SIBO Disordered Gut Microbiome Functional Medicine Discussion Group

SIBO & Disordered Gut Microbiome Functional Medicine Discussion Group Modulator Dr. Ben Weitz DO

Farshid Rahbar M. D. , FACP, ABIHM Founder and Practicing Physician “Combining Traditional Approaches with Complementary and Alternative Medicine”.

Presentation Objectives Goals of presentation: ● Introduction to Microbiome and its Modulation of Health. ● Introduction to the increasing importance of SIBO: SIBO Pathophysiology. ● SIBO Breath testing for diagnosis & management. ● SIBO Presentations and pattern recognition. ● SIBO Clinical associations with other illnesses. ● SIBO Principles of management. ●

Microbiota and Microbiome Are Not just limited to the gut ! • • • - Urogenital microbiome - Oral microbiome - Lung microbiome - Skin microbiome - Sinus cavity microbiome and more…

The “Blind Spot” Our Observations: Low grade chronic sinusitis, bacterial or fungal, may contribute to persistent or recurrent gut dysbiosis. Blind Spot Sinus es Hypothesis: Low grade sinus inflammation and post nasal discharge may find access to the upper GI system-especially if associated with hypochlorhydria. Therefore, the sinuses cavities microbiome may have an intricate relationship with gut microbiome and may affect each other. Low Stomach Acid Gut Dysbiosis Integr Med (Encinitas). 2016 Jun; 15(3): 44 -54. Chronic Rhinosinusitis and Irritable Bowel Syndrome: A Case Report. Kogan M 1, Castillo CC 1, Barber MS 1. Illustration adapted from the National Cancer Institute “swallowing difficulties in the elderly”

The ‘Downstream Problem’ 40 yr. female - Presented with Multiple symptoms: Indigestion Occasional diarrhea Irregular bowels Abdominal distention Flatulence Malaise & Fatigue Dyspepsia Nausea

The ‘Downstream Problem’ Breath test: Methane Producer.

Heidelberg Gastric p. H Testing Findings suggestive of Bile Reflux and Pyloric Insufficiency

Patient Case 1 - The ‘Downstream Problem’ Stool Test:

Patient Case 1 - The ‘Downstream Problem’ Endoscopy: The following day Bile in the stomach

Microbiota and Microbiome The Cell Number and Genetic Ratios to Human Cells GI microbiome: ● - At least 10 times as many cells when compared to human cells ● - With at least 1000 times the genetic content! A separate organ of its own.

Interplay of Microbiomes with Host and Each Other: Not entirely independent ecosystems! ● Commonly discussed: -- Microbes and their hosts exerting pressure on one another. ● Less commonly discussed: -- One microbiome ecosystem affecting another. EXAMPLES: ➢ Gut -- affecting vaginal flora. ➢ Nose and sinus microbiota -- affecting gut dysbiosis. - MARCo. NS – common in our SIBO patients.

Interplay of Microbiomes with Host and Each Other: PCR technology generally is expressed at the level of Phylum. The Human Intestinal Microbiome in Health and Disease Susan V. Lynch, Ph. D. , and Oluf Pedersen, M. D. , D. M. Sc. N Engl J Med 2016; 375: 2369 -2379 December 15, 2016 DOI: 10. 1056/NEJMra 1600266

Healthy Adult Gut Microbiome Bacteroidetes Dominating population Firmicutes Dominating population Physiologic ratio of Firmicutes to Bacteroidetes Actinobacteria smaller population Proteobacteria smaller population Verrucomicrobia smaller population Archaeota Methanogenic archaea ➢ ➢ Fusobacteria Archaea have no cell nucleus. Primarily Methano. BREVIBacter Smithii No other membrane-bound organelles in their cells. Other Methanogens smaller population Eucarya Predominantly yeast Bacteriophages ➢ A virus that infects and replicates within a bacterium. ➢ Bacteriophages are ubiquitous viruses, found wherever bacteria exist. ➢ It’s estimated there are more than 1031 bacteriophages on the planet! ➢ Found in soil or the intestines of humans and animals.

Microbes have Potential Associations with: Autoimmunity Body Weight Inflammation IBS Autism Spectrum Disorder Metabolic disorders Diversity of Gut Microbiota Oncologic risk Immune Modulation

Microbes & Potential Associations EXAMPLE: Methano. BREVIBacter smithii ● Higher levels are linked to constipation. High levels of Methanogens are also seen in: Ø colon cancer Ø colonic polyposis Ø ulcerative colitis Ø diverticular disease

Microbes & Potential Associations In our Experience: High methane is commonly seen in patients with: ➢Immune dysregulation. ➢Immune suppression associated with Vector Borne Illness (borrelia, babesia, bartonella).

The Gut Microbiome A vulnerable and dynamic ecosystem Affected by: ● - diet, e. g. high protein vs complex carbs and fiber. ● - physical activity - favorable for mild to moderate. ● high intensity physical activity- unfavorable ● - antibiotics in food or medications ● - hormones, e. g. estrogen, progesterone. . ● - stress, CRF, cortisol ● - immune dysregulations from “stealth infections” npj Biofilms and Microbiomes (2016) 2, 16003; doi: 10. 1038/npjbiofilms. 2016. 3; published online 4 May 2016 - Too much exercise can cause acute, chronic GI issues Costa RJS, et al. Aliment Pharmacol Ther. 2017; doi: 10. 1111/apt. 14157.

Gut Microbiome– A vulnerable and dynamic ecosystem Affected by: ● - early ● ● life trauma, unfavorable - animals, pets favorable - prebiotics, may combat obesity - heavy metals, mercury, lead, cadmium. . . - xenobiotics (such as glyphosate) Environmental contaminants from various chemical families have been shown to alter the composition and/or the metabolic activity of the gastrointestinal bacteria. Prebiotic fiber supplement reduces body fat in overweight children by altering gut microbiome - Nicolucci AC, et al. Gastroenterol. 2017; doi: 10. 1053/j. gastro. 2017. 055.

MICROBIOTA AND DISEASE ASSOCIATIONS Microbiome-host interactions are well established: ü Enteric infections and infestations ü Helicobacter Pylori ü Antibiotic – associated diarrhea ü Clostridium Difficile-associated disease (CDAD) ü Small Intestinal Bacterial Overgrowth ü Complication of Liver Disease ü Portal systemic Encephalopathy ü Spontaneous Bacterial Peritonitis ü Biliary and Pancreatic Sepsis The Gut Microbiome, PRACTICAL GASTROENTEROLOGY JULY 2015, pages 14 -35

MICROBIOTA AND DISEASE ASSOCIATIONS Microbiota and Host-Microbiome interactions – postulated ➢ Functional Dyspepsia (FD) ➢ Irritable Bowel Syndrome (IBS) ➢ Diverticulitis ➢ Celiac Disease ➢ Necrotizing Enterocolitis (NEC) ➢ Non-Alcoholic Fatty Liver Disease (NAFLD) ➢ Inflammatory Bowel Disease (IBD) ➢ Alcoholic Liver Disease ➢ Ulcerative Colitis (UC) ➢ Intestinal Failure – Associated Liver Disease ➢ Crohn’s Disease ➢ Primary Sclerosing Cholangitis (PSC) ➢ Pouchitis ➢ Primary Biliary Cirrhosis ➢ Pancreatitis The Gut Microbiome, PRACTICAL GASTROENTEROLOGY JULY 2015, pages 14 -35

Disordered Microbiome: SIBO - Small Intestinal Bacterial Overgrowth Defined as a quantitative overgrowth of bacteria in small bowel. ● A form of dysbiosis Normal bacterial load from proximal small bowel to colon: Duodenum Jejunum Colon 1000 100, 000 13, 000, 000

SIBO Definition Traditional Diagnosis: Duodenal aspirate and culture technology. ● threshold of >1000 c. f. u. /ml for the definition of SIBO. ● culture techniques are not fully satisfactory. 3 Evolving Diagnosis: PCR technology. ● As little as 500 bacterial count may be abnormal in duodenum Am J Gastroenterol 2017; 112: 775– 784; doi: 10. 1038/ajg. 2017. 46; published online 21 March 2017 Hydrogen and Methane-Based Breath Testing in Gastrointestinal Disorders: The North American Consensus

SIBO – Breath Test Basis for Diagnosis: gases produced in the intestine which diffuse into the systemic circulation and are expired through the lungs. The breath test relies on the measurement of Fermentation. MICROBE Output: SUBSTRATE OUTPUT Gas, Energy, Heat, Alcohol, Water, Organic Compounds

Gas content in healthy subjects: Healthy subjects have an average of about 100 ml of intestinal gas. (Normal range 30 - 200 ml) Gas Composition MAIN Gases: LESSER Gases: )H 2), Hydrogen – The main component. Oxygen (O 2), (CO 2), Carbon Dioxide - quality measure Nitrogen (N 2), (CH 4), Methane - Clinically relevant Hydrogen sulfide (H 2 S), Other gases: indole, skatole and ammonia (NH 3)

The principle behind breath testing Clinical Implications – ● H 2 and CH 4 are exclusively produced via microbial (bacterial) fermentation in the gut. ● Hydrogen Sulfide may have relevance in patients with negative H 2 and CH 4 but currently there is little research, with no commercially standardized way for testing.

SIBO Preparation The day before the test: • Avoid fermentable foods, (complex carbohydrates). • 12 hour fast required, water OK.

The SIBO Breath test

Indications for SIBO Breath Test Abdominal Pain Abnormal Antibody, Ocludin, LPS. Acne Rosacea Altered Bowel Habits Autoimmune Disease Bad Breath Bile Gastritis Bloating Celiac Disease Chronic Fatigue Constipation Cramps Diarrhea Elevated CRP Excess Gas Failure to Thrive Food Sensitivities IBD Interstitial Cystitis Itching Joint Pains Known Bacterial Overgrowth “Leaky Gut” Malabsorption Nausea vomiting, unexplained Pernicious Anemia Previously Abnormal Breath Test Rash, Hives Restless Leg Syndrome Tick Borne illness

Hypothalamus sends TRH to pituitary gland Pituitary sends TSH to thyroid gland TSH stimulates TPO to use iodine to create T 4 and T 3 hormones 7% is T 3 93% is T 4 60% of T 4 is converted to T 3 in the liver Additional 20% T 3 activated in the GUT Adopted from Dr. Kharrazian ‘Why do I still have thyroid symptoms’

Main SIBO symptoms The Classical Text Book: Abdominal Pain Bloating Constipation Diarrhea IBS type symptoms

Conditions That Predispose Toward the Development of Small Intestine Bacterial Overgrowth Achlorhydria Motor abnormalities Resection of ileocecal valve Alcoholism Systemic and intestinal immune deficiency states Structural abnormalities Surgical loops Duodenal or jejunal diverticula Partial obstruction of small bowel Large small Intestine diverticulosis Systemic diseases Scleroderma Intestinal pseudo-obstruction Diabetic enteropathy Vagotomy Abnormal communication between colon and small bowel Fistulas between colon and small bowel Volume 3, Number 3 • May 2014 • www. gahmj. com GLOBAL ADVANCES IN HEALTH AND MEDICINE Level of evidence: Level C

The Evolution of a “Concept” Patients with “chronic”/persistent Tick Borne Diseases (TBD) presenting PRIMARILY with Gastrointestinal Manifestations. Common Tick Borne Diseases: ● - Borreliosis, HME, HGA, Babesia, Bartonella

Initial GI presentations in TBD Top 10 Symptoms: 1. Bloating/Gas 76% 2. Tire easy/weakness 65% 3. Anxiety 50% 4. Abdominal Pain 48% 5. Sleeplessness 44% 6. Constipation 42% 7. Food Intolerance 42% 8. Irregular Bowel Movements 37% 9. Weight Loss / Weight Gain 36% 10. Joint Pain 34%

What Clinical Scenarios to Watch For – The Red Flags SIBO: Small Intestinal Bacterial Overgrowth PARTICULARLY WHEN: - Very abnormal results with high hydrogen - Very abnormal with high methane - Recurrent SIBO - Intractable SIBO - Not responding to traditional treatments/hard to treat/longer treatment required - Lack of history of “food poisoning”/gastroenteritis, a risk factor for SIBO - Lack of anatomical abnormality

Think of This…. . HIGH METHANE SIBO LYME & TBD

Basis For Diagnosis 1. Strong Clinical History 2. Definite Lab Results ● ● ● Positive Western Blot Meeting CDC Criteria Positive Borrelia Culture (polyclonal/monoclonal) Positive PCR for Borrelia Positive Elispot for Borrelia Combination of above Or a borderline abnormal result PLUS: ● Definite co-infection of HME, HGA, Babesia, Bartonella

What Clinical Scenarios to Watch For – The Red Flags In our experience…. . ● New patient, no prior history of Lyme treatment…. …. . approximately 65% had SIBO on breath testing ● Previously treated for Lyme…. . approximately 15% had SIBO on breath testing

Types of SIBO HYDROGEN PRODUCER METHANE PRODUCER COMBINATION OF BOTH HYDROGEN SULFIDE PRODUCER

Sample Normal Curve Hydrogen Methane Breath Test Report 16 PPM 12 ppm H 2 ppm CH 4 8 4 0 0 20 40 60 Time (min) 80 100 120

Sample Abnormal Hydrogen Curve Hydrogen Methane Breath Test Report 180 135 PPM ppm H 2 ppm CH 4 90 45 0 0 20 40 60 80 100 Time (min) 120 140 160 180

Sample Abnormal Methane Curve Hydrogen Methane Breath Test Report 90 PPM ppm H 2 ppm CH 4 45 0 0 20 40 60 Time (min) 80 100 120

Sample Abnormal Methane & Hydrogen Curve Hydrogen Methane Breath Test Report 180 135 PPM ppm H 2 ppm CH 4 90 45 0 0 20 40 60 Time (min) 80 100 120

Sample Abnormal Patient MIN ppm H 2 ppm CH 4 H 2+CH 4 H 2 S % OF CO 2 IN BREATH 0 59 12 71 - 5. 50% 20 56 9 65 - 5. 60% 40 84 8 92 - 5. 30% 60 118 12 130 - 1. 90% 80 118 12 130 - 1. 90% 100 120 10 130 - 4. 60% 120 161 14 175 - 5. 20%

Hydrogen Sulfide The area of research is evolving. Not readily commercially available. Most patients are >50, with diarrhea and urgency, and a Hydrogen Sulfide gas level of 1. 2 ppm. Ref: Portland 2017 SIBO presentation, courtesy adaptation of Dr Pimentel slide.

Your Most Challenging Patient: The “Bloater” Who Doesn’t Respond ● Patient has completed SIBO treatment ● Patient has received anti-fungal treatment ● Patient follows excellent eating habits ● Patient follows restricted diet ● Patient avoids stress ● Patient is taking HCL & Enzymes …. . and yet continues with significant bloating and visible distention of the abdomen….

Your Most Challenging Patient: The “Bloater” Who Doesn’t Respond

Interpreting the Breath Test What is a positive test? Hydrogen: ● Baseline >20 ppm. (Baseline <10 ppm is normal). ● Rate of rise >20 ppm from baseline in 90 minutes. Based on 2016 SIBO consensus conference criteria.

Interpreting the Breath Test What is a positive test? Hydrogen Variation: where clinical correlation is needed: ● When baseline is between 10 -20 ppm. (This my be SIBO or improper diet the day before). ● When rate of rise is between 15 – 20 points. ● The rise occurs, but it is between 90 – 120 minutes. ● Zero trace of Hydrogen and Methane ● This usually suggests H 2 S production.

Interpreting the Breath Test What is a positive test? Methane: ● Methane <3 ● is ideal and normal. A methane level between 3 – 10 is considered normal by the 2016 consensus SIBO conference criteria. ● Methane >10 ppm is abnormal. Based on 2016 SIBO consensus conference criteria.

Interpreting the Breath Test What is a positive test? Methane Variation: where clinical correlation is needed: ● baseline between 3 – 10 ppm. . ● Zero trace of Hydrogen and Methane ● This usually suggests H 2 S production.

Proposed SIBO Treatments Elemental Diet • The ability of an elemental diet to normalize the LBT was determined for days 15 and 21. • Of the 93 subjects available for analysis, 74(80%) had a normal LBT on day 15 of the elemental diet. • When those who continued to day 21 were included, five additional patients normalized the breath test (85%). Level of evidence: Level B.

Proposed SIBO Treatments Antibiotics – in general “A variety of antibiotics have been reported to be affective in SIBO but little evidence exists to favor one agent, over another. Antibiotics that have been reported to be effective include: • • Metronidazole Amoxicillin – Clavolanate Ciprofloxacin Tetracycline Cotrimoxazole Norlfloxin Neomycin Rifaxamin” Gastrointestinal and Liver Disease – Sleisenger and Fordtran’s 9 th Edition. Level of evidence: Level B

Antibiotic regimens used for SIBO 1. Shah SC, Day LW, Somsouk M, Sewell JL. Meta-analysis: antibiotic therapy for small intestinal bacterial overgrowth. Aliment Pharmacol Ther. 2013; 38(8): 925 -34. 2. Volume 3, Number 3 • May 2014 • www. gahmj. com – Mullins et. al 2014

Proposed SIBO Treatments Rifaxamin Consensus Bottom line for 2017 “We suggest antibiotic treatment for SIBO with rifaximin (1650 mg/day for 7 to 10 days). However, a major limitation to the use of rifaximin is the high cost. Adequate antimicrobial coverage can also be achieved with other antibiotic combinations. ” In daily practice most physicians use 14 days of treatment. Adopted from Up. To. Date, Author Mark Pimentel MD et. al. Level of evidence: Level C

Combined antibiotic therapy for Methane positive SIBO A combination of rifaximin and neomycin is most effective in treating irritable bowel syndrome patients with methane on lactulose breath test. • Rifaxamin + Neomycin =87% clinical response. • Neomycin only =33% • Rifaxamin only = 28% Of the patients who did not eliminate the methane with only rifaximin treatment, 66% of those who subsequently used the rifaximin and neomycin treatment were able to normalize their breath test. J Clin Gastroenterol. 2010 Sep; 44(8): 547 -50. doi: 10. 1097/MCG. 0 b 013 e 3181 c 64 c 90. Level of evidence: Level B

Proposed SIBO Treatments HERBAL PROTOCOLS Herbal Therapy Is Equivalent to Rifaximin for the Treatment of Small Intestinal Bacterial Overgrowth Victor Chedid, MD, United States; Sameer Dhalla, MD, United States; John O. Clarke, MD, United States; Bani Chander Roland, MD, United States; Kerry B. Dunbar, MD, United States; Joyce Koh, MD, United States; Edmundo Justino, MD, United States; Eric Tomakin, RN, United States; Gerard E. Mullin, MD, Volume 3, Number 3 • May 2014 • www. gahmj. com GLOBAL ADVANCES IN HEALTH AND MEDICINE Level of evidence: Level B

HERBAL PROTOCOLS Volume 3, Number 3 • May 2014 • www. gahmj. com GLOBAL ADVANCES IN HEALTH AND MEDICINE Level of evidence: Level B

Protective Factors That Protect Against the Development of Small Intestine Bacterial Overgrowth Gastric acid Pancreatic enzymes Bile acids Cholecystectomy Motility Migrating motor complex Biofilm Secretory immunoglobulin A Volume 3, Number 3 • May 2014 • www. gahmj. com GLOBAL ADVANCES IN HEALTH AND MEDICINE Level of evidence: Level C

Proposed Treatments SIBO Treatment “Toolbox” Keep stress low No food 2 hours before sleep Slow eating & chew well Betaine HCL Pancreatic Enzymes Oral Immunoglobulin Ox Bile Zinc Carnosine Level of evidence: Level C – Expert opinion

Proposed SIBO Treatments Promotility agents: AFTER the SIBO treatment, to stimulate the Motor Migratory Complex (MMC) and prevent recurrence of SIBO. Example: Low dose Erythromycin 50 mg – 100 mg PO HS Low-dose nocturnal tegaserod or erythromycin delays symptom recurrence after treatment of irritable bowel syndrome based on presumed bacterial overgrowth. Pimentel M 1, Morales W, Lezcano S, Sun-Chuan D, Low K, Yang J. Gastroenterol Hepatol (N Y). 2009 Jun; 5(6): 435 -42. Level of evidence: Level B

Proposed Diet to Prevent SIBO after Treatment A variety of Low Fermentation diets have been proposed. No formal comparison of one to another. A good reference is put forward by Dr. Allison Siebecker ND. http: //www. siboinfo. com/uploads/5/4/8/4/5484269/sibo_specific_diet_food_guide_sept_2014. pdf Level of evidence: Level C – Expert opinion

Take Home Message SIBO is a common clinical finding in a variety of patients with chronic inflammatory conditions.

Take Home Message SIBO may be the primary underlying cause. Or. . SIBO, particularly with high methane, may be a biological marker of underlying immune dysregulation, such as those seen in vector borne diseases.

Take Home Message Methane is usually associated with IBS -C. Hydrogen is associated with IBS –D.

Take Home Message Patients with… abdominal pain bloating constipation diarrhea food sensitivities chronic inflammatory conditions - should have breath testing to look for evidence of SIBO!

Take Home Message A negative SIBO test in a patient that has bloating and IBS symptoms – may indicate presence of SIFO - Clinical picture of yeast.

Take Home Message Microbiome Restoration Methods MEDICAL: Fecal Transplant FMT PREBIOTICS: Foods, Supplements PROBIOTICS: Foods, Supplements EXERCISE: Increasing vagal tone and….

Take Home Message Microbiome Restoration THE WET KISS - The Probiotics Exchange Technique!

Case Review The ‘Blind Spot’

The ‘Blind Spot’ 35 year male, Presented with Multiple symptoms: Excessive Burping Sense of Illness after eating Abdominal distention Post Nasal Drip Flatulence Brain Fog Peripheral Neuropathy Sweet Cravings This patient was already taking 2 natural herbal products, that if he did without, he explained would feel ‘very bad’.

The ‘Blind Spot’ Microbiology Dx Nasal Swab

The ‘Blind Spot’ Heidelberg Gastric p. H Test: Findings suggestive of Bile Reflux and Pyloric Insufficiency

The ‘Blind Spot’ Breath test Hydrogen Producer

The ‘Blind Spot’ Multiple Severe Food Sensitivities

The ‘Blind Spot’ Nil Gluten Sensitivities

The ‘Blind Spot’ Stool test – Yeast Enteritis, and Klebsiella pneumoniae positive

The ‘Blind Spot’ Urine Mycotoxin – Quadruple Positive Gliotoxin Derivative – 18 times normal limit

The ‘Blind Spot’ IGG Subclass 4 and Natural Killer Cells - Low Elevated C 4 A

The ‘Blind Spot’ Multiple “Companion infections”

The ‘Blind Spot’ Lyme Screening

Case Review ‘Hypochlorhydria’

‘Hypochlorhydria’ 39 year old female, referred by a Gastroenterologist. Presented with dyspeptic symptoms Requiring up to 12 betaine per meal to ‘digest food’

‘Hypochlorhydria’

‘Hypochlorhydria’ Normal

‘Hypochlorhydria’

‘Hypochlorhydria’ Bartonella Screen Borderline Abn – But Highly Suspicious because…

Patient Case 7 – ‘Hypochlorhydria’

‘Hypochlorhydria’

‘Hypochlorhydria’

‘Hypochlorhydria’

‘Hypochlorhydria’

‘Hypochlorhydria’ Treated with Ozone treatment Ultraviolet Light Therapy (UVL Rx) Patient felt significantly better with alternative approach. Need for Betaine dropped to 2 per meal within 1 month of treatment.

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