1. Raj Patel, M.D. Optimizing GI Function and Heavy Metal Burden in Lyme Disease Raj Patel, MD Medical Options for Wellness Los Altos, CA 650-964-6700 www.DrRajPatel.net

2. Raj Patel, M.D. Overview Overview A.Optimize GI Function  Antibiotic induced diarrhea  Intestinal dysbiosis (definition, causes, treatment)  Liver/GB Support B. Heavy Metals  Prevalence  Signs & symptoms  Testing  Treatment options  Methylation in non-responders C. Conclusion

3. Raj Patel, M.D. A. Optimize GI Function 1. Antibiotic Induced Diarrhea (AID)  Common complication from extended antibiotic use  Probability increases with use of >2 antibiotics Doxy + Flagyl for 10 d caused a significant increase in GI and vaginal candida counts than either alone. Maraki S. J Chemother. 2003 Aug;15(4):369-73.  Certain antibiotics more commonly associated with AID (Cephalosporins and Penicillins)  Clostridium difficile induced enterocolitis Symptoms: diarrhea, abdominal pain, fevers Incidence: only accounts for 10-20% of all AID cases E. Bergogne-Bérézin Int J Antimicrob Agents. 2000 Dec;16(4):521-6

4. Raj Patel, M.D.  Non-Clostridium AID Common pathogens include Clostridium perfringens, Staphylococcus aureus, Klebsiella oxytoca, Candida species, and Salmonella species. Accounts for 80-90% of all AID cases Clin Infect Dis. 1998 Oct;27(4):702-10  AID Treatment Options Mild Symptoms: Saccharomyces boulardii Probiotics Bland diet Drug holiday/Change antibiotics Elmer GW. et al JAMA. 1996 Jul 3 ;276(1):29-30 Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. Severe Symptoms: Metronidazole Vancomycin

5. Raj Patel, M.D. 2. Intestinal Dysbiosis a. Definition:  Term originally coined by Metchnikoff to describe altered pathogenic bacteria in gut. Today, abnormal milieu due to bacterial and fugal imbalance.  These abnormal bacteria have been shown to produce: toxic products- endotoxins, phenols, ammonia, & indoles Macfarlane C et al. Proteolysis and amino acid fermentation. In: Gibson GR, Macfarlane GT, eds. Human Colonic Bacteria: Role in Nutrition, Physiology, and Pathology. Boca Raton, FL: CRC Press; 1995:75-100.  Chronic degenerative diseases - inflammatory bowel disease, ankylosing spondylitis, & RA Peltonen R, Nenonen M, Helve T, et al. Br J Rheumatol 1997;36:64-68. Brandtzaeg P. Review article: Aliment Pharmacol Ther 1997;11:24-37.

6. Raj Patel, M.D. Intestinal Dysbiosis (con’t) b. Functions of the microflora  Immune stimulation  Vitamin synthesis (B group & K)  Enhancement of gut motility, digestion & nutrient absorption  Improve epithelial function via increased SCFA production, decreased apoptosis, increased barrier integrity  Inhibit pathogenic bacteria via decreasing luminal pH, decreasing epithelial binding, and decreasing epithelial invasion  Metabolism of certain drugs Holzapfel WH, et al. Int J Food Microbiol 1998;41:85-101. Noack J, et al. J Nutr 1998;128:1385-1391. Gibson GR, Roberfroid MB. J Nutr 1995;125:1401-1412. Sartor, RB. J. Clin. Gastro 2007;41:537-543

7. Raj Patel, M.D. Intestinal Dysbiosis (con’t) c. Causes of Intestinal Dysbiosis I. Antibiotics-based on spectrum of activity, route of excretion, dosage, & length of use. Hawrelak, JA Alternative Medicine Review Vol 9, No 2 2004

8. Raj Patel, M.D. Antibiotics Entero- bacteria Entero- cocci AnaerobicResistant Strains Lactobacilli /Bifidus Candida Ampicillin Amoxicillin Cefaclor Ceftriaxone Ciprofloxacin Clindamycin Doxycycline Metronidazole Moxalactam Ofloxacin Effects of Antibiotics on Intestinal Flora Hawrelak, JA Alternative Medicine Review Vol 9, No 2 2004

9. Raj Patel, M.D. c. Causes of Intestinal Dysbiosis (con’t) II. Stress:  Altered gut motility and increased bicarbonate production potentially leading to decreased survival/adherence/replication of healthy flora Lenz HJ. Et al. Gastroenterology 1988;94:598-602. Lenz HJ. Proc Natl Acad Sci U S A 1989;86:1417-1420.  Decreased mucin and mucopolysaccharide production leading to increased adherence and replication of dysbiotic flora

10. Raj Patel, M.D. c. Causes of Intestinal Dysbiosis (con’t) III. Lyme and Coinfections  Lyme is well documented to invade and multiply in the GI tract Fried MD, et al Gastrointestinal pathology in children with Lyme disease. Jour. of Spirochetal & Tick-Borne Diseases 1996; 3:101-04  Lyme and more commonly ehrlichiosis, tick borne relapsing fever, & Rocky Mountain Spotted Fever are commonly associated with diarrhea and intestinal dysbiosis. Reisinger EC. et al. Nat. Clin. Pract. Gastrenterol. Hepatol. 2005 May; 2(5):216-22. Zaidi SA. et al. Clin. Infect. Dis. 2002 May 1;34(9):1206-12

11. Raj Patel, M.D. c. Causes of Intestinal Dysbiosis (con’t) IV. Maldigestion  Pancreatic exocrine deficiency Fecal elastase marker for pancreatic enzyme production  Gallbladder dysfunction with decreased bile production -> fat maldigestion Consider fecal fat testing  Increased intestinal permeability/inflammation Microscopically characterized by blunting/loss of micro-villi and compromised tight junctions between cells Corresponding loss of disaccharidases resulting in carbohydrate maldigestion, increased disaccharide load to colon, and resulting dysbiosis. Diagnosed by Lactulose/Mannitol test (increased ratio indicates increased permeability)

12. Raj Patel, M.D. c. Causes of Intestinal Dysbiosis (con’t) V. Diet - Composition of diet affects type and metabolic activity of gut flora Gibson GR. Dietary modulation of the human gut microflora using prebiotics. Br J Nutr 1998;80:S209-S212.  High Protein Diet: Typical American diet contains 100g of protein per day. Up to 12g can escape digestion & become available for fermentation by colonic bacteria. The resulting harmful byproducts include ammonia, sulfides, indoles, phenols & amines-> migraines, carcinogens, damage lining, contribute to portal encephalopathy. Significant issue in Lyme patients with compromised GI function

13. Raj Patel, M.D. c. Causes of Intestinal Dysbiosis (con’t) V. Diet (con’t)  High Carbohydrate Diet: High refined carbohydrate diet -> slows bowel transit time -> increases bacterial fermentation -> increases exposure to potentially toxic bowel contents (96) -> promotion of fungal overgrowth (esp. in presence of multiple antibiotics) Lewis SJ, Heaton KW. Am J Gastroenterol 1999;94:2010-2016. High carbohydrate diet (esp gluten and casein) -> increases disaccharide load to colon (due to intestinal inflammation and disaccharidase deficiency) -> abnormal bacterial overgrowth and fermentation

14. Raj Patel, M.D. Intestinal Dysbiosis (con’t) d. Treatment Options for Intestinal Dysbiosis  Antibiotics: All things being equal choose antibiotics with less effect on gut flora. Support intestinal flora-probiotics (research carefully) prebiotics (FOS, etc.) fermented foods  Stress: Help patients manage stress effectively Support endocrine systems esp. adrenals and thyroid as covered earlier Treat insommnia aggressively (melatonin, 5HTP, Ramelteon, Trazodone, etc.) Treat depression/anxiety if needed

15. Raj Patel, M.D. Intestinal Dysbiosis (con’t) d. Treatment Options for Intestinal Dysbiosis  Lyme: Expect improvement in gut issues as load of Lyme and coinfections reduced  Maldigestion: Digestive enzmes-Use broad spectrum digestive aids that include protease, lipase, & amylase as well as disaccharidases (lactase, maltase, and sucrase) Gallbladder support-Taurine, ox bile, and bile salts can aid in bile production and fat digestion Intestinal inflammation/permeability-Glutamine, slippery elm, and DGL aid in reducing gut inflammation. Eliminate allergenic/intolerant foods & consider desensitization

16. Raj Patel, M.D. Intestinal Dysbiosis (con’t) d. Treatment Options for Intestinal Dysbiosis (con’t)  Diet: Consider decreasing protein intake if excessive Eliminate gluten, casein, and refined carbohydrates Consider Specific Carbohydrate Diet (SCD) in those severely carbohydrate intolerant Gottschall, E (1994). Breaking the Vicious Cycle: Intestinal Health Through Diet, Revised edition, Kirkton Press..

17. Raj Patel, M.D. Intestinal Dysbiosis (con’t) 3. Liver/Gallbladder Function  Dysfunction/Inflammation of liver and gallbladder I. Lyme and coinfections II. Antibiotics: Elevate liver function tests Those with biliary excretion can result in GB dysfunction  Testing I. Comprehensive liver detoxification screen to evaluate phase I & II function II. Genomic testing  Hepatic nutritional support

18. Raj Patel, M.D. Bio-Chem Site CauseIntervention Phase I Upregulated Dysgiosis/gut derived toxins increased intes. Permeab. environ. Toxic exposure Address source Antioxidants Support phase II Phase I Downregulated P450 inhibitors (HM, drugs, EFA deficiency, hypothyroid, & increased sat. fat intake Correct source, liver support with PC, taurine, silymarin, EFAs, & antioxidants Phase II- Glucoronidation Mitochondrial damage, Fe deficiency, drugs, genetic uniqueness (Gilbert’s) Address underlying cond’t. Cruciferous veg. to induce conjugation enzymes, B6, Mg, L-glutamine, asp acid, niacin Glycination Hepatic disease, nutritional deficiency, genetics Glycine, alkaline foods to enhance glycination, B5, Mg, cysteine Glutathione conjugation Glutathione depletion due to increased toxic load, nutritional deficiency, genetics Reduced glutathione, N-acetyl cysteine, glycine, L-methionine, L-glutamine Sulfation Sulfate depletion, toxic load, hepatic disease, genetics High sulfur foods, red. Glutathione, L-methionine, L-cysteine, Zn, Cu, Se, Mg, B6, B12, Mg, FA Patrick Hanaway, MD Genova Diagnostic Laboratories Hepatic Nutritional Support

19. Raj Patel, M.D. B. Heavy Metals 1. Heavy Metals - Hg, Cd, Pb, & Ar are the best studied a. Hg I. Sources:  Thimersol (50% Hg by volume) was the preservative in most vaccines until approx 2001.  Cumulative dose in vaccines from birth to age 5 years exceeded the EPA guidelines for safety.  Large population of older children and young adults have had significant exposure.  Study on NYC adult population revealed 24.8% had blood levels at or exceeding 5ug/l, the NY State reportable level. McKelvey W. Environ Health Perspect. 2007 Oct;115(10):1435-41  Seafood, dental amalgams, and industrial output account for the major sources of exposure today. (26,27) WHO. Methyl Mercury. Environmental Health Criteria, vol. 101. Geneva: World Health Organization, 1990 Sallsten G, et.al., J Dent Res 1996; 75: 594–8

20. Raj Patel, M.D. 1. Heavy Metals (con’t) a. Hg II. Toxicity:  Low level chronic exposure can lead to nervous system damage resulting in depression, anxiety & cognitive loss Weiss B, Clarkson TW, Simon W. Environ Health Perspect 2002; 110 (Suppl 5): 851–4  Autoimmunity Hultman, P. et al. The FASEB Journal Nov 1994; 1183-90  Paresthesias, insommnia, cognitive difficulties, neuromuscular changes, headaches and anxiety. http://www.epa.gov/iris/subst/0692.htm

21. Raj Patel, M.D. 1. Heavy Metals (con’t) b. Cd I. Sources: Color pigment (dyes & paints) Cigarette smoke Ni-Cd batteries Phosphate fertilizers Jarup L et al. Health effects of cadmium exposure—a review of the literature and a risk estimate. Scand J Work Environ Health 1998; 24 (Suppl 1): 1–51 WHO. Cadmium. Environmental Health Criteria, vol. 134. Geneva: World Health Organization, 1992 II. Toxicity: Kidney damage Osteoporosis Cancer Jarup, L. Br. Med. Bull. 68:167-182 (2003)

22. Raj Patel, M.D. 1. Heavy Metals (con’t) c. Pb I. Sources: Gasoline (Worldwide major source but not in US) Lead in drinking water primarily due to the presence of lead in certain pipes, solder, and fixtures. In kids toys and lead based paints in old homes II. Toxicity: Decreased IQ Memory deterioration Cancer Anemia Peripheral nerve symptoms WHO. Lead. Environmental Health Criteria, vol. 165. Geneva: World Health Organization, 1995 Steenland K, Boffetta P. Am J Ind Med 2000; 38: 295–9

23. Raj Patel, M.D. 1. Heavy Metals (con’t) d. Ar I. Sources: Wood preservative Fish Pesticides/food Industrial exposure II. Toxicity: Cancer-lung, bladder, & kidney Peripheral neuropathy Anemia GI Effects WHO. Arsenic and Arsenic Compounds. Environmental Health Criteria, vol. 224. Geneva: World Health Organization, 2001 Chilvers DC, Peterson PJ. Global cycling of arsenic. In: Hutchinson TC, Meema KM (eds) Lead, Mercury, Cadmium and Arsenic in the Environment. Chichester: John Wiley & Sons, 1987; 279–303 www.epa.gov/ttn/atw/hlthef/arsenic.html

24. Raj Patel, M.D. B. Heavy Metals (con’t) 2. Testing for Heavy Metals  Blood levels useful for acute exposure, but unreliable tool for chronic low level exposures. Mercury has affinity for fatty tissue. Rarely seen in blood. The half-life of Pb in blood is about one month whereas the half-life in bone is 20-30 years. (35) WHO. Lead. Environmental Health Criteria, vol. 165. Geneva: World Health Organization, 1995  Difficult to accurately assess total body burden. Urinary porphyrins have some utility – currently probably the best clinical test available.  Hair Mineral Analysis may be helpful, but show false negative in individuals with compromised detoxification pathways  Provocative challenge-involves administering a test dose of a chelator (DMPS, DMSA, or EDTA) and measuring pre- and post- fecal &/or urine for heavy metals.

25. Raj Patel, M.D. B. Heavy Metals (con’t) 3. Treatment - best done once Lyme/coinfection load reduced  Pharmacological Chelators: DMPS DMSA EDTA Penicillamine  Non-pharmacological chelators: Sauna Alginate/Chlorella Zeolite

26. Raj Patel, M.D. B. Heavy Metals (con’t) 3. Treatment (con’t)  Nutritional support during chelation essential I. Gut binding agents-Bentonite Charcoal Cholestyramine II. Mineral replacement-depending on the chelator used, replace minerals aggressively with special attention to Ca & Mg with EDTA and Cu & Zn with DMPS/DMSA III. Antioxidant support-necessary to quench free radicals generated during heavy metal removal. Supplement with A, C, E, Zn, selenium, and reduced glutathione. IV. Hepatic support-as outlined earlier

27. Raj Patel, M.D. B. Heavy Metals 4. Assess methylation function in non-responders  Definition: Methylation involves transfer of methyl group  Methylation plays a role in: Neurotransmitter synthesis and breakdown Renal disease Cardiovascular disease Cancer Heavy metal detoxification Anti-viral immune modulation

28. Raj Patel, M.D. Methionine Synthase Homocysteine SAH SAM 5 MTHF 5,10 MTHF MSR B12ZnMg Cystathione Cysteine Glutathione Homocysteine Taurine CBS P5P Methylation Cycle MTHR

29. Raj Patel, M.D. B. Heavy Metals 4. Assess methylation in non-responders (con’t)  Single Nucleotide Polymorphisms (SNPs): Can impair methylation Commonly found in the general population SNPs involving MTHFR C677T have a 47% incidence among Caucasians Ulrich CM. et al. Cancer Epidemiol Biomarkers Prev. 1999 Aug;8(8):659-68  Heavy metals at low levels can suppress key enzymes involved in methylation

30. Raj Patel, M.D. B. Heavy Metals 4. Assess methylation in non-responders (con’t)  Testing to assess methylation: genomic testing urine/serum amino acid analysis  Nutritional Support to open/bypass areas of impairment: Methyl B12 / Cyano B12 TMG (or DMG) Folic/Folinic acid P5P/B6 Reduced Glutathione

31. Raj Patel, M.D. C. Conclusion 1. Aggressive GI support before, during and after antibiotic treatment can greatly assist in reducing complications and improve outcome 2. Heavy metals are ubiquitous. They can compromise immune functioning, promote overgrowth of candida as well as dysbiotic flora. Judicial heavy metal detoxification, once the lyme/coinfection load has been reduced, with appropriate methylation support as needed, may improve outcome and potentially reduce the likelihood of relapse