Gluten sensitivity presenting as a neuropsychiatric disorder . Gastroenterol Res Pract. (2014);2014:293206. doi: 10.1155/2014/293206.
  • Nemani K1, Hosseini Ghomi R2, McCormick B3, Fan X3. Schizophrenia and the gut-brain axis. Prog Neuropsychopharmacol Biol Psychiatry. (2014) Sep 19;56C:155-160. doi: 10.1016/j.pnpbp.2014.08.018.
  • Severance EG1, Yolken RH2, Eaton WW3. Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res. (2014) Jul 14. pii: S0920-9964(14)00319-3. doi: 10.1016/j.schres.2014.06.027.
  • De la Monte S, Wands J. Alzheimer's Disease Is Type 3 Diabetes–Evidence Reviewed. J Diabetes Sci Technol. (2008) 2(6): 1101–1113.
  • Velasquez-Manoff Moises (2014 October 12). Can Celiac Disease Affect the Brain? The New York Times. Retrieved from:http://www.nytimes.com/2014/10/12/opinion/sunday/can-celiac-disease-affect-the-brain.html?smid=tw-share&_r=0

The Role of Vitamins, Antioxidants, and Anti-Inflammatories in Breast Cancer Prevention and Treatment

Terri Hirning

October is Breast Cancer Awareness Month. As such, we would like to take a moment to focus on how nutritional and supplement therapy can play a role in the prevention and treatment of cancer. When we look at how antioxidants impact cancer, we can see that there is scientific documentation of reduced development of breast cancer in those with high dietary intake of antioxidants. One study in late 2014 titled The Rotterdam Study provides this information: "These results suggest that high overall dietary antioxidant capacity are associated with a lower risk of breast cancer."1 Women who had higher rates of antioxidant intake via diet were less likely to develop breast cancer. What about those who already had breast cancer? Could it help with treatment? A March 2014 issue of Anticancer Research featured a study showing the use of lycopene and beta-carotene in cell death of human breast cancer cell lines. "Our findings show the capacity of lycopene and beta-carotene to inhibit cell proliferation, arrest the cell cycle in different phases, and increase apoptosis."2 Vitamin C has also been studied in terms of its potential impact on breast cancer deaths and has been shown to have a positive effect on mortality rates. "Dietary vitamin C intake was also statistically significantly associated with a reduced risk of total mortality and breast cancer-specific mortality."3

If we can look at the data and determine that higher intake of antioxidants and nutrients can not only reduce development of breast cancer but can also positively impact the mortality rates of cancer, the question then becomes how do we encourage our patients and clients to incorporate these into their diets with higher frequency? We must educate them on the role antioxidants play and the resources available to obtain them, whether from foods or supplements. For example, lycopene is a nutrient that is highlighted for its anticancer properties, specifically in reference to breast cancer. Lycopene is a carotenoid that gives many fruits and vegetables their red color. Unlike other carotenes, lycopene does not get converted into vitamin A. The top 10 sources of dietary lycopene are:

  • Guava
  • Watermelon
  • Tomatoes (cooked)
  • Papaya
  • Grapefruit
  • Sweet Red Peppers (cooked)
  • Asparagus (cooked)
  • Red (purple) cabbage
  • Mango
  • Carrots

Continued from BioMed Today:

Encouraging patients to incorporate more foods with lycopene, like those listed above, into their diets is one component. Supplements can also be suggested as a potential option. This is especially true in the case of vitamin D, for which there are many studies showing its role in the prevention of cancers. Adequate vitamin D is being revealed as a critical factor for preventing many diseases, including breast cancer, today.8 "Case-control studies and laboratory tests have consistently demonstrated that vitamin D plays an important role in the prevention of breast cancer."9 Unfortunately due to a variety of reasons, many people are deficient in vitamin D which then can then compromise optimal health. Testing for vitamin D levels, ideally twice a year, is a great way to monitor this critical nutrient and help your patients optimize their health and wellness. Supplementation can then also be recommended to optimize levels. Another promising resource for warding off disease and cancer is curcumin, the extract of the turmeric root. Because of its potent antioxidant and antimicrobial properties, it is being studied extensively for its potential in cancer treatment. The American Cancer Society's website has this to say about it: "Curcumin can kill cancer cells in laboratory dishes and also slows the growth of the surviving cells. Curcumin has been found to reduce development of several forms of cancer in lab animals and to shrink animal tumors."4 The typical therapeutic dose, between 3 and 10 grams per day, exceeds what is normally used in cooking and obtained through dietary consumption so a supplement would be most effective.

Could another reason for the efficacy of curcumin on cancer cell death be its potent anti-inflammatory properties? Curcumin has been studied widely for both its safety and anti-inflammatory potential.5,6 "The laboratory studies have identified a number of different molecules involved in inflammation that are inhibited by curcumin including phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, tumor necrosis factor (TNF), and interleukin-12 (IL-12)."7 We see science validating the role our lifestyle has in development of cancer. Diet, exercise, supplementation, our stress level, and other factors all contribute to the whether or not we develop disease and also to our ability to reverse it. It is important to find ways to offer a variety of prevention and treatment options that work with our patients' lifestyles.

Clinical References:

  • Pantavos A, Ruiter R, Feskens E, E deKeyser C, Hofman A, H Stricker B, H Franco O, C Kiefte-deJong J (2014). Total dietary antioxidant capacity, individual antioxidant intake and breast cancer risk: The rotterdam study, International Journal of Cancer. 2014 Oct 4. doi: 10.1002/ijc.29249. [Epub ahead of print]
  • Gloria NF, Soares N, Brand C, Oliveira FL, Borojevic R, Teodoro AJ (2014).Lycopene and beta-carotene induce cell-cycle arrest and apoptosis in human breast cancer cell lines, Anticancer Research. 2014 Mar;34(3):1377-86.
  • Harris HR, Orsini N, Wolk A (2014). Vitamin C and survival among women with breast cancer: a meta-analysis,European Journal ofCancer. 2014 May;50(7):1223-31. doi: 10.1016/j.ejca.2014.02.013. Epub 2014 Mar 7.
  • Turmeric (2012). Retrieved on October 5, 2014 from Link
  • Chainani-Wu NJ (2003). Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa), Journal of Alternative and Complementary Medicine. 2003 Feb; 9(1):161-8.
  • Jurenka, JS (2009). Anti-inflammatory Properties of Curcumin, a Major Constituent of Curcuma longa: A Review of Preclinical and Clinical Research, Alternative Medicine Review. Volume 14, Number 2, 2009.
  • Nita Chainani-Wu (2003). The Journal of Alternative and Complementary Medicine. February 2003, 9(1): 161-168. doi:10.1089/107555303321223035.
  • Vitamin D and Cancer Prevention (2013). Retrieved on October 5, 2014 from http://www.cancer.gov/cancertopics/factsheet/prevention/vitamin-D
  • Walentowicz-Sadłecka M, Sadłecki P, Walentowicz P, Grabiec M (2013). The role of vitamin D in the carcinogenesis of breast and ovarian cancer, Ginekologia Polska. 2013 Apr;84(4):305-8.

The SCD, GAPS, and Paleo Diets: How They Compare and How They May Help Your Patients

Terri Hirning

Special diets have become increasingly common and more popular in recent years. Reports from both physicians and patients, many with laboratory tests confirming, say they can be helpful for a variety of diseases including autism, ADHD, multiple sclerosis, auto-immunity, rheumatoid arthritis, bowel conditions, and many more. Three diets in particular appear to help address gut dysbiosis, the overgrowth of microbes such as yeast and bacteria, which can be problematic for many individuals. Research shows that more than 70% of children with an Autism Spectrum Disorder (ASD) report a history of GI complaints.1 "Leaky Gut", or intestinal permeability, results from larger than normal spaces between the cells of the gut wall. These spaces allow undigested food and toxins to enter the blood stream. When this happens, the immune system can mount an attack against the foreign particles which may result in food sensitivities and/or allergies. When the offending foods are eaten again, the release of antibodies triggers inflammation. This chronic inflammation further exacerbates the cycle by lowering Immunoglobulin A (IgA) levels. Adequate IgA levels are required to protect the intestinal tract from the gut pathogens such as clostridia and yeast. This continuous cycle can increase gut dysbiosis and negatively impact the overall health of your patients. All three of these special diets – SCD, GAPS, and Paleo may help address these issues by reducing the amount of undigested and allergenic foods being consumed and healing both the gut and brain.

Understanding how the SCD, GAPS, and Paleo diets may help the gut and brain, as well as the major differences between the three diets, can help you provide guidance to your patients when addressing food allergies, autoimmunity, and gut dysbiosis. All three diets share the basic foundations of reducing carbohydrates, avoiding grains (including those that are gluten-free) avoiding refined sugar, avoiding packaged/processed foods, focusing on nutrient-dense foods, and emphasizing the importance of eating a variety of vegetables. Each diet also has its own unique elements, and here is how they compare:

SCD – Specific Carbohydrate Diet:

  • This diet was pioneered by Dr. Sidney V. Haas.

  • Patients are encouraged to follow the program in the book Breaking the Vicious Cycle by Elaine Gottschall.

  • Carbohydrates allowed on this diet are classified by their molecular structure.

  • Allowed carbohydrates are monosaccharides and have a single molecule structure that allow them to be easily absorbed by the intestine wall.

  • Disaccharides (double molecules) and polysaccharides (chain molecules) are not allowed.

  • Some dried beans and legumes can be added in after symptoms resolve and in accordance with the soaking and preparing instructions from the book.

  • This diet does allow some dairy (fermented/cultured).

  • Results of a Rush University SCD study show the diet leads to better microbial gut diversity.2

  • This diet focuses on reduction of pathogenic organisms in the gut rather than introducing beneficial bacteria.

  • Website: http://www.breakingtheviciouscycle.info/home/

GAPS – Gut and Psychology Syndrome Diet:

  • Dr. Natasha Campbell-McBride expanded on the principles of GAPS in her book The Gut and Psychology Syndrome.

  • GAPS is very similar to SCD except for that it adds many probiotic-rich, cultured foods.These foods may help recolonize good bacteria and counteract bad bacteria.

  • This diet has more phases and may be seen as more rigorous than SCD.

  • GAPS emphasizes addressing brain health over gut health, but should certainly assist with both.

  • Website: http://www.gapsdiet.com

Paleo Diet:

  • This diet is based upon the concept that the optimal diet is the one to which we are genetically adapted. It recommends modern, everyday foods that mimic the food groups of our pre-agricultural, hunter-gatherer ancestors

  • Paelo allows some starches that the other diets do not allow.

  • It does not allow dairy products.

  • It does not allow legumes or beans.

  • This diet may be seen as the least restrictive of the three diets.

  • Website: http://thepaleodiet.com/

How to know when to suggest a diet like SCD, GAPS or Paleo for your patients: Have clinical tests like our Organic Acids Test or Microbial Organic Acids Test indicated yeast and/or bacterial overgrowth? Have repeated courses of antibiotics and/or antifungals failed to resolve these often chronic disorders? Have you tried multiple probiotics which have failed to repopulate the gut with good bacteria and yeast? Has IgG food allergy testing shown continued food allergies despite removal of the common allergens like wheat, dairy, and soy? Has your patient developed new or increasing food allergies despite being on an "allergy-friendly" diet? If you answered yes to any of these questions, considering a more specific and restrictive diet beyond GFCF (Gluten Free, Casein Free) could be the next step in healing for your patients.

Diet can be a very effective way to reduce harmful gut pathogens by removing their food supply and decreasing the inflammation they cause. Diligence, dedication, and strict adherence is required from your patients to see the full benefits of these special diets. In cases where antibiotics, antifungals, supplements, and probiotics have not been successful, these diets may help reverse the gut dysbiosis, after which reintegrating various supplements and probiotics may be effective . For newly diagnosed patients, implementing one of these diets may be a good way to begin their healing process quickly and effectively. As Ann Wigmore, health practitioner, nutritionist, and whole foods advocate said, "The food you eat can be either the safest and most powerful form of medicine or the slowest form of poison".

Clinical References

Rickets and eye-poking in autism associated with calcium deficiency

William Shaw Ph.D

I strongly disagree with the assertion by some individuals in the autism field that calcium is a problem to individuals on the autistic spectrum. Failure to provide adequate calcium is very dangerous and could lead to the loss of the eyes due to severe eye-poking behavior. Calcium deficiency can be a severe problem in normal children on a milk free diet since milk is a significant source of protein, vitamin D, and calcium needed for strong bones and teeth. Some physicians have reported rickets (1), a severe bone deformity, occurs in children with autism on the gluten and casein free diet who did not receive added calcium supplements. Calcium and vitamin D supplementation is essential to children on a casein free diet since most children with autism do not eat substantial amounts of other calcium-rich foods. Use of milk substitutes like B-Unique® provides adequate calcium, protein, and fat comparable to whole milk without the presence of casein and lactose that are problematic in most children with autism.

Children with autism may have an even more severe problem with calcium deficiency. Mary Coleman, M.D. (2) reported that children with autism who are calcium deficient are much more likely to poke out their eyes and a substantial number of children with autism have done so. I have talked to numerous parents of children with autism that began to touch their eyes after starting the casein-free diet. This abnormal behavior is associated with low urine calcium; blood calcium levels were usually normal. Treatment with calcium supplementation prevents this behavior. (I suspect that this behavior is due to increased eye pain due to high substance P or to deposits of oxalate crystals in the eye. Low calcium may act to intensify this pain and poking out the eye relieves the pain.) Dr. Coleman also found that speech developed very quickly after calcium supplementation in a portion of mute children with autism who had low urine calcium. Parathyroid hormone, calcitonin, and vitamin D were all normal in patients with autism but all of them had low urine calcium. In one case, according to a parent who contacted me, her child with autism persisted in poking at the eyes even after one eye had been poked out and surgically replaced. Calcium supplementation stopped this behavior immediately. I am aware of many other children with eye-poking behavior in which calcium supplements stopped this behavior in less than two days. Verbal autistic children say that their eye pain is severe and that calcium supplementation stopped their pain quickly. The urine calcium and magnesium tests will soon be a part of the Organic Acids Test offered by The Great Plains Laboratory, Inc.

It is important that calcium, magnesium, and zinc be in balance for optimal nutrition. Vitamin D supplementation may also be needed when milk is eliminated unless other sources of vitamin D are included in the diet or the child is exposed to adequate sunlight. Children with autism also need additional calcium to prevent oxalate deposition in the tissues. Although sardines and dark leafy greens like spinach, kale, turnips, and collard greens are high in calcium, all of these foods except sardines are high in oxalates. High oxalates can be fatal if formed in the renal tract. Oxalates in the urine are much higher in individuals with autism than in normal children. As a matter of fact, 36% of the children on the autistic spectrum had values higher than 90 mmol/mol creatinine, the value consistent with a diagnosis of genetic hyperoxalurias while none of the normal children had values this high. 84% of the children on the autistic spectrum had oxalate values outside the normal range (mean ± 2 std dev). None of the children on the autistic spectrum had elevations of the other organic acids (glyceric and glycolic acids) associated with genetic diseases of oxalate metabolism, indicating that oxalates are high due to external sources. When calcium is taken with foods that are high in oxalates, oxalic acid in the intestine combines with calcium to form insoluble calcium oxalate crystals that are eliminated in the stool. This form of oxalate cannot be absorbed into the body. When calcium is low in the diet, oxalic acid is soluble in the liquid portion of the contents of the intestine (called chyme) and is readily absorbed from the intestine into the bloodstream. If oxalic acid is very high in the blood being filtered by the kidney, it may combine with calcium to form crystals that may block urine flow and cause severe pain. However, such crystals may also form in the bones, joints, blood vessels, lungs, eyes, skin, heart, thymus, skeletal muscle, joints, fat, teeth, mouth, nerves, and even the brain. In addition, oxalate crystals in the bone may crowd out the bone marrow cells, leading to anemia and immunosuppression. Calcium citrate is the best source of calcium to prevent oxalate absorption because citrate ion blocks the absorption of oxalates in the intestinal tract (3). A combination of calcium citrate and magnesium citrate is the best form of supplement to provide calcium and magnesium needs while preventing excess oxalate buildups in the body.

Clinical References:

  • 1. Hediger ML, England LJ,Molloy CA, Yu KF, Manning-Courtney P, Mills JL. Reduced bone cortical thickness in boys with autism or autism spectrum disorder. J Autism Dev Disord. 2008;38(5):848–856
  • 2. Coleman, M. Clinical presentations of patients with autism and hypocalcinuria. Develop. Brain Dys. 7: 63-70, 1994
  • 3. Caudarella R, Vescini F, Buffa A, Stefoni S. Citrate and mineral metabolism: kidney stones and bone disease. Front Biosci. 2003 Sep 1;8:s1084-106.

Vitamins E, C and Age‐Related Diseases

Matt Pratt‐Hyatt, Ph.D.

Age‐related diseases are becoming more commonplace as the population's average age increases. These age‐related diseases include macular degeneration (AMD), hearing loss, and dementia. Many people believe that development of these diseases is inevitable, and that nothing can be done to control their occurrence; however studies have shown that treatment with antioxidant vitamins prevents and sometimes reverses the onset of these age‐related diseases.

As our population's average age increases, the incidence of dementia as well as hearing and vision loss has also increased. The Eye Diseases Prevalence Research Group projects that the rate of age‐related macular degeneration (AMD) in the United States would double from 2004 to 2020. The Better Hearing Institute reports that 3 in 10 people over the age of 60 have hearing loss. The development of vision and hearing loss can be a very stressful situation for patients. Difficulty with hearing can cause stress in social situations due to the production of muffled sounds, required frequent repetition of others speaking, and ringing in the ears. Loss of vision can also create its own difficulties such as struggles with reading and the decreased ability to drive over time.

Recent studies have found that antioxidant intake can have beneficial effects in the alleviation of these age‐related diseases. In 2001 the National Institutes of Health published a report in the Journal of the American Medical Association Ophthalmology of a study with 3,640 participants that indicated that supplementation with vitamins C and E, beta carotene, and zinc decreased AMD and vision loss. In 2013 a joint study between the University of Michigan, University of Toronto, and Seoul National University of Medicine found that patients that took supplements of vitamin C and magnesium had significantly better hearing at high frequencies. Finally a 2010 study of 5,395 participants who were 55 years and older found that patients that took vitamin E supplements were 25% less likely to develop dementia. This study collaborates an earlier longitudinal study in 2000 of 3,385 men that suggested that vitamin E and C supplements may protect against dementia.

These studies raises the question of how much vitamin E and C someone worried about age‐related disease should be taking. The consensus of these studies is that 500 mg of vitamin C and 400 international units (I.U.) of Vitamin E were sufficient to obtain these results. However, patients should consult with their medical practitioner before starting a vitamin regiment.

Clinical References:

  • 1. Kochkin S. (2001). MarkeTrak VI: The VA and direct mail sales spark growth in hearing aid market. The Hearing Review, 8 (12): 16‐24,63‐65.
  • 2. Age‐Related Eye Disease Study Research Group. (2001) A Randomized, Placebo‐Controlled, Clinical Trial of High‐Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age‐Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol. 2001;119(10):1417‐1436.
  • 3. Choi Y et al. (2014) Antioxidant vitamins and magnesium and the risk of hearing loss in the US general population. Am J Clin Nutr. 99 (1) 148‐55.
  • 4. Devore EE et al. (2010) Dietary antioxidants and long‐term risk of dementia. Arch Neurol. 67 (7) 819‐825.
  • 5. Masaki KH et al. (2000) Association of Vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 54 (6): 1265‐72.

Tiny Friends in Hidden Places (But Sometimes They "Unfriend" You): Man's Evolving Relationship with the Microbiome

Pamela Gilford, MA, CCN

Acceptance of the germ theory of disease unleashed a two-century war between humanity and the unseen microbial world. First, better sanitation, and after WWII, the advent of antibiotic treatment, saved millions of lives. Bacteria were the enemy; babies were even bathed in a toxic, chlorinated wash now withdrawn from the market. The presence of bacteria in the GI tract was treated as nature's "mistake." Who cared that oral antibiotics killed off some gut flora? Oral delivery avoided that unpleasant shot in the buttocks.

The mysterious rise in autoimmune disease since the development of modern antibiotic therapy has been one clue that humans might not be winning the war against microbes (see references below). A slow reassessment of the microbes, grudgingly referred to as "GI commensals" (harmless organisms) began. The genesis of pathogenicity has been discovered to be a two-way street between the human immune system and microbes, now referred to as a "relationship". Multi-celled, "higher" organisms clearly coevolved with one-celled organisms to mutual benefit. Microbes help us digest our food and provide certain vitamins. The microbes that line most of our GI tract defend our GI mucosal lining against invading pathogens, and as they begin to colonize the sterile gut of a newborn, they "educate" the child's immune system.

Multi-celled host organisms (like us) provide food, water, physical safety, and transportation. How else could microorganisms have extended their range without transportation? Humans have been particularly helpful. If this notion seems odd, think about syphilis coming to the New World with the first ocean explorers, and more recently, HIV and ebola making the crossing.

Although the variety of our GI flora has been known for a long time (See Theodor Rosebury's Life on Man, 1969), the advent of DNA tools to catalog species has spurred new interest in how human metabolism interacts with GI flora. The National Institute of Health's huge Human Microbiome Project is now nearing completion (seehttp://www.hmpdacc.org/). Evidence-based probiotic supplements for medical use are eagerly anticipated, although the first truly "evidence-based"probiotic was probably Lactobacillus GG, or Culturelle, discovered in cheek swabs by two researchers from Tufts University (see references below). Goldin and Gorbach patented Culturelle in 1985 for treatment of diarrhea caused by Clostridia difficile in children and has since been the subject of several hundred studies. Subsequent DNA analysis has granted this strain of bacteria a species designation of Lactobacillus rhamnosus and it is now incorporated into many commercial probiotic blends.

Studies have shown that variations in the species composition of gut microflora are related to the risk of obesity and that probiotic treatment often improves mood (see references below). Inflammation, which can be modulated by healthy gut flora, has become definitively linked to the epidemic of depression worldwide, as well as the genesis of many chronic diseases (see www.Medscape.com – many articles).

Clinical Endocrinology News reports that 64% of family physicians are stressed and uncomfortable when faced with treating autoimmune disease (see reference below) The fact that available allopathic therapies come with substantial side effects does not improve the practitioners' or patients' comfort levels. The frustration of both in finding safe therapies for autoimmune and chronic disease has certainly contributed to the growing popularity of integrative or CAM approaches. An article in Science magazine from November 2013 (see reference below) cited research by Mathis and Littman who found that Prevotella copri was present in 75% of RA patients' intestines. Later, they were able to trigger inflammation in mice by inoculating with the bacterium. Such studies add weight to clinicians' observations that probiotic treatments and even fecal implants can often halt the progress of chronic diseases.

We have been discussing our microbial passengers and an important part of the organic acids test is the assessment of the level of metabolites of pathogenic microbes, including yeast and Clostridia bacteria. The COMP stool test cultures both beneficial and potentially pathogenic microbes and microscopic examination can catch both yeast and one-celled parasites. When we added the Candida marker to the IgG food allergy test, we discovered a very useful tool for determining if a patient has become sensitive to his/her own native fungal flora. At The Great Plains Laboratory, we believe that the metabolic and and toxic element assessments we offer assist in directing treatment protocols that can mediate many chronic conditions, eliminate harmful microbes, and reinforce beneficial gut flora for improvement in overall health.

Clinical References:

  • Hunter, P. 2012. The changing hypothesis of the gut. The intestinal microbiome is increasingly seen as vital to human health. Science and Society DOI 10.1038/embor.2012.68 |Published online 15.05.2012, EMBO reports(2012)13,498-500
  • Thomas Jefferson University. 2014. Can antibiotics cause autoimmunity? ScienceDaily. March 31, 2014:http://www.sciencedaily.com/releases/2014/03/140331153520.htm
  • Chalmers, R.A., Valman. H.B., and Liberman, M.M., Measurement of 4-hydroxyphenylacetic aciduria as a screening test for small-bowel disease. Clin Chem 25:1791, 1979
  • Whiteman, H. 2014. Antibiotic use in children linked to juvenile idiopathic arthritis. Medical News Today. November 16, 2014:http://www.medicalnewstoday.com/articles/285453.php
  • Parry, W. 2011. Overuse of antibiotics is seen behind many human ills. LiveScience. August 24, 2011:http://www.livescience.com/15740-helpful-bacteria-antibiotics.html
  • Golden, B.R. and Gorbach, S.L. 2008. Clinical indications for probiotics: An overview. Clinical Infectious Dieases 46(12): S96-S100.
  • Mason, J. 2013. Can probiotics keep my gastrointestinal system happy? Tufts Now. September 16, 2013:http://now.tufts.edu/articles/can-probiotics-keep-gastrointestinal-health
  • Baumler, M.D. 2013. Gut bacteria. Today's Dietitian. June 2013: http://todaysdietitian.com/newarchives/060113p46.shtml
  • Wells, J.M. and Allison, C. Molecular genetics of intestinal anaerobes. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Page28
  • 10. Conway, P. Microbial ecology of the human large intestine. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Pages 1-24

A Primer on Natural Antifungal Agents: Evidence and Rationale for Their Use

Jessica Bonovich RN, BSN

Guidelines for the treatment of yeast have been documented in the literature for nearly every major organ system (Pappas). Yet, a standard of care for gastrointestinal yeast treatment is surprisingly absent despite the large body of work demonstrating that pathogenic yeast causes harm to various aspects of the gastrointestinal tract (Zwolinska, Brzozowski). Clinicians suspicious of GI yeast overgrowth typically perform a fecal analysis with culture and sensitivity. While this method is ideal for the effective treatment of yeast, it is poorly understood why patients with yeast overgrowth often test negative upon laboratory examination of stool (Maaroufi, Shaw). Up to 50% of stool analysis negative for yeast species returned positive on PCR (Maaroufi). Metabolites of yeast detected in The Great Plains Laboratory Organic Acids Test are a very reliable method of detecting yeast (Shaw). However, this test cannot determine the exact organism and therefore its susceptibility to antifungals (Shaw). It also cannot determine the exact location of the yeast overgrowth but clinical experience has shown that the majority of cases are in fact GI related. The documentation set forth is based broadly on in vivo and in vitro studies on the antifungal properties of the natural agents, documentation of yeast infections involving organ systems other than the GI tract, and yeast overgrowth in the GI of the irritable bowel patient population.

Probiotic Support

Evidence:

Candida: Promising data by several small studies has demonstrated the use of probiotics as effective against numerous pathological conditions caused by Candida. In these studies, Lactobacillus GG, L. acidophilus, and Saccharomyces boulardi were the predominant probiotics shown to be effective with L. GG demonstrating the ability to induce antibody formation against Candida in immune deficient mice. Probiotics have been shown to accelerate the healing of various pathological conditions in the gastro-intestinal tract when Candida is present (Zwolinska 2006 & 2009, Hatakka). Probiotics have also been shown to accelerate immune response to Candida in several murine simulations (Wagner, Zwolinska 2006 & 2009).

Aspergillus: Data on the effectiveness of probiotics against Aspergillus infection is not available. Aspergillus infections are thought to be rare in comparison to other yeast species such as Candida. However, a recent study indicated a high percentage of Aspergillus in stool samples of patients with Crohn's disease. (Li) Aspergillus infections are usually associated with pulmonary infection and or post-surgical complications that are often very acute. The severity of the Aspergillus complications and small numbers of infection are presumably responsible for the lack of research in this regard. The relative safety of Lactobacilli, bifidobacteria, and lactococci has been demonstrated extensively in the literature. Incorporation of these probiotics into a protocol for Aspergillus treatment may be considered appropriate in many cases.

Studies on the use of probiotics for gastrointestinal healing have been aimed at a wide range of populations. To date, the most promising studies have been in the treatment and prevention of acute infectious diarrhea, viral gastroenteritis, antibiotic associated diarrhea, ulcerative colitis, and necrotizing enterocolitis in preterm infants (Manzoni, Zwolinska, Szajewska). In all of these conditions, inflammation is of a primary concern.

Risks: Reports of bacteremia and even a few isolated cases of sepsis have been documented in the literature from the Lactobacillus genera including L. rhamnosis, L. plantarum, L. casei, L. paracasei, L. salivarius, L. acidophilus (Snydman, Borriello). Cases of sepsis have also been documented for the usually beneficial yeast Saccharomyces boulardi. In some cases, the cultures were linked to a probiotic supplement, in others, the bacteria were found to be intrinsic to the patient's own microflora (Snydman, Borriello). In all of the cases, the patients were severely immunocompromised and often had feeding tubes, short gut syndrome, and/or a central line (Snydman, Borriello, Munoz, Herbrecht). The cases of sepsis have most commonly been associated with S. boulardi (Munoz, Herbrecht). However, fungemia from S. boulardi infection is rare in comparison to the population believed to be taking the supplement (Herbrecht, Munoz). In one study, increase in bacteremia from Lactobacillus did not increase over a decade, despite the 6 fold increase in probiotic use (Borriello). These data indicate that individuals taking probiotics are not at any greater risk than the general population for bacteremia associated with Lactobacillus. Regardless, the practitioner should exercise caution in severely immunocompromised patient populations to reduce any risk to the patient.

Rationale:

Promote the immune response against intestinal yeast overgrowth. To promote healing and reduce inflammation in the intestinal mucosa during yeast overgrowth.

Dosing:

The strain most commonly championed in the literature is that of Lactobacillus GG in doses of 10 billion colony forming units (CFU's) taken early in treatment. Saccharomyces thermophilus and S. boulardi were found to be effective in some studies and less effective in others. A daily intake of 10^6 to 10^9 CFUs is reportedly the minimum effective dose for therapeutic purposes.

Allicin

Evidence:

Allicin is the active ingredient found in garlic. The most commonly understood mode of action for allicin is linked to its ability to cross cell membranes and combine with sulfur-containing molecular groups in amino acids and proteins, thus interfering with cell metabolism (Davis, Singla). The antimicrobial properties of allicin have been demonstrated in numerous in vitro and in vivo murine models (Davis, Guo, Shadkchan). The antifungal properties of allicin have been shown to potentiate the effectiveness of fluconazole, the synergistic combination being the most effective at killing Candida species in kidney cells (Guo). Human studies have been targeted largely toward cardiovascular and antihypertensive effects and little has been done to demonstrate the antimicrobial properties (Fugh-Berman, NACAM). However, a study in China reports successful use of intravenous allicin against invasive fungal infections (Davis).

The strength of the supplement is affected by the preparation of garlic. Studies have shown that water, oil, and high temperatures can degrade allicin content (Singla). Interestingly powdered garlic is found to be the highest in allicin (Singla). Interestingly, powdered preparations of garlic for cooking were found to have a greater allicin content than nine supplement tablets studied (PDR). There are also pure allicin extracts available on the market for use.

Risks: Studies have demonstrated that allicin can inhibit platelet aggregation in blood and several cases of bleeding complications have been documented. All of which were following an invasive procedure (Fugh-Berman). Allicin may also increase production of insulin by pancreatic cells causing the potential for hypoglycemia in some patient populations. Allicin may also inhibit cholesterol synthesis in the liver causing exacerbation of developmental delay in children with low cholesterol levels. Physicians should use caution in patients with bleeding conditions, on blood thinners, with hypoglycemia, or diabetics who are insulin dependent. Cholesterol testing is advised for children with developmental disorders prior to supplementation with allicin.

Rationale:

Mild antifungal therapy when prescriptive agents are unavailable or contraindicated and where dosing by weight is required (such as for children). Promote the synergistic modulation of antifungal therapy with fluconazole.

Dosing:

Insufficient evidence exists in US literature for dosing recommendations, especially for children. However, there are several governing bodies outside of the US that regulate supplementation and provide a guideline for dosing. According to the National Center for Complementary and Alternative Medicine in the US, allicin is considered safe for most adults. Use of allicin for antifungal treatment may be appropriate in doses as high as one milligram per kilogram of body weight. Human studies have demonstrated that doses of allicin effectively potentiated the effects of antifungal treatment in doses of 7.8 - 27 mg per dose. The European Scientific Cooperative on Phytotherapy (ESCOP) recommends 3 to 5 milligrams allicin daily (1 clove or 0.5 to 1.0 gram dried powder) for the prevention of atherosclerosis. The World Health Organization (WHO) recommends 2 to 5 grams fresh garlic, 0.4 to 1.2 grams of dried powder, 2 to 5 milligrams oil, 300 to 1,000 milligrams of extract, or other formulations that are equal to 2 to 5 milligrams of allicin daily. The European Scientific Cooperative on Phytotherapy (ESCOP) recommends 2 to 4 grams of dried bulb or 2 to 4 milliliters of tincture (1:5 dilution in 45% ethanol), by mouth three times a day for upper respiratory tract infections.

MCT Oil/ Caprylic Acid/Monolauren/Coconut Oil

Evidence:

There are numerous in vitro and in vivo animal studies that demonstrate the effectiveness of coconut oil and/or its medium chain fatty acid constituents (Caprylic Acid, Capric Acid, and Lauric Acid) against Candida and other pathogens (Bergsson, Batovska, Huang, Dayrit). Human trials are much more limited. Therefore the evidence for treating yeast with this substance is based on the clinical observation of physicians who commonly treat yeast conditions. Physicians who routinely treat patients for Candida report very good success with using MCT oil/Caprylic acid. In his book, The Yeast Connection, Dr. Crook sites numerous examples of physicians who have reported this supplement as clinically useful (Crook).

Immunomodulating Properties: Like Omega-3 fatty acids, MCT's produce fewer inflammatory eicosanoids of the two- and four-series (Wan). Several in vivo studies have demonstrated anti-inflammatory properties of MCT oil and antipyretic and analgesic properties have also been documented (Canela, Intahphuak). In vivo MCTs may reduce intestinal injury and protect from hepatotoxicity which is a concern in patients taking fluconazole and itraconazole antifungal therapy (Berit, Kono). Human studies are few but promising as many of the studies are on severely immunocompromised patients who require total parernteral nutrition (TPN) and the HIV/AIDS patient population (Wanke, Dayrit, Craig, Wolfram, Chen). This patient population has responded well to the addition of MCT's. The degree to which these results apply to the general population is unclear. However, the safety of this supplement can be inferred given its effective use in severely immune compromised patient populations.

Risks: Acute toxicity tests conducted in several species of animal demonstrate that MCTs are essentially non-toxic. Ninety-day toxicity tests did not result in notable toxicity, whether the product was administered in the diet up to 9375mg/kg body weight/day or by intramuscular injection (up to 0. 5ml/kg/day, rabbits). Levels of up to 1g/kg/day have been confirmed safe in several clinical human trials (Traul). The use of MCT is only contraindicated in patients with impaired states of fat metabolism such as ketosis, acidosis, and cirrhosis (Bach).

Rationale:

Mild antifungal therapy when prescriptive agents are unavailable or contraindicated and where dosing by weight is required (such as for children).

Dosing:

Caprylic acid: PDR for nutritional supplements indicate dose as 300-1200 mg daily
Monolauren: 240 – 720 mg three times daily (adults)
Virgin coconut Oil: 2 ml/kg/day of virgin coconut oil in children
MCT: levels of up to 1g/kg/day have been confirmed safe in several clinical human trials.

Clinical References:

  • Bach, AC., Babayan, VK. (1982). Medium Chain Triglycerides: un update. American Journal of Clinical Nutrition, 36(5); 950-962
  • Batovska, D., et al. (2009). Antibacterial study of the medium chain fatty acids and their 1-monoglycerides: individual and synergistic relationships. Polish journal of Microbiology, 58(1); 43-7.
  • Bergsson, G., et al. (2001). In vitro killing of Candida albicans by fatty acids and monoglycerides. Antimicrobial Agents and Chemotherapy, 45(11); 3209-12.
  • Berit, M., Pfeuffer, M., Schrezenmeir, J., (2006). Medium Chain triglicerides. International Dairy Journal, 16(11) 1378-1382.
  • Borriello, S., et al. (2003). Saftey of Probiotics that Contain Lactobacilli or Bifidobacteria. Clinical Infectious Disease, 36(6); 775-780. Doi 10.1086/368080
  • Brzozowski, T., et al (2005). Influence of gastric colonization with Candida albicans on ulcer healing in rats: Effect of ranitidine, asprin and probiotic therapy. American Journal of Gastroenterology, 40(3); 286-296.
  • Canani, R., et al. (2007). Probiotics for treatment of acute diarrhea in children: randomized clinical trial of five different preparations. BMJ, 335-340. Doi 10.1136/bmj.39272.581736.55
  • Canela, GO., (2007). Anti-inflammatory activity of virgin coconut oil. The Philippine Journal of Internal Medicine, 45(2) 85-88.
  • Craig, GB., et al. (1997). Decreased fat and nitrogen losses in patients with AIDS receiving medium chain triglyceride-enriched formula vs those receiving long-chain-triglyceride containing formula. Journal of the American Dietetic Association, 97(6); 605-11.
  • Chen, FM., et al. (2005). Efficacy of medium-chain triglycerides compared with long-chain triglycerides in total parenteral nutrition in patients with digestive tract cancer undergoing surgery. The Kaohsiung Journal of Medical Sciences, 21(11); 487-94.
  • Crook, W. (2000). The Yeast Connection Handbook. Jackson, TN: Woman's Health Connection.
  • Davis, S. (2005). An overview of the antifungal properties of allicin and its breakdown products-the possibility of a safe and effective antifungal prophylactic. Mycoses, 48(2); 95-100. DOI: 10.1111/j.1439-0507.2004.01076.
  • Dayrit, C. (2000). Coconut oil in Health and Disease: Its and Monolauren's potential as cure for HIV/AIDS. Read at the XXXVII Cocotech Metting Chennai, India July 25, 2000. http://coconutresearchcenter.org/article10526.pdf
  • Fugh-Berman, A., (2000). Herbs and Dietary Supplements in the Prevention and Treatment of Cardiovascular Disease. Preventive Cardiology, 3(1); 24-32. Doi:10.1111/j.1520-037X.2000.80355.
  • Guo, N., Wu, X.,, et al. (2010). In vitro and in vivo interactions between fluconazole and allicin against clinical isolates of fluconazole-resistant Candida albicans determined by alternative methods. FEMS Immunology and Medical Microbiology, 58(2); 193-201. Doi: 10.1111/j.1574-695X.2009.00620.
  • Hatakka, K., et al. (2007). Probiotics Reduced the Prevalence of Oral Candida in the Elderly – a Randomized Controlled Trial. Journal of Dental Research, 86 (2); 125-130. doi: 10.1177/154405910708600204
  • Herbrecht, R., Nivoix, Y., (2005). Saccharomyces cervisiae Fungemia: an adverse effect of Saccharomyces boulardi probiotic Administration. Clinical Infectious Disease, 40(11); 1635-1637. Doi 10.1086/429926
  • Huang, CB., Alimova, Y., Myers, TM., Ebersole, JL. (2011). Short and medium chain fatty acids exhibit antimicrobial activity for oral microorganisms. Archives of Oral Biology, 56(7); 650-4.
  • Intahphuak, S. et al. (2010). Anti-inflammatory, analgesic, and antipyretic activities of virgin coconut oil. Pharmaceutical Biology, 48(2); 151-7.
  • Khodavandi, A., Alizadeh, F., et al. (2011). Comparison between efficacy of allicin and fluconazole against Candida albicans in vitro and in a systemic candidiasis mouse model. FEMS Microbiology Letters, 315. Kono, H., et al. (2003). Protective effects of medium-chain triglycerides on the liver and gut in rats administered endotoxin. Annals of Surgery, 237(2); 246-55.
  • Li, Qiurong., et al. (2014). Dysbiosis of Gut Fungal Microbiota is Associated with Mucosal Inflammation in chrohn's Disease. Journal of Clinical Gastrointerology, 48:513-523.
  • Maaroufi, Y., Heymans, C., De Rune, J., Duchateau, H. (2003). Rapid Detection of Candida albicans in Clinical Blood Samples by Using a TaqMan-Based PCR Assay. Journal of Clinical Microbiology, 41; 3293-3298.
  • Manzoni, P., et al. (2006). Oral Supplementation with Lactobacillus casei Subspecies rhamnosus Prevents Enteric Colonization by Candida Species in Preterm Neonates: a Randomized Study. Clinical Infectious Diseases, 42(12); 1735-1742. doi: 10.1086/504324
  • Munoz, P., et al. (2005). Saccharomyces cerevisiae fungemia: and emerging infectious disease. Clinical Infectious Disease, 40(11); 1625-34.
  • National Center for Complimentary and Alternative Medicine (NCCAM). Herbs at a Glance: Garlic. Retrieved on 3/3/2014 from http://nccam.nih.gov/health/garlic/ataglance.htm
  • Snydman, D. (2008). The Safety of Probiotics. Clinical Infectious Diseases, 46(2); S104-S111. Doi 10.1086/523331
  • Pappas, P., et al. (2004). Guidelines for Treatment of Candidiasis. Clinical Infectious Diseases. 38; 161-189
  • Shadkchan, Y., Shemesh, E., et al. (2004). Efficacy of allicin, the reactive molecule of garlic, in inhibiting Aspergillus spp. In vitro, and in a murine model of disseminated aspergillosis. Journal of Antimicrobial Chemotherapy, 53; 832-836. doi: 10.1093/jac/dkh174.
  • Shaw ,W., (2008) Biological Treatments for Autism and PDD. Publisher: Author.
  • Singla, V., Bhaskar, R, (2011). Garlic: a review. International Journal of Drug Formulation, 2. Retrieved from http://www.ordonearresearchlibrary.org/Data/pdfs/IJDFR80.pdf
  • Szajewska, H., Skorka, A., Dylag, M. (2006) Meta-analysis: Saccharomyces boulardii for treating acure diarrhea in children. Alimentary Pharmacology and Theraputics, 25(3); 257-264. Doi 10.1111/j.1365-2036.2006.03202.x
  • Szajewska, et al., (2006). Probiotics in Gastrointestinal Diseases in Children: Hard and Not-So-Hard Evidence of Efficacy. Journal of Pediatric Gastroenterology and Nutrition, 42(5); 454-475. Doi 10.1097/01.mpg.0000221913.88511.72
  • Wagner, D., et al. (2000). Effects of probiotic bacteria on humoral immunity to Candida albicans in immunodeficient bg/bg-nu/nu and bg/bg-nu/+ mice. Journal of Microbiology/Immunology, 17; 55-59. Pdf http://www.reviberoammicol.com/2000-17/055059.pdf
  • Traul, KA., Driedger A., Ingle DL., Nakhasi, D. (2000). Review of the toxicologic properties of medium-chain triglycerides. Food and Chemical Toxicology, 38(1), 79-98.
  • Wan, JM., TEO, TC., Babayan, VK., Blackburn GL. (1988). Invited Comment: lipids and the development of immune dysfunction and infection. Journal of Parenteral and Enteral Nutrition, 12(6 supplment); 43s-52s.
  • Wanke, CA., et al. (1996). A medium chain triglyceride-based diet in patients with HIV and chronic diarrhea reduces diarrhea and malabsorbtion: a prospective, controlled trial. Nutrition, 12(11-12); 766-71.
  • Wolfram, G., (1986). Medium Chain Triglicerides for Total Parenteral Nutrition. World Journal of Surgery, 10; 33-37.
  • Zwolinska, M., et al. (2009). Effect of Candida colonization on Human Ulcerative Colitis and the Healing of Inflammatory Changes of the Colon in the Experimental Model of Colitis Ulcerosa. Journal of Physiology and Pharmcology, 60(1); 107-108. Pdf http://jpp.krakow.pl/journal/archive/03_09/pdf/107_03_09_article.pdf
  • Zwolinska-Wcislo, M., et al. (2006). Are probiotics effective in the treatment of fungal colonization of the gastrointestinal tract? Eperimental and clinical studies. Journal of Physiology and Pharmcology, 57(9); 35-49. Pdf http://www.jpp.krakow.pl/journal/archive/11_06_s9/pdf/35_11_06_s9_article.pdf

The Implications of Low Cholesterol in Depression and Suicide

James M. Greenblatt, M.D.

For the last quarter century, we have been told that cholesterol is dangerous for our health and were advised to avoid it in order to live a healthier life. However, cholesterol is essential in maintaining good mental health. The brain is the most cholesterol-rich organ in the body, and depriving the brain of essential fatty acids and cholesterol can lead to detrimental health problems. Lower levels of cholesterol in the blood are associated with a heightened risk of developing major depressive disorder, as well as an increased risk of death from suicide. A study published in the Journal of Psychiatric Research found that depressed men with low total cholesterol levels (less than 165 milligrams per deciliter [mg/dL]) were seven times more likely to die prematurely from unnatural causes such as suicide and accidents.

Most recently, the continued allegation that cholesterol is dangerous came under scrutiny. A meta-analysis published in the March 2014 issue of Annals of Internal Medicine found that there's not enough evidence supporting the claim that saturated fat increases the risk of heart disease. After reviewing 72 different studies, researchers did not find that people who ate higher levels of saturated fat had more heart disease than those who ate less. Researchers came to the conclusion that instead of avoiding fats, which are essential to maintaining brain health, scientists are identifying the real villains as sugar and highly processed foods.

Low Cholesterol and Depression

Several studies have linked low cholesterol levels to an increased risk of developing depression. Consider the following examples:

  • A 1993 paper published in the Lancet reported, "Among men aged seventy years and older, categorically defined depression was three times more common in the group with low total plasma cholesterol . . . than in those with higher concentrations."
  • A 2000 study published in Psychosomatic Medicine, researchers compared cholesterol levels to depressive symptoms in men ranging in age from forty to seventy. They found that men with long-term, low total cholesterol levels "have a higher prevalence of depressive symptoms" compared to those with higher cholesterol levels.
  • Women with low cholesterol levels are also vulnerable to depression. In 1998, Swedish researchers reported the results of their examination of cholesterol and depressive symptoms among 300 healthy women, ages thirty-one to sixty-five, in and around Stockholm. Women in the lowest cholesterol group (the bottom tenth percentile) suffered from significantly more depressive symptoms than did the others.
  • A 2001 study published in Psychiatry Research looked at primary care patients in Ireland, finding that low levels of cholesterol were linked to higher ratings on depression rating scales.
  • Italian researchers measured the cholesterol levels of 186 patients hospitalized for depression and found an association between low cholesterol and depressive symptoms.

This research is supported by other studies, including a 2008 meta-analysis, which found that higher total cholesterol was associated with lower levels of depression. A 2010 study published in The Journal of Neuropsychiatry & Clinical Neurosciences looked at the levels of HDL in depressed people and found that low levels of HDL were linked to "long-term depressive symptomatology."

Low Cholesterol and Suicide

Suffering through a depressive episode can be very difficult, and one of the great fears is that someone in the throes of depression does not see any point in continuing to live.

Early evidence of a link between low cholesterol and suicide came from the Multiple Risk Factor Intervention Trial study, a large-scale, long- term look at various health factors involving hundreds of thousands of volunteers. Data from the study was analyzed by researchers from the University of Minnesota, who found that people with total cholesterol levels lower than 160 mg/dL were more likely to commit suicide than those with higher cholesterol levels. Other studies are equally alarming:

  • A 2008 study looked at forty men who were hospitalized due to bipolar disorder. Twenty had attempted suicide at some point in the past, and the other twenty had not. Both cholesterol and blood fat levels were lower, on average, among those who had attempted suicide.
  • A paper published in the Journal of Clinical Psychiatry in the same year reported the results of an examination of cholesterol levels in 417 patients who had attempted suicide at some point, 155 hospitalized psychiatric patients who had not, and healthy controls. Results of the study suggest that low cholesterol may be associated with suicide attempts.
  • The suicidal method of choice, self-inflicted fatal gun wound versus pills, for example, may also be related to cholesterol levels. A2008 study published in Psychiatry Research compared nineteen people who had attempted suicide using violent methods to sixteen who had attempted to kill themselves nonviolently, as well as to twenty healthy controls. The researchers found that "violent suicide attempters had significantly lower total cholesterol and leptin levels compared with those with nonviolent suicide attempts."

The connection between low cholesterol and suicide is highlighted in a 2004 study, which concluded that a low total cholesterol level can be used as an indicator of suicide risk. This study, involving suicide attempters with major depressive disorder, nonsuicidal depressed patients, and normal controls, found significant differences in cholesterol levels among the various groups.

The average total serum cholesterol level was 190 mg/dL among the normal controls, 180 mg/dL in nonsuicidal depressed group, and 150 mg/dL among the suicidal depressive patients. This study showed that the total cholesterol level can be used to gauge possible suicide risk (less than 180 mg/dL) and probable risk (150 mg/dL and lower).

Suicide is not the only type of violence associated with lower cholesterol levels. Homicide and other violence committed against others is also associated with low cholesterol. Swedish researchers compared one-time cholesterol measurements on nearly eighty thousand men and women, ranging in age from twenty-four to seventy, to subsequent arrests for violent crime. The researchers reported that "low cholesterol is associated with increased subsequent criminal violence."

What's the Cholesterol-Depression Link?

There is strong scientific evidence indicating that low cholesterol and suicide, particularly violent suicide, are linked. The vast majority of studies linking low cholesterol to depression, suicide, and violence looked at the serum cholesterol level. But what about the amount of cholesterol in the brain?

Canadian researchers were the first to examine this question in their 2007 study published in the International Journal of Neuropsychopharmacology. The researchers measured and compared the cholesterol content in various parts of the brains of forty-one men who had committed suicide and twenty-one men who had died of other, sudden causes that had no direct impact on the brain. The results were intriguing: When the suicides were categorized as violent or nonviolent, those who had committed violent suicide were found to have less cholesterol than the others in the gray matter of their brains. This was seen specifically in the frontal cortex, a part of the brain that handles "executive functions," including processes involved in planning, cognitive flexibility, abstract thinking, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information. The frontal cortex essentially controls the ability to make good decisions.

Cholesterol is a critical precursor to many essential physiological molecules in the human body that directly and indirectly affect our moods and optimal brain function. Some researchers theorize that low levels of cholesterol alter brain chemistry, suppressing the production and/or availability of the neurotransmitter serotonin. Cholesterol is essential for the synthesis of all steroid and sex hormones, including DHEA, testosterone, and estrogen. Cholesterol is also needed in the synthesis of vitamin D.

Clinically low cholesterol is a significant variable in the treatment and recovery from mood disorders. A simple blood test looking at total cholesterol can reflect multiple factors influencing treatment. In my clinical practice for the past 20 years, I have found that low cholesterol (<130) has significant implications for what is referred to as "treatment-refractory" depression. This refers to patients who have failed to recover from traditional antidepressant medications. Treatment-refractory patients often struggle with intense suicidal ideation and aggressive behavior. Often, we are able to determine that low cholesterol is genetic, as there are other members in the family who also have low cholesterol levels, despite eating a diet rich in cholesterol and saturated fats. For individuals with low cholesterol, a diet with adequate cholesterol and saturated fats is highly recommended in order to replenish cholesterol levels, although supplemental cholesterol may also be needed for many.

New Beginning's Sonic Cholesterol supplement provides 250 milligrams of cholesterol per capsule. Individuals with low cholesterol levels may take between two to six capsules per day in order to restore adequate cholesterol levels for optimal brain function. Cholesterol repletion is often slow and can take many months. Once cholesterol levels are normalized, we often see an improvement in symptoms and a decreased dependency on medications. It is quite striking to consistently witness the high correlation between cholesterol levels and behavioral and mood symptoms.

Conclusion

There is a growing amount of research looking at the use of essential fatty acids, particularly omega-3's in psychiatry, but we often overlook cholesterol. Low levels of cholesterol and essential fatty acids are intimately linked to depression. Understanding the consequences of deficiencies in essential fats and cholesterol is important for the effective treatment of depression. Whether it is drug induced, genetic, or a result of dietary patterns, low cholesterol impairs optimal brain function and often prevents successful recovery from chronic depression.

Clinical References:

  • 1. Hediger ML, England LJ,Molloy CA, Yu KF, Manning-Courtney P, Mills JL. Reduced bone cortical thickness in boys with autism or autism spectrum disorder. J Autism Dev Disord. 2008;38(5):848–856
  • 2. Coleman, M. Clinical presentations of patients with autism and hypocalcinuria. Develop. Brain Dys. 7: 63-70, 1994
  • 3. Caudarella R, Vescini F, Buffa A, Stefoni S. Citrate and mineral metabolism: kidney stones and bone disease. Front Biosci. 2003 Sep 1;8:s1084-106.