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Dietary Supplements:An Integrative and Functional ApproachDietitians in Integrative and Functional MedicineDIFM DPG Symposium – Boston 2016
by Sheila Dean, DSc, RDN, LDN, CCN, CDE, IFMCP
Integrative and Functional Nutrition Academy – CoFounder
Palm Harbor Center for Health & Healing
University of Tampa, Adjunct Professor
Disclosures
• Sponsored by Emerson Ecologics
– www.EmersonEcologics.com
• Co‐founder of Integrative and Functional Nutrition Academy
– www.IFNAcademy.com
Participant Objectives
• Identify and review specific non‐herbal dietary supplements for therapeutic application in cardiometabolic and gut related disorders based on findings from the nutrition‐focused physical exam (NFPE), functional diagnostic testing and nutrigenetictesting
• Evaluate dosing and delivery systems of various non‐herbal dietary supplements
• Identify mechanism of action and safety issues of non‐herbal dietary supplements in disease management
Note: The following statements have not been evaluated by the Food and Drug Administration. The dietary supplements discussed are not intended to diagnose, treat, cure, or prevent any disease.
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The United States of Supplements
http://www.crnusa.org/CRNconsumersurvey/2014/
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Bill 5’9” yes
53 5.0 50.519151.00 140/90474937.5253 5.643% 42.2
No n/aNo No
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ZD
Integrative Medicine. Vol 14, No.2, April 2015
“The TI‐VAS can be used as a taste‐acuity test for zinc sulfate and as a benchmark for future analyses of zinc sulfate taste acuity and zinc taste tests.”
Nutrition‐Focused Physical Exam Summary
Dx: Obesity, HTN, CVD, prediabetes and IBS • ↑ BP (140/90)• Mouth:
• 3 amalgams• White coating of tongue
• Nails:• Longitudinal ridges
• Skin:• Mild rosacea
• Male pattern balding • BIA – 5.6% phase angle• Ear Exam→ clear• Zinc Taste Test → ZD• Urinalysis• Pt c/o low energy; chronic fatigue symptoms, bloating, belching & indigestion after meals
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Bill’s Meds
• Zocor (simvastatin)
• Prinovil (lisinopril)
• Lexapro (escitalopram)
• Glucophage (metformin)
Drug‐Induced Nutrient Depletions
There are many drug‐induced nutrient depletions however, some of the most susceptible nutrients to keep in mind are:
• Magnesium
• CoQ10
• All the B vitamins but especially:– Folate
– B12
– B2
– niacin
• Iron
Bill’s Labs:
• Hb‐A1C – 5.7%
• FBG – 110 mg/dl
• Alk Phos – 32 U/L
• (zinc status – ZD)
• RDW‐15%
• Homocysteine – 15 µmol/L
• 25 OH Vt D – 32 ng/ml
• hsCRP – 4.5 mg/L
• Triglycerides – 170 mg/dl
• HDL – 32 mg/dl
• Thyroid panel normal, no ab’s
• Testosterone, total – 350 ng/dl
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arbl.cvmbs.colostate.edu
3 possible outcomes:‐/‐ Normal or “wild‐type”‐/+ Heterozygous for the SNP+/+ Homozygous for the SNP
Bill’s NGX results:‐MTHFR C677T variant ‐/+ ‐MTHFR A1298C variant ‐/‐‐ COMT Val/Met 158 ‐/+
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ABC’s of Organic Acids
block caused by nutrient insufficiency
enzyme AB enzyme BC enzyme CD
spills into urine
A B C D
A
Significant Organic Acids Findings
Organic Acids (continued)
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Glutathione helps regenerate Vitamin C and E
Biochim Biophys Acta. 2013 May;1830(5):3143‐53.
SUPPLEMENTS TO CONSIDER COMMONMETABOLIC ASSOCIATION/CONDITION
Medical food with NAC
Liposomal glutathione
L‐arginine + magnesium (citrate) combo
CoQ10/ubiquinol
EPA/DHA + Vitamin D3 combo
Chromium/vanadyl sulfate/gymnema sylvestre/lipoic acid/zinc combo
Methyl folate + adenosyl/hydroxycobalamin combo
Digestive enzymes + Betaine HCL combo
Zinc Carnosine
Soluble Fiber and/or Probiotics and/or N‐butyrate
Low dose glutamine + curcumin combo
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My In‐Office Dispensary
Glutathione (GSH)
• Tripeptide ‐ 3 amino acids linked together:– L cysteine
– L‐glutamine
– Glycine
• Function– Primarily synthesized in the liver
– Involved in DNA synthesis and repair, protein and prostaglandin synthesis, amino acid transport, metabolism of toxins and carcinogens, immune system function, prevention of oxidative cell damage, and enzyme activation
– MAJOR intracellular thiol‐disulfide redox buffer that serves as a cofactor for many antioxidant enzymes preventing damage to important cellular components caused by reactive oxygen species such as free radicals and peroxides.
• Source: Robaczewska J. et al. J Physiol Pharmacol. 2016 Jun;67(3):331‐7.
• Considered non‐essential nutrient
Mol Aspects Med.2009 Feb‐Apr;30(1‐2):42‐59.
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Glutathione – Typical Use• ORALLY ‐ treating cataracts, glaucoma, preventing aging, treating or preventing
alcoholism, asthma, cancer, heart disease (atherosclerosis and hypercholesterolemia), hepatitis, liver disease, diseases that cause immunosuppression (including AIDS and chronic fatigue syndrome), memory loss, Alzheimer's disease, osteoarthritis, Parkinson's disease, and detoxifying metal and drugs.
• INHALED, glutathione is used for treating lung diseases, including idiopathic pulmonary fibrosis, cystic fibrosis, and lung disease in individuals with HIV disease.
• INTRAMUSCULARLY, glutathione is used for preventing toxicity of chemotherapy and for treating male infertility.
• INTRAVENOUSLY, glutathione is used for preventing anemia in patients undergoing hemodialysis, preventing renal dysfunction after coronary bypass surgery, treating Parkinson's disease, improving blood flow and decreasing clotting in individuals with atherosclerosis, treating diabetes, and preventing toxicity of chemotherapy.
Natural Medicine Database, Glutathione. Accessed 9‐4‐16
Glutathione• Mechanism of action: Phase 2 conjugation
– Antioxidant
– Anti‐cancer
– Antiviral
– Neuroprotective
• Typical dose and delivery:
– Reduced, free form – 100‐300 mg QD
– Liposomal form – 250‐500 mg QD
– N‐acetyl cysteine (precursor) – 750‐1500 mg QD
• Safety concerns: There is little information on adverse effects associated with glutathione. In a clinical trial examining the safety of oral and topical glutathione products in children, an intolerable rash occurred in two children using topical glutathione, resulting in the withdrawal of the children
– Kern JK, Geier DA, Adams JB, Garver CR, Audhya T, Geier MR. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit. 2011 Dec;17(12):CR677‐82.
Glutathione Food Sources
• Whey protein ‐ provides all the key amino acids for glutathione production (cysteine, glycine and glutamate)
• Eggs
• Allium vegetables
• Garlic
• Onions
• Scallions
• Shallots
• Leeks
• Cruciferous vegetables
• Broccoli
• Cauliflower
• Brussel sprouts
• Cabbage
• Bok Choy
• Collard greens
• Kale
Foods richest in sulfur‐containing amino acids are usually the best sources.
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L‐Arginine – Typical Use• ORALLY, L‐arginine is used for cardiovascular conditions including congestive heart failure (CHF), angina pectoris, hypertension, and coronary artery disease. L‐arginine is also used for intermittent claudication, senile dementia, erectile dysfunction, and male infertility. Furthermore, L‐arginine is used for prevention of the common cold, interstitial cystitis, cyclosporine nephrotoxicity, pre‐eclampsia, improving athletic performance, improving immune function, and preventing necrotizing enterocolitis in premature infants.
• TOPICALLY, L‐arginine is used as an aid in wound healing, for treating cold hands and feet, and for male and female sexual dysfunction. L‐arginine is also used topically to increase circulation in the feet of people with diabetes.
• INTRAVENOUSLY, L‐arginine is used for intermittent claudication, for detecting growth hormone deficiency, nutritional supplementation for the critically ill, metabolic acidosis, and persistent pulmonary hypertension in newborns.
Natural Medicine Database, L‐Arginine. Accessed 9‐4‐16
Rosselli, M. et al. Hum Reprod Update. 1998; 4:3‐24.
L‐ Arginine – key mechanism
• (Semi‐essential) precursor to nitric oxide→vasodilator
• Improves endothelial function→ BP ↓– also involved in erectile function, smooth muscle relaxation, decreases
inflammation, platelet aggregation inhibition, ammonia detoxification and vasodilation.
• Arginine N.O. + L‐citrullineEndothelial nitric oxide synthase (eNOS)
• Tetrahydrobiopterin (BH4) is required for eNOS activity
• If you supplement with arginine, you need to always be sure folate is sufficient
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L‐Arginine
• Typical dose: 3‐6 grams QD
• Delivery: capsule, effervescent powders/commonly combined with other ingredients i.e. magnesium
• Safety concerns: the L‐arginine and nitric oxide pathway may be involved in both tumor development (stimulation of genes involved in proliferation, metastasis, and apoptosis, and stimulation of angiogenesis) and cancer therapy (tumorigenesis and tumor killing) Ma, Q., Wang, Z., Zhang, M., Hu, H., Li, J., Zhang,
D., Guo, K., and Sha, H. Targeting the L‐arginine‐nitric oxide pathway for cancer treatment. Curr. Pharm.Des2010;16(4):392‐410
Magnesium – Typical Use
• ORALLY, as a laxative for constipation and for preparation of the bowel for surgical or diagnostic procedures. Magnesium is also used orally for treating cardiovascular diseases including angina, arrhythmias, hypertension, metabolic syndrome, stroke, vasospastic angina, coronary artery disease, myocardial infarction, multiple sclerosis; pregnancy‐induced leg cramps, nocturnal leg cramps, diabetes, migraine headaches, Magnesium is also used orally by athletes to increase energy and endurance.
• TOPICALLY, magnesium is used for treating infected skin ulcers, boils, and carbuncles; and for speeding wound healing.
• PARENTERALLY magnesium is used for acute hypomagnesemia occurring in conditions such as pancreatitis, malabsorption disorders, and cirrhosis, and for treating pre‐eclampsia and eclampsia and other pregnancy associated complications or preterm labor. It is also used as an additive to total parenteral nutrition (TPN) for prevention of hypomagnesemia.
• INTRAVENOUSLY magnesium is used for controlling seizures associated with epilepsy, glomerulonephritis, or hypothyroidism when low serum magnesium levels are present. It is also used intravenously in the treatment of atrial and ventricular arrhythmias. Magnesium is also used intravenously for treating acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD), for migraine and cluster headaches, jellyfish stings, poisonings, neuropathic pain, chronic pain, and postoperative pain.
Natural Medicine Database, Magnesium. Accessed 9‐4‐16
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Magnesium
• Mechanism of action: Plays an essential role in more than 300 cellular reactions Shils M, Olson A, ShikeM. Modern Nutrition in Health and Disease. 8th ed. Philadelphia,
PA: Lea and Febiger, 1994.
• Dose: as low as 100 mg QD to 3.5 grams depending on form of magnesium. Typical dose: 200 mag glycinate/500 mg of mag citrate
• Delivery – tablet, capsule, liquid, powder
• Safety concerns: generally well tolerated. Orally, magnesium can cause gastrointestinal irritation and diarrhea. In CKD stage 3 and 4, limited ability of kidney to excrete increased magnesium load may result in toxic serum concentrations Mountokalakis TD. Magnesium metabolism in chronic renal failure. Magnes Res. 1990. Jun; 3(2): 121‐127.
Various Forms of Magnesium
• Magnesium Oxide
• Magnesium Gluconate
• Magnesium Glycinate
• Magnesium Citrate/Malate
• Magnesium Aspartate
• Oral Magnesium Chloride
• Magnesium Hydroxide ‐ found in milk of magnesia
• Magnesium Lactate
• Magnesium Sulfate
• Magnesium Stearate – Human research has not demonstrated any adverse effect of magnesium stearate upon the immune system, nor have any studies shown that magnesium stearate impedes the absorption of nutrients. Tebbey PW, Buttke TM.Molecular basis for the immunosuppressive action of stearic acidon T cells. Immunology 1990;70:379‐84.
Source: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202644.html
Magnesium and Drug Induced Nutrient Depletions (“Drug Muggers”)
Oral contraceptives – “the pill”
Hormone replacement therapy
Digoxin (Lanoxin)
Loop Diuretics (i.e. furosemide)
Potassium Sparing Diuretics – (ie‐Spironolactone)
HCTZ –hydrochlorothiazide
Corticosteroids – anti‐inflammatory drugs
Antiviral drugs
Antifungal drugs
Antibiotics – tetracyclines
Source: Pelton R. et al. Drug Induced Nutrient Depletion Handbook. 2001
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CoQ10 / Ubiquinol• Typical use: CHF, HTN, Angina, Cardiomyopathies / myalgia (from statins), fatigue
• Mechanism of action: fat soluble antioxidant, produced endogenously but may be conditionally essential, prevents oxidative damage in membranes and lipoproteins, aids in creation of ATP, decreases lactic acid, increases vasodilation
• Typical dose and delivery
– Ubiquinone/CoQ10 – (oxidized) commercially available; usually found in store brands but also in professional products. Dose: 200‐600 mg per day – available as a softgel, chewable gels/blister packs, powders, “micro‐emulsified”
– Ubiquinol: (reduced) 100 – 200 mg per day in divided doses – capsules, softgels – usually found in professional products
• Safety concerns:
– very safe overall up to 1200 mg/d; can decrease BP; may antagonize warfarin
– absorption may be a problem unless in a lipid based form, take with food to help with absorption
https://es.wikipedia.org/wiki/Coenzima_Q10
Potgieter M. Nutr Res. 2013;71(3):180‐8Mancuso M. Curr Drug Targets. 2010;11(1):111‐121
Banach M et al.Mayo Clin Proc.2015 Jan;90(1):24‐34Littlefield N. J Am Assoc Nurse Pract. 2014;26(2):85‐90Fotino AD. Am Jour Clin Nutr. 2013;97(2):268‐75
10 repeating units of CH3 groups!
Design – meta analysis of 7 randomized controlled trialsParticipants ‐ total of 409 subjectsDosage: CoQ10 in dosages of 100‐300 mg per day for 4‐12 weeksKey Findings: In the pooled analysis, compared with controls, CoQ10 supplementation resulted in a significate decrease in Lp(a) ; p<0.0001
CoQ10 and “Drug
Muggers”
Baker et al. Clinical and Investigative Medicine 2001;24(5):258‐72.
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“Orally ingested CoQ10 regardless of whether it is in the form of ubiquinol or ubiquinone and regardless of dose is reported to appear in the plasma with little or no change in its redox status, suggesting that an efficient mechanism is in place to convert orally administered CoQ10 as ubiquinone to ubiquinol in vivo.”
INDICATION DAILY DOSE of CoQ10
Healthy patients over 40 > 100 mg
Hypertension 200 mg
Statin use 200 mg
Hx of statin‐associated myopathy 200‐600
Chronic stable angina/CHF 400 mg
Cardiomyopathy 400 mg
Angina pectoris 150‐200 mg
Heart attack recovery 100‐200 mg
Parkinson’s disease 1400 mg
Alzheimer’s disease 1200‐1400 mg
Endurance athletes 300 mg
Source: http://www.mayoclinic.org/drugs‐supplements/coenzyme‐q10/dosing/hrb‐20059019
Fish Oils – Typical Use
• ORALLY, fish oil is used for hypertriglyceridemia, CHD, depression, and auto‐immune conditions
• INTRAVENOUSLY, fish oil is used for chronic plaque psoriasis, sepsis, cystic fibrosis, pressure ulcers, rheumatoid arthritis, and psoriasis.
• TOPICALLY, fish oil has been used for psoriasis.
Natural Medicine Database, Fish Oil. Accessed 9‐4‐16
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Fish Oils
• Mechanism of action: anti‐inflammatory, PPAR‐agonist, reduced platelet aggregation, improves vascular elasticity, decreases VLDL production, decreases blood viscosity, reduces inflammatory cytokine production.
• Typical dose: Up to 3 grams EPA/DHA is considered GRAS by the FDA, some people may need higher levels – coordination of care recommended.
– 4‐6 grams has been used to lower TGs
– 2‐4 grams for lowering blood pressure
• Delivery:– Softgels, liquid, combo products common
– look for molecularly distilled fish oil, protect from light, heat and oxygen, not made with fish by‐products. Look for IFOS (International Fish Oil Standards) certification. Source: http://nutrasource.ca/ifos/
• Safety concerns: Higher than 3 grams per day may reduce blood clotting (INR may be affected with as little as 1‐2 grams), diarrhea and belching, increased bleeding in surgery, may increase need for vitamin E
Gene X Environment
Outcome
G e n e E x p r e s s i o nω‐3 fat
TF = transcription factor complex
PPAR is a transcription factor
PPAR RXR
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Various fish oil dose recommendations
TYPE EPA DHA RECOMMENDATION
General Use 430 mg 290 mg 1 softgel
High EPA (liquid) 1500 mg 500 mg 1 teaspoon
High DHA 60 mg 600 mg 1 softgel
Fish oil with Vitamin D 600 mg 400 mg 1 softgel
Fish oil with Red Yeast Rice 585 mg 405 mg 3 softgels
Fish oil with Glucosamine Sulfate 540 mg 360 mg 3 softgels
Fish oil for children 75 mg 105 mg 4 softgels
Fish oil for infants 304 408 mg 4 mls
Fish oil for pregnancy 205 mg 480 mg 2 softgels
International Fish Oils Standards Program
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Vitamin D ‐ Background
• Vitamin D is a steroid hormone and fat soluble vitamin that has long been known for its important role in regulating body levels of calcium and phosphorus, and in mineralization of bone. More recently, it has become clear that receptors for vitamin D are present in a wide variety of cells, and that this hormone has biologic effects which extend far beyond control of mineral metabolism.
• Two forms are important in humans:
– ergocalciferol (vitamin D2) – Synthesized by plants
– cholecalciferol (vitamin D3) ‐ synthesized by humans in the skin when it is exposed to ultraviolet B (UVB) rays from sunlight.
• Foods may be fortified with vitamin D2 or D3.
Vitamin D – Typical Use
• ORALLY, vitamin D is used for preventing osteoporosis, muscle weakness, enhancing immune function, preventing autoimmune diseases, multiple sclerosis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, diabetes and cancer.
• TOPICALLY, vitamin D is used as calcitriol or calcipotriene for plaque‐type psoriasis.
• INTRAVENOUSLY, vitamin D, administered as calcitriol, is used for hypocalcemic tetany in premature infants, hypocalcemia and hyperparathyroidism in renal dialysis patients.
• INTRAMUSCULARLY, vitamin D is administered as ergocalciferol for hepatic osteodystrophy, as an injectable source of vitamin D, and to treat severe proximal myopathy associated with vitamin D deficiency.
Natural Medicine Database, Vitamin D. Accessed 9‐4‐16
Vitamin D• Mechanism of action: binds to intracellular receptors that then function as transcription factors to
modulate gene expression.
• Typical dose of D2 – Rx: 10,000 IUs per month
• Typical dose of D3: 1,000‐2,000 IUs
– Titrate based on blood levels
– VDR and DHCR7 polymorphisms may affect Vitamin D needs
– Up to 50,000 IUs in wafer form available (as a medical food)
• Delivery:
– Vitamin D2 (ergocalciferol) – available as prescription and OTC.
– Vitamin D3 (cholecalciferol) Available as softgels, chewables, tablets, wafers. Also found in combo with fish oils, calcium supplements, MVIs
• Safety concerns: generally well tolerated; may cause hypercalcemia and hypercalciuria, particularly at high doses. Ringe, J. D., Faber, H., Fahramand, P., and Schacht, E. Alfacalcidol versus plain vitamin D in the treatment of glucocorticoid/inflammation‐induced osteoporosis. J Rheumatol Suppl2005;76:33‐40
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““The consensus of scientific understanding appears to be that vitamin D (25‐OH D) levels show:•Deficiency = less than 20 ng/mL (50 nmol/L)•Insufficiency = 20‐32 ng/mL•Sufficiency = 33‐80 ng/mL•(Optimal = 50‐80 ng/mL)•With normal in sunny countries 54‐90 ng/mL and •Excess = greater than 100 ng/mL”
(Multiply by 2.5 to convert to nmol/L)
Grant WB., Holick MF. Alt Med Review. Vol 10, No.2, 2005
• J Steroid BiochemMol Biol. 2007 Mar;103(3‐5):708‐11.
• Vitamin D and prevention of breast cancer: pooled analysis.
• Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, Newmark H, Holick MF, Garland FC.
• Department of Family and Preventive Medicine, University of California‐San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. [email protected]
• BACKGROUND: Inadequate photosynthesis or oral intake of Vitamin D are associated with high incidence and mortality rates of breast cancer in ecological and observational studies, but the dose‐response relationship in individuals has not been adequately studied. METHODS: A literature search for all studies that reported risk by of breast cancer by quantiles of 25(OH)D identified two studies with 1760 individuals. Data were pooled to assess the dose‐response association between serum 25(OH)D and risk of breast cancer. RESULTS: The medians of the pooled quintiles of serum 25(OH)D were 6, 18, 29, 37 and 48 ng/ml. Pooled odds ratios for breast cancer from lowest to highest quintile, were 1.00, 0.90, 0.70, 0.70 and 0.50 (p trend<0.001). According to the pooled analysis, individuals with serum 25(OH)D of approximately 52 ng/ml had 50% lower risk of breast cancer than those with serum <13 ng/ml. This serum level corresponds to intake of 4000 IU/day. This exceeds the National Academy of Sciences upper limit of 2000 IU/day. A 25(OH)D level of 52 ng/ml could be maintained by intake of 2000 IU/day and, when appropriate, about 12 min/day in the sun, equivalent to oral intake of 3000 IU of Vitamin D(3). CONCLUSIONS: Intake of 2000 IU/day of Vitamin D(3), and, when possible, very moderate exposure to sunlight, could raise serum 25(OH)D to 52 ng/ml, a level associated with reduction by 50% in incidence of breast cancer, according to observational studies.
“Intake of 2000 IU/day of Vitamin D(3), and, when possible, very moderate exposure to sunlight, could raise
serum 25(OH)D to 52 ng/ml, a level associated with reduction by 50% in incidence of breast cancer,
according to observational studies.”
Insulin’s ability to bind with the receptor, and the strength of this cellular signal is dependent upon the presence of adequate nutrients.Used with permission, Metagenics, Inc.
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If the capacity of the insulin receptors is compromised due to nutrient insufficiencies, the internal message to the cells is reduced and the efficiency of the cell is compromised.Used with permission, Metagenics, Inc.
“In adults at risk of type 2 diabetes, short‐term supplementation with cholecalciferol improved
beta cell function…”
“Based on available clinical and epidemiological data, the positive effects of vitamin D seem to be primarily related to its action on insulin secretion and sensitivity and
secondary to its action on inflammation.”
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“Meta‐analysis of a modest number of trials in people with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce both the risk of severe asthma exacerbation and healthcare use.”
Martineau AR, Cates CJ, Urashima M, Jensen M, Griffiths AP, Nurmatov U, Sheikh A, Griffiths CJ.Vitamin D for the management of asthma. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD011511.
Alpha‐Lipoic Acid – Typical Use
• ORALLY, alpha‐lipoic acid is used for diabetes, peripheral neuropathy, cardiac autonomic neuropathy, retinopathy, cataracts, and glaucoma.
• INTRAVENOUSLY, alpha‐lipoic acid is used for improving insulin‐resistance and glucose disposal in type 2 diabetes, diabetic neuropathy, and Amanita mushroom poisoning.
• TOPICALLY, alpha‐lipoic acid is used to reduce facial wrinkles, lines, and sun damage.
Natural Medicine Database, Vitamin D. Accessed 9‐4‐16
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Alpha lipoic acid
• Mechanism of action:
– Covalently bound to specific proteins that serve as cofactors for mitochondrial enzyme complexes
– Contains two thiol groups, which may be oxidized or reduced• The oxidized form is alpha‐lipoic acid
• Reduced form is dihydrolipoic acid (DHLA)
– Reduces symptoms of peripheral neuropathy in diabetes patients
– Improves insulin sensitivity, fasting blood glucose levels, and glucose disposal in patients with type 2 diabetes
References for previous slide on alpha‐lipoic acid• Konrad T, Vicini P, Kusterer K, et al. Alpha‐lipoic acid treatment decreases serum lactate and pyruvate
concentrations and improves glucose effectiveness in lean and obese patients with Type 2 diabetes. Diabetes Care 1999;22:280‐7
• Jacob S, Henriksen EJ, Tritschler HJ, et al. Improvement of insulin‐stimulated glucose‐disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabet 1996;104:284‐8.
• Jacob S, Henriksen EJ, Schiemann AL, et al. Enhancement of glucose disposal in patients with type 2 diabetes by alpha‐lipoic acid. Arzneimittelforschung 1995;45:872‐4
• Jacob S, Ruus P, Hermann R, et al. Oral administration of RAC‐alpha‐lipoic acid modulates insulin sensitivity in patients with type‐2 diabetes mellitus: a placebo‐controlled, pilot trial. Free Rad Biol Med 1999;27:309‐14
• Porasuphatana S., Suddee S., Nartnampong A., Konsil J., Harnwong B., Santaweesuk A. Glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha‐lipoic acid: a randomized double‐blinded placebo‐controlled study. Asia Pac J Clin Nutr 2012;21(1):12‐21
• Ansar H., Mazloom Z., Kazemi F., Hejazi N. Effect of alpha‐lipoic acid on blood glucose, insulin resistance and glutathione peroxidase of type 2 diabetic patients. Saudi Med J 2011;32(6):584‐588
• Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha‐lipoic acid. Diabetes Care 2003;26:770‐6.
Alpha – lipoic acid
• Typical dose: 300‐600 mg QD but as high as 1800 mg
• Delivery: tablet, controlled release available
• Safety concerns:
– alpha‐lipoic acid might interfere with blood glucose control during and after surgical procedures.
– Thiamine appears to prevent issues with alpha‐lipoic acid
– Excessive alcohol consumption can decrease thiamine
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“…LA ameliorates the effects of fructose by improving glucose homeostasis, possibly by
preserving β‐cell function.”
“…LA could emerge as a safe and effective adjunctive antidiabetic agent with insulin sensitizing activity.”
Lipoic Acid – what about R‐lipoic acid?
• 2 forms:
– RS alpha‐lipoic acid form (racemic mixture)
– R‐ lipoic acid
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“The current study and previous findings from this laboratory conclude that pure RLA is not suitable for use in nutraceutical or pharmaceutical products. Rather, it should be treated as raw material of further processing into stable, bioactive dosage forms.”
Zinc – Typical Use
• ORALLY, zinc is used for treatment and prevention of zinc deficiency. It is also used orally for treating the common cold, recurrent ear infections, asthma, improving immune function and preventing acute lower respiratory infections. Other oral uses include macular degeneration, night blindness, cataracts.
• TOPICALLY, zinc is used for treating acne, aging skin, herpes simplex infections, speeding wound healing and as suncreen. Zinc citrate is used in toothpaste and mouthwash to prevent dental plaque formation and gingivitis.
• INTRANASALLY, zinc is used for treating the common cold.
• OPHTHALMICALLY, zinc sulfate is used in products for eye irritation.
• INTRAVENOUSLY, zinc is used as a component of total parenteral nutrition and for improving outcomes in burn patients.
Natural Medicine Database, Zinc. Accessed 9‐4‐16
Zinc
• Mechanism of action:
– Zinc is a trace element and cofactor essential for numerous physiological processes.
– There are over 100 zinc metalloenzymes, such as nicotinamide dinucleotide dehydrogenases, DNA and RNA polymerases, alkaline phosphatase, superoxide dismutase, and carbonic anhydrase, which assure an essential role for zinc in basic catalytic, structural, and regulatory aspects of protein, including DNA, RNA, and carbohydrate synthesis.
– It plays a role in cell division, cell growth, wound healing, and the breakdown of carbohydrates.
– Zinc is also needed for the senses of smell and taste.
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Zinc
• Typical dose: 8 – 15 mg QD – best with food/gastric HCL ↑ absorption– Age‐related macular degeneration: 200mg of zinc has been taken once daily or in two
divided doses with food for up to two years • Newsome DA, Swartz M, Leone NC, et al. Oral zinc in macular degeneration. Arch Ophthalmol 1988;106:192‐8
• Stur M, Tittl M, Reitner A, Meisinger V. Oral zinc and the second eye in age‐related macular degeneration. Invest Ophthalmol Vis Sci 1996;37:1225‐35
– Common cold: Doses ranged from 4.5 to 24mg of zinc (gluconate or acetate) as a lozenge taken every 1‐2 hours during waking hours while cold symptoms were present Jackson JL, Lesho E, Peterson C. Zinc and the common cold: a meta‐analysis revisited. J Nutr 2000;130:1512S‐5S
• Delivery: liquid, tablet, capsule
• Safety concerns: Zinc is regarded as a relatively safe mineral when taken at recommended doses, with few reported side effects. Silk, R. and LeFante, C. Am J Ther. 2005;12(6):612‐617.
– According to the U.S. Food and Drug Administration (FDA), there have been well over 100 reports of loss of smell associated with zinc‐containing Zicam® products.
“Participants with prediabetes have lower zinc levels than controls and zinc is significantly associated with beta cell function and insulin resistance.”
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“As a consequence of its regulation and other common factors that can influence its distribution, plasma zinc levels are not considered an accurate reflection of dietary zinc intake or status.”
“Thus, RBC MT may be responsive to a very labilefunctional zinc pool and could prove to be a useful marker of zinc deficiency.”
“In conclusion, current evidence indicates that metallothionein in leukocyte subtypes may be a component in determining zinc status.” Hennigar. Adv
Nutr. 2016 Jul 15; 7 (4): 735‐746.
Folic Acid
One of the B‐vitamins – “B‐complex”
Hundreds of functions but especially involved in:
Energy metabolism
Brain health
Heart health/Vascular health
Endothelial health (eNOS)
Proper cell division (deficiency during pregnancy causes neural tube defects such as spina bifida and anencephaly)
Detoxification
excretoryderivatives
Supportive Nutrients for Detoxification Pathways Supportive Nutrients for Detoxification Pathways
Lipid‐soluble molecule
polarwater‐soluble( )
Bile
Feces/stools
Serum
Kidneys
Urine
SulfationGlucuronidationMethylationAcetylationAminoAcid ConjugationGlutathione Conjugation
riboflavin (vit. B2)
niacin (vit. B3)pyridoxine (vit. B6)folic acidvitamin B12glutathionebranched‐chain amino
acidsflavonoidsphospholipids
Phase II[conjugation pathways]
Phase I[cytochrome P450 enzymes]
ActivatedIntermediates
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Folic Acid– Typical Use
• ORALLY, folic acid is used for preventing and treating folate deficiency, megaloblastic anemia, iron‐deficiency anemia, hyperhomocysteinemia, reducing methotrexate toxicity and side effects, fatigue, ulcerative colitis, and preventing neural tube defects
• TOPICALLY, folic acid is used for treating gingival hyperplasia and gingivitis.
• PARENTALLY, folic acid is used intramuscularly, subcutaneously, or intravenously for treating folate deficiency, particularly in patients with malabsorption or those who cannot take oral treatment. Folic acid has also been used parenterally to treat chronic fatigue syndrome.
Natural Medicine Database, Folic Acid. Accessed 9‐4‐16
Diseases/Conditions Related to Poor Folate Metabolism
Spina bifida and other NTDs
Depression, Anxiety, OCD
Alzheimer’s
Cognitive Decline
Heart Disease and Stroke
Cancer
High blood pressure
Poor detoxification
Poor energy
Anemia – especially macrocytic and megaloblasticanemia
Folic Acid
• Typical dose: 400‐800 mcg’s QD
– Those with methylation SNPs may go as high as 2 – 5 mg QD
• Delivery: tablets, capsules, liquid, injection
• Safety concerns:
– Orally, folic acid is well‐tolerated in amounts found in fortified foods and supplements in doses less than 1 mg per day
– A large‐scale population study suggests that men who take a multivitamin more than 7 times per week and who also take a separate folic acid supplement have a significantly increased risk of developing prostate cancer Lawson KA, Wright ME, Subar A, et al. Multivitamin use and risk of prostate cancer in the National Institutes of Health‐AARP Diet and Health Study. J Natl Cancer Inst 2007;99:754‐64
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Folic Acid, B6, B12 and Macular Degeneration in Women
• “These randomized trial data from a large cohort of women at high risk of cardiovascular disease indicate that daily supplementation with folic acid, pyridoxine, and cyanocobalamin may reduce the risk of AMD.”
– Folic acid (2.5 mg/d),
– Pyridoxine hydrochloride (50 mg/d),
– Cyanocobalamin (1 mg/d))
Arch Intern Med. Feb 2009;169(4):335‐341
Drug Induced Nutrient DepletionSource: Pelton, Lavalle, Hawkins, Krinksky. Drug Induced Nutrient Depletion Handbook. 2nd ed. Lexi‐Comp, Inc.
• Antibiotics (tetracycline, penicillin)
• Tuberculosis drugs (isoniazid, INH)
• Barbiturates
• Dilantin
• Depakote (valproic acid)
• Metformin
• Salicylates
• NSAIDS
• Corticosteroids
• 5‐aminosalicyclic acid derivates (sulfasalazine)
• Loop diuretics (furosemide)
• Potassium Sparing Diuretics
• Oral Contraceptives
• H2 antagonists (cimetidine)
• Methotrexate
• Metabolically active form of folic acid that doesn’t require the enzymatic conversion
• Naturally found in foods• Results support a protective effect of supplementation with either
folinic acid for patients with RA treatment with MTX• Can be take orally, intravenously, intramuscularly• Increases toxicity of fluorouracil when administered together• Available as Rx
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Methyl folate
• Observational studies have shown that individuals with high plasma concentrations or dietary intake of folate and vitamin B‐6 have a decreased risk of coronary heart disease /decreased homocysteine
• L‐5‐MTHF ensures folate and tetrahydrobiopterin (BH4) adequacy for neurotransmitter biosynthesis
• Folate might also convey protection against cancers of other tissues such as the breast, and cervix
• May decrease the production of certain neurotransmitters such as serotonin and catecholamines.
• Associated with incidence and severity of mood concerns in studies
References for previous slide on methyl folate
– Robinson K, Arheart K, RefsumH, et al. Circulation. 1998 February 10;97(5):437–43.
– Folsom AR, Nieto FJ, McGovern PG, et al. Circulation. 1998 July 21;98(3):204–10.
– Martinez ME, Giovannucci E, Jiang R, et al. Int J Cancer. 2006 Sep 15;119(6):1440–6.
– McCullough ML, Giovannucci EL. Oncogene. 2004 Aug 23;23(38):6349–64.
– Reif A et al. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:1162‐68.
– Nielsen GM et al. J Affect Disord 2015; 183:179‐86.
– Lamers Y, et al. Am J Clin Nutr. 2006; 84(1):156‐61.
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Enjoy one minute of serenity at Clearwater Beach, FL
Courtesy of Carrie Magudu
Vitamin B12 – Typical Use• ORALLY, vitamin B12 is used for treating pernicious anemia and preventing and treating vitamin B12
deficiency. It is also used orally for treating hyperhomocysteinemia, atherosclerosis, heart disease, hypertriglyceridemia, diabetes, diabetic neuropathy, peripheral neuropathy, cognition, memory loss, mood elevation, boosting energy, circadian rhythm sleep disorders, Alzheimer's disease, depression, psychiatric disorders, schizophrenia,
• INTRAMUSCULARLY, vitamin B12 is used to treat anemia, pernicious anemia, and fatigue.
• TOPICALLY, vitamin B12 is used alone or in combination with avocado oil for psoriasis and atopic dermatitis (eczema).
• INTRANASALLY, vitamin B12 is used for pernicious anemia and vitamin B12 deficiency.
• PARENTARELLY, vitamin B12 is used for pernicious anemia and preventing and treating vitamin B12 deficiency and associated myelopathy. It is also used parenterally for tremor associated with shaky‐leg syndrome or orthostatic tremor. Vitamin B12 is also used parenterally to treat cyanide poisoning, diabetic neuropathy, tiredness or fatigue, chronic fatigue syndrome, hepatitis C. It is also used parenterally to decrease restenosis in angioplasty.
Natural Medicines Database, Vitamin B12. Accessed 9‐5‐16
Vitamin B12
• Mechanism of action: essential water‐soluble vitamin required for nucleoprotein and myelin synthesis, cell reproduction, normal growth, and normal erythropoiesis. Vitamin B12 is essential for folate utilization, and its absence results in a functional folate deficiency. McEvoy GK, ed. AHFS Drug Information. Bethesda, MD: American Society of Health‐System Pharmacists, 1998.
• Typical dose: 500 mcg – 2 mg but should be titrated based on labs. – Normal serum vitamin B12 levels range between 200‐900 pg/mL. Optimal levels
closer to 500‐900. Serum concentrations less than 200 pg/mL indicate deficiency, and concentrations less than 100 pg/mL usually result in megaloblastic anemia or neurologic damage. Total serum vitamin B12 may not reliably indicate vitamin B12 status
– Functional biomarker – serum or urinary MMA which can detect deficiency but not toxicity. Herrmann W. Clin Chem Lab Med. 2003 Nov;41(11):1478‐88.
• Delivery: tablet, capsule, liquid, IM, sprays, lozenges
• Safety concerns: generally well‐tolerated. PPIs can decrease B12 absorption leading to deficiency
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“There is now substantial evidence for common decreases in serum/red blood cell folate, serum B12 and in increase in homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs homocysteine metabolism is shown to be over represented among depressed patients, strengthening the association.”
Coppen A., Bolander‐Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12. J. Psychopharmacol. 2005. Jan; 19(1): 59‐65.
Methylation co‐factors – low folate and B12 implicated in emotional stability
L‐methylfolate, B12 and SAMe Synergy
Bottiglieri T Psychiatr Clin North Am. 2013 Mar;36(1):1‐13
When to use adenosyl/hydroxycobalamin
• If a patient carries the COMT Met 158 allele and/or experiences restlessness, irritability or stimulation with methylcobalamin.
• When you are unsure of the patients genotype. Hydroxycobalamin is easily methylated in the body where needed. It is universally applicable as a B12 supplement, regardless of genotype.
Behav Neurosci. 2008;122(4):901–909.
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Digestive Enzymes:Let’s start with Proline Rich Proteins (PRPs)
• Proline provides stability, conformational/structural rigidity, and elasticity to proteins
• Proline
– Gives bread structure and elasticity
– Gives strength and elasticity to the collagen and elastin fibers in cartilage
– Is essential to the survival of thermophilic microbes
Nehete JY. et al. Natural proteins: Sources, isolation, characterization and applications. PharmacognRev. 2013 Jul‐Dec; 7(14): 107‐116.
PRPs are difficult to digest
• Due to their high stability, proline‐rich proteins are very difficult to break down
• The digestive enzymes present in the GI tract are insufficient to completely break down PRPs including gluten
Food Microbiol. 2007; 24:115‐119.
Acta Paediatr Suppl. 1996; 412_3‐9.
Am J Physiol Gastrointest Liver Physiol. 2002;283:G996‐G1003.
Endopeptidases vs Exopeptidases
• Exopeptidases
– comprehensive plant based enzyme blend with DPP IV (dipeptidyl peptidase) activity
• Endopeptidases
– contains Prolyl Endopeptidase (from Aspergillus niger) and supports the breakdown of gluten proteins
• Products with exo and endopeptidases are also available
Ehren et al. PLoS One.2009 Jul 21;4(7):e6313.
Lone et al. AAPS J. 2010 Dec;12(4):483‐91.
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A. Niger prolyl endoprotease
• A. niger prolyl endoprotease is considered an “endoprotease” because it digests proteins and peptides over their entire length.
• A. Niger is proline‐specific – cleaves proteins specifically after the amino acid proline
• This is in contrast to “exoproteases”, which preferentially break down only the ends of peptide chains
Proline Specificity
• In vitro data has shown that A. niger prolyl endopeptidase is a “proline‐specific endoprotease”.
– Proline‐specific – cleaves proteins specifically after the amino acid proline
– Endoprotease – cleaves proteins over their entire length
– J. Agric Food Chem. 2005 Oct 5;53(20):7950‐7957.
– Am J Physiol Gastrointest Liver Physiol. 2006 Oct; 291(4): G621.629.
Digestive Enzymes• Typical use: pancreatitis, cystic fibrosis, steatorrhea, malabsorption, gas, bloating, lactose
intolerance, SIBO
• Mechanism of action: catalyze the breakdown of macronutrients and plant based compounds and fibers
• Typical dose: for pancreatitis and cystic fibrosis – dosed off of lipase units (LU) – usually 25,000 – 50,000 units per meal. Other units are USP, DU and HUT. Plant enzymes are expressed in mg and gram doses. Wide ranging doses for other uses. Typically ‐1 cap with small meal and 2 caps with a large meal. Take with the first few bites or in the middle of the meal.
• Delivery: capsules; plant based come from fungus, papaya or pineapple (vegetarian) and are broad spectrum and active at a broad pH range. Pancreatic enzymes come from animals (porcine) and have a more narrow pH range and should be enteric coated.
• Safety concerns: contraindicated with gastric ulcers; protease and HCL can irritate the GI if ulcers or GERD is present, caution with fungal enzymes in the immunocompromised and with central line access
Roxas, M. Alternative Medicine Review 14.4 2008: 307‐14
Natural Medicines Database. Pancreatin. Accessed 9‐5‐16
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Functions of Hydrochloric Acid (HCL)
• Denatures proteins, stimulates peristalsis and begins their digestion so they can cross the intestinal epithelium
• Converts pepsinogen to pepsin→ aa’s absorbed in the small intesting
• Barrier ‐ protects against orally‐ingested pathogens
• Helps prevent bacterial or fungal overgrowth of the small intestine
• Stimulates pancreatic enzyme and bile secretion
• Facilitates absorption of minerals, vitamin B12 and a variety of other nutrients
• HCL and pepsin
– As we age, we produce less and less HCL and pepsin.
Timiras PS. Aging of the gastrointestinal tract and liver. In: Timiras PS, ed. Physiological basis of aging and geriatrics. 2nd ed. Boca Raton: CRC Press 1994:247‐57.
HCL – a barrier
• “The low pH of the intragastric environment constitutes one of the major non‐specific defense mechanisms of the body. Reduction of gastric acid secretion predisposes to infection
with a variety of organisms . . .”
Howden, CW and Hunt, RH. Progress Report: Relationship between gastric secretion and infection. Gut 1987;28:96‐107
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Betaine HCL
• Typical use: ORALLY, betaine HCL is used to assist with absorption (i.e. B12, calcium, K+) and assists with breakdown of protein. Gut support ie. Bloating and prevention/treatment of SIBO
• Mechanism of action: increases gastric acidity
• Typical dose: 1 – 5 grams. Take 1‐3 tabs with each meal. Betaine HCL should ideally be taken during or immediately after eating. The HCL must mix in with the contents of the stomach to be effective. (see next slide for HCL challenge)
• Delivery: tablet
• Safety concerns: may irritate ulcers
HCL Challenge
• Always take Betaine HCL immediately after the meal when your normal digestive processes have started.
• Day 1: Take one Betaine HCL tablet at the end of each meal all day long.
• Day 2: Take two Betaine HCL tablets at the end of each meal all day long.
• Day 3 – Day 7: Continue increasing by one Betaine HCL tablets per day, for each meal, until you feel a warmth in your stomach or until you reach seven Betaine HCL tablets per meal. Do not take more than seven tablets per meal.
• NOTE: Drink 8 oz of water with one tablespoon of baking soda if warming is uncomfortable.
• IMPORTANT: This test should not be undertaken if there is gastritis or any recent history of gastric ulceration (stomach ulcers).
http://www.beyondmthfr.com/
“Functional” fiber
• Absorb very large amounts of water
• Nourish and support gut flora (prebiotic)
• Lubricate distal GI wall and help with ease of elimination
• Best sources: apples, pears, plums, beans, lentils, oats, onions, chicory, squash
• Dietary Reference Intakes →14 g dietary fiber per 1,000 kcal, or 25 g for adult women and 38 g for adult men. (JADA 2008, 108(10):17:1716‐1731.)
• Dietary Reference Intakes recommend consumption of 14 g dietary fiber per 1,000 kcal, or 25 g for adult women and 38 g for adult men, based on epidemiologic studies showing protection against cardiovascular disease. Ancestral diet contributed up to 100 g/day of dietary fiber! Leach JD. Evolutionary perspective on dietary intake of fibreand colorectal cancer. Eur J Clin Nutr. 2007. Jan;61(1): 140‐142.
• Daily fiber intake generally has not progressed toward national goals during the past decade. (J Acad Nutr Diet. May 2012;112:642‐648.)
• Important to ease up in patients who start with low fiber intake.
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Short Chain Fatty Acid (SCFA): N‐Butyrate
• Fiber critical for the production of SCFAs
– SCFAs are metabolic products of anaerobic bacterial fermentation of dietary soluble fiber and resistant starch.
– SCFA heal the digestive lining. Several investigators identified the inhibitory effect of the SFCA, butyrate, on proinflammatory cytokine‐induced NF‐kappa B activation.
• “We concluded that butyrate has a wide spectrum of inhibitory activity on cytokine release stimulated by LPS.” Nancey S. Dig Dis Sci. 2002 Apr;47(4):921‐8.
• “Butyrate decreases proinflammatory cytokine expression via inhibition of NFκB activation and IκBα degradation. These anti‐inflammatory properties provide a rationale for assessing butyrate in the treatment of Crohn’s disease.” Segain JP. et al. Gut. 2000; 47:397‐403.
– SCFAs lower the pH in the colonic lumen, thus increasing bioavailability of some minerals (i.e. calcium) and inhibiting growth of pathogenic bacteria. Meijer et al., 2010
N‐Butyrate• Typical use: GI disorders, inflammatory diseases, and microflora integrity; potent
detoxifier of ammonia and neurotoxins. Encourages formation of friendly bacteria in the gut.
• Mechanism of action: preferred fuel of the colonic epithelial cells
• Typical dose: 500‐1000 mg QD
• Delivery: capsules; available as sodium butyrate, sodium/potassium butyrate and calcium/magnesium butyrate. NaBu is for those‐‐especially the elderly‐‐who are low in sodium, who sweat profusely, or are athletic. NaBu is not indicated for the salt‐sensitive hypertensive types. Na/KBu has the balance of Na and K needed to maintain Na:Kbalance at the membrane. Ca/MgBu is most commonly used.
• Safety concerns: generally well tolerated. More than 7‐8 grams a day can tax the kidneys in people with renal disease. “Make sure nobody snorts it.” – Tom Wnorowski, PhD, biochemist
Louis P. Flint HJ. Diversity, metabolism and microbial ecology of butyrate‐producing bacteria from the human large intestine. FEMS Microbiol Lett. 2009. May; 294 (1): 1‐8.
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Zinc Carnosine
• Typical use: relieves mild and occasional gastric mucosal lining and indigestion
• Mechanism of action: targets and adheres to gastric mucosal lining in need of support. Helps to deliver zinc to the mucosal lining, where it exerts its antioxidant and tissue supportive benefits; supports healthy mucus secretion
• Typical dose: 75 mg – 150 mg QD between meals
• Delivery: tablet (1 tab usually 75 mg)
• Safety concerns: generally well tolerated
Mildonado, H. Zinc‐Carnosine: An exciting approach to gastric mucosal health and dyspeptic symptom relief. Applied Nutritional Science Reports, 2003.
BENEFICIAL EFFECT PROPOSEDMECHANISM
Inhibits H. pylori Anti‐urease activity
Attenuates gastric inflammation Inhibits expression of TNF‐alpha and IL‐8 cytokines without affecting PGE2 production
Protects cellular integrity Antioxidant activity
Protects gastric epithelium Stimulations mucus secretion
Adheres to wound site L‐carnosine transports zinc to wound site, zinc is an important cofactor for many proteins
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“We conclude that 1) trace micronutrients such as Zn2+ could be successfully measured in the gastric juice and gastric mucosa during ulcer healing; 2) compounds chelating of Zn2+ can exert a beneficial influence on the ulcer healing…”
Probiotics ‐ benefits
Digestion
– Produce SCFA to nourish enterocytes
– Improve extraction of nutrients and bioactive compounds from food
– Regulate peristalsis (prevent and treat diarrhea and constipation)
Immunity
– Prevent colonization of pathogenic bacteria
– Lower inflammatory cytokines
– Reduce risk of infection and illness
Renal/Urinary health
– Reduce risk of UTI
– Reduce creatinine and BUN
Metabolism
– Prevent metabolic syndrome
– Improve glycemic control
– Reduce blood lipids
– Support healthy metabolism
Mood
– Reduce anxiety and depression
Bioessays. 2013;35(9):810-817Donia.Science.2015 July;349(6246):395J Am Soc Nephrol.2014;25(4):657-70J Med Food.2014;17(12):1261-1272
Probiotic Classification Chart
LACTOBACILLI
L. bulgaricus
B. infantis
B. lactis
B. longum
L. rhamnosis
L. casei
L. plantarum
L. acidophilus
BIFIDOBACTERIA
SACCHAROMYCES
S. boulardii
B. adolescentis
GENUS
SPECIES
STRAIN DDS 1 685 1195
4008 NCFM GG CR14
33200
448 17930
837
B734
15708
15706 25962
15705
BI07
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Examples of Common Probiotic Species used in supplements (bacteria and yeast):
• Lactobacillus
– L. acidophilus
– L. rhamnosus GG
– L. reuteri
– L. DDS‐1
– L. NCFM
– L. plantarum
– L. casei
– L. bulgaricus
• Streptococcus
– S. thermophilus
• Bifidobacterium
– B. bifidum
– B. lactis
– B. breve
– B. longum
– B. infantis
• Saccharomyces (yeast)
– S. boulardii
Units of Measurement
• CFU – Colony Forming Units
Probiotic Manufacturers
• Reputable companies will:
– Use human strains known to be GI colonizers and that have research behind them for specific conditions
– Ensure their products contain live microorganisms
– Batch test every batch for potency and purity
– DNA verify
– Protect /Refrigerate their products to prevent degeneration
• Although some preparations are shelf stable
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Probiotic Considerations • Single strain vs. multi strain
– Research supports both
– Multistrain is probably better
– Strain specific for conditions
• High potency vs low potency
– Generally higher potency is better although potency seems to be improved with multiple strains
– Lower potency for maintenance: 1‐10 billion CFU, high potency for treatment up to 900 billion CFU (average 1‐30 billion CFU can often go higher without negative side effects in most people)
nutritionovereasy.com
Probiotic Considerations
• With or without food?
– Many strains can survive stomach acid
– Some are enteric coated – may not be necessary if strain is hardy and acid resistant
• With or without prebiotics (i.e. inulin, FOS)?
– They can sometimes cause gas and bloating if taken in large amount
– Individuals following a ↓FODMAPs
diet may need to avoid probiotics
with prebiotics
nutritionovereasy.com
Probiotic + Prebiotics = Symbiotics
• Many contain prebiotics (inulin, FOS) along with the probiotic bacteria
• These supplements are called “symbiotics”
http://www.prebioticproducts.com/v/vspfiles/assets/images/prebiotics-ingredients.jpg
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Probiotic Considerations
• Look for stability and expiration guarantees
– Refrigerated vs Stable at room temperature – buy a reputable brand (Consumer Lab)
• Temperature stability ensures potency over time
• For many manufacturers, stability at room temperature is a significant challenge
– Multiple assays ensure product quality
– Guaranteed label claim at time of expiration
• Sustained use is important for long term effects
nutritionovereasy.com
Safety Assessment of Probiotics for Human Use Sanders, ME et al. Gut Microbes. 2010;1(3):164‐185
• Documented correlations between adverse events and probiotic consumption are few considering their widespread use
• With few exceptions, adverse events have been reported primarily in patients with underlying medical conditions
• The risk of lactobacillis infection is estimated at less than 1 case per million
• Studies where probiotics have been safely administered to immunocompromised pts (HIV, premature infants, elderly, Crohn’s) without side effects provide further evidence of poor pathogenic pathophysiology
• Yeast based probiotics are contraindicated for those on dialysis or severely immune compromised (Natural Medicines Database. Saccharomyces Boulardii monograph. Accessed Sept 2, 2016)
Live vs Dead cultures?
• “Live probiotic cells influence both the gastrointestinal microflora and the immune response whilst the components of dead cells exert an anti‐inflammatory response in the gastrointestinal tract.”
Adams CA. The probiotic paradox: live and dead cells are biological response modifiers.Nutr Res Rev. 2010 Jun;23(1):37‐46.
Kataria, J., N. Li, J.L. Wynn and J. Neu. Probiotic Microbes: Do They Need to Be Alive to Be Beneficial? 2009. Nutrition Review 67 (posted online Aug. 21):546.
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• VSL#3 high‐potency probiotic medical food contains 8 different strains of live lactic acid bacteria selected to produce an optimal synergistic composition of bacteria. The 8 strains are:
– Bifidobacterium breve
– Bifidobacterium longum
– Bifidobacterium infantis
– Lactobacillus acidophilus
– Lactobacillus plantarum
– Lactobacillus paracasei
– Lactobacillus bulgaricus
– Streptococcus thermophiles
• Primary conditions studied: ulcerative colitis, pouchitis
– Chapman et al. Drugs. 2006;66(10):1371‐1387
– Bibiloni et al. Am J Gastroenterol. 2005 Jul;100(7):1539‐1546.
• There are three formulations of VSL#3:
– Capsules that contain 112.5 billion live bacteria
– Packets that contain 450 billion live bacteria
– Double Strength (DS) packets that contain 900 billion live bacteria. Due to the potency of this formulation, VSL#3 DS is a prescription only medical food.
Soil Based Organisms (SBO)/Hemostatic soil organism (HSO)
• B. subtilis species abundant in soil
– obligate aerobics→anaerobes→commensal microbes
– Used to produce Japanese fermented soy → natto
– widely used in the poultry industry to reduce Salmonella
• Some SBO’s based products are available as broad spectrum prebiotic (humic/fulvic acids)+ probiotic complexes → “Symbiotics”; Some as dual strains of B. subtilis +B. coagulans
• Encapsulated in endospores to survive heat and gastric acidity
• Must be accurately identified via DNA verification and tested for antibiotic resistance
Soil Based Organisms (SBO)/Hemostatic soil organism (HSO)
• Recommended for short‐term use (< 3 months)
• Peer‐reviewed, DBPC clinical trial for IBS
– Kalman DS, Schwartz HI, Alvarez P, et al. A prospective, randomized, double‐blind, placebo‐controlled parallel‐group dual site trial to evaluate the effects of a Bacillus coagulans‐based product on functional intestinal gas symptoms. BMC Gastroenterol2009;9:85.
– Bittner AC, et al. Prescript‐Assist probiotic‐prebiotic treatment for irritable bowel syndrome: an open‐label, partially controlled, 1 year extension of a previously published controlled clinical trial. Clin Ther. 2007. Jun;29(6):1153:1160.
• “GFDF, Vegan, SCD and GAPS compliant”
• Safety concerns: rare cases of septicemia in critically ill patients/ambulatory immunosuppressed patients have been reported
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Probiotic yeast: Saccharomyces boulardii• Can be taken at the same time as antibiotic without affecting potency of either
• Shelf stable (no need for refrigeration)
• Mechanism of action/Intended use:
– Treatment of C. Diff.
• Produces a protease that inhibits the binding of pathogenic bacteria to the gut wall (like C. Diff and E. coli)
– Anti‐secretory effects helps reduce diarrhea
– Supports healthy cytokine profiles (anti‐inflammatory)
– Encourages healthy mucosal/epithelial barrier function
• Dose and duration:
– Usually 5‐10 billion CFUs
– Duration is not specifically outlined – long term use is suspected to be safe
• Contraindications:
– Risk of fungemia in people on IV therapy, on hemodialysis or in the seriously immune compromised, may reduce effectiveness of anti fungal meds (in theory)
Natural Medicines Database. Saccharomyces boulardii monograph. Accessed Sept 4, 2016
Probiotics ‐ Summary• Typical use: multiple forms of diarrhea, constipation, C. diff prevention and
treatment, pouchitis, reduce inflammation in IBD, regulate peristalsis in IBS (but can make it worse if SIBO), correct dysbiosis, support immunity (60% of the immune system is in the gut)
• Mechanism of action: produce SCFA to nourish enterocytes, inhibit pathogens, reduce luminal pH, correct dysbiosis, regulate intestinal motility, produce vitamins, activate bioactive compounds
• Typical dose: no typical dose – start low and go slow if serious GI concerns, However, doses range from 1 to 450 billion CFUs. Average is about 1‐30 billion CFU.
• Delivery: available as capsules and powders; take separately from antibiotics unless using probiotic yeast, live organisms are best, some are shelf stable in blister packs or special capsules, multi strain is usually preferable
• Safety concerns: very safe overall, can increase sx in SIBO, can cause gas, bloating esp. if present with prebiotics like inulin
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Glutamine ‐ Background
• Single most important amino acid that “feeds” the cells of the gut
• Utilized in rapidly dividing cells in the splanchnic area
• Improves gut permeability
• Is considered “standard‐of‐care” when parenteral nutrition is administered
• Involved in neurotransmitter messaging
• Also used for muscle recovery/overtraining/immune modulation
• Is an important precursor for de novo synthesis of arginine in humans
Glutamine• Typical use: intestinal damage due to injury or infection, intestinal
permeability and leaky gut, diarrhea (associated with HIV, chemo and XRT), IBD, Ulcers, mucositis, conditionally essential amino acid
• Mechanism of action: preferred fuel source of (small intestinal) enterocytes, aids in mucin production, cellular regeneration, stabilizes actomyosin and tight junctions between enterocytes
• Typical dose: Can begin with as little as 100 mg→ 10,000 mg/typical is 5‐30 grams per day (divided doses). Assess individually!
• Delivery: powder is more economical than capsules, mild tasting
• Safety concerns: overall very safe, caution if glutamate sensitive (may worsen some psychiatric conditions – P5P and Mg may reduce risk ), may lower seizure threshold in some, contraindicated in cirrhosis, may be used by tumors in some cancer types (new research)
chemistry.about.com
Natural Medicines Database. Glutamine. September 4, 2016Rao R et al.J Epithel Biol Pharmacol. 2012;5(Suppl 1‐M7):47‐54Chen L et al. Int J Mol Sci. 2015 Sep 22;16(9):22830‐55Kucuktulu E et al. Supportive Care in Cancer. April 2013;21 (4): 1071‐1075.
Beware of Certain Supplements!
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What happened to Bill?
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SUPPLEMENTS TO CONSIDER COMMONMETABOLIC ASSOCIATION/CONDITION
Medical food with NAC Overall GI support/Hepatic support/cytokine balance + glutathione wasting
Liposomal glutathione Additional support for glutathione wasting
L‐arginine + magnesium (citrate) combo Vascular support/healthy blood pressure
CoQ10/ubiquinol Drug induced nutrient depletion/CVD
EPA/DHA + Vitamin D3 combo Inflammation/insulin sensitization
Chromium/vanadyl sulfate/gymnemasylvestre/lipoic acid/zinc combo
Insulin sensitization/pre‐diabetes
Methyl folate + adenosyl/hydroxycobalamincombo
Methylation/Energy support/ COMT MET158 ‐/+ allele
Digestive enzymes + Betaine HCL combo IBS / digestive support/bloating
Zinc Carnosine Digestive support/bloating/belching/indigestion
Soluble Fiber and/or Probiotics and/or N‐butyrate
anaerobic bacteria fermentationSoluble Fiber SCFA such as n‐butyrate
Low dose glutamine + curcumin combo Gut support→go with low dose due to COMT MET 158 ‐/+ allele
Reevaluate/titrate supplement doses at follow up if necessary but maintain supplement regimen for 4‐6 months
A few extra’s for Bill – Helpful Tools for Compliance
10/6/2016
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Closing Reflections• LISTEN to the patients story
• Recognize patterns
• Avoid micromanaging every symptom, especially all at once
• Assess and honor patient readiness
• Co‐investigate possible barriers to taking supplements:
– Don’t like taking supplements
– Forget to take them
– Cost $$$
– Too many supplements
– Pills too large
– Tolerance issues? i.e. metallic taste, nausea, change in BMs, anxiety, etc.
– Adverse event/side effect
• Prioritize supplement needs/use combo products! Get to know your reps!
Special Thank‐You to:
• Jason Tremblay
– Emerson Ecologics
• Kathie Swift, MS, RDN, FAND
– Integrative and Functional Nutrition Academy
• Kelly Morrow, MS, RDN, CD
– DIFM Chair
• Mary Alice Gettings, MS, RDN, CDE
– DIFM, Planning Chair
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