1 Microbiota GI tract consists of approximately 10 15 /mL - - PDF document

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Sm all I ntestinal Bacterial Overgrow th

The old and the new

Jack A. Di Palm a, M.D. University of South Alabam a Mobile, Alabam a

The “Old” The ”New ”

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Microbiota



GI tract consists of approximately 1015 /mL (Million trillion)



30 genera and over 500 species



Quantity and characteristics of bacteria vary depend

• n anatomic site



Newborns colon colonized within 6 days Anaerobes – B. fragilis Vaginal Birth 60%; Cesarean section 9%



Commensals- No great benefit, no great harm

Bacterial Effects

 Metabolism of androgens and estrogens  Production of nutrients folate and Vitamin K  Production of short chain fatty acids

Helps support integrity of colonic mucosa Conserves energy May play role in regulation of normal enteric flora

 Degradation of protein and urea  Metabolism of drugs  Helps prevent colonization by pathogenic

bacteria

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GI Bacterial Presence

 Stomach < 103/ ml  Jejunum < 103/ ml  Ileum < 108 / ml  Colon < 1010/ ml Health: Gram -positive, aerobic Overgrow th: Gram -negative, anerobic

Physiological Suppression of Overgrow th

 Low gastric pH  Secretory IgA  Defensins/ other Paneth cell products  Gastric and small bowel motility Migrating motor complex during fasting  Ileocecal valve

Sm all Bow el Bacterial Overgrow th

 Malabsorption due to bile acid deconjugation  Low B12 Iron deficiency High folate  Abnormal small bowel mucosa

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Clinical Presentation

 Steatorrhea, weight loss, malabsorption, malnutrition  Metabolic bone disease  Nutritional deficiencies  Low B12, high folate  Diarrhea, bloating cramps

Bacterial Overgrow th

 Accounts for 20-43% of chronic diarrhea in diabetes  Results from UGI surgery  50% of neonatal diarrhea  Probably significant in the elderly  and in I BS and constipation

Prevalence of SI BO*

 Healthy volunteers 20%  Celiac Disease 66%  Neuropathic dysmotility 55%

(Including renal failure)

 Diabetes with diarrhea 43%  Chronic alcohol 90%

* varying by testing method used

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Prevalence of SI BO*

 H2RA 17%  PPI 53%  Chronic diarrhea 33%  Older patients 14.5-15.6%  IBS 10-78%

* varying by testing method used

Clinical Predictors of SI BO

Choung, Alim ent Pharm Ther 2 0 1 1

 675 who had duodenal aspirates  8% positive for SIBO  Associated:

Older age Steatorrhea Narcotic use IBD SB diverticula Pancreatitis

Setting for I BS

 Hypochlorhydria

Gastric disease or drugs

 Immunodeficiency

IgA

 Dysmotility

Diabetes, Scleroderma, Pseudo-obstruction

 Structure

Blind Loop Diverticulosis, stricture, fistula

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The “Old”

 Scleroderma  Steatorrhea/ Malnutrition  Structural disorders  Immunodeficiency  Sprue  Malnutrition

The “New ”

 Diarrhea  Older age  Hypochlorhydria  IBD  Pancreatitis  Colorectal cancer  Fatty liver  Rosacea  Any dysmotility- Disease, IBS, medications, narcotics

W hat are the diagnostic

• ptions?

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Diagnostic Options

 Jejunal aspiration for bacterial colony counts and strain identification  Schilling’s test  Nuclide tests

14C-glycocholic acid 14C-D-xylose 14C-sorbitol

 Hydrogen and methane testing after glucose or lactulose challenge

Lim itations of Culture Testing

 Invasive  Oral flora contamination  Culture transport difficulties  Miss distal overgrowth  Unclear relevance of increased bacterial colonization in the elderly

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H2 Response to Lactulose Challenge

Fasting elevation, early rise Double-peak

Call for Good Testing Methods

 Hydrogen and methane  Standard dose of challenge  Confirm fasting state when fasting elevation found in lactose and fructose testing  Test 30d after antibiotics and before colon cleansing for colonoscopy (or 30d afterwards)

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SI BO test results vary greatly by m ethodology

Positivity criteria % positive tests

Fasting H2 > 10ppm

22%

Fasting H2+ 2X CH4> 10

43%

Early rise H2 > 20ppm < 20min

4%

Early rise H2+ CH4 > 20ppm < 20 min

11%

Rise H2> 20ppm < 90min

37%

Rise H2+ CH4> 20ppm < 90 min

45%

Rise H2 + distinct 2nd peak

17%

Rise H2 + CH4 + 2nd peak

21%

Knudsen, Di Palma ACG 2010

Perform ance Characteristics

• f Breath Tests

 Highly variable  Few careful studies of hydrogen vs. quantitative cultures  Glucose Sensitivity 27-93% Specificity 30-86%  Lactulose Sensitivity 17-89% Specificity 44-100%

Sm artPill Capsule

 Senses and records pH, pressure and temperature data  Wirelessly transmits data to the SmartPill Data Receiver

pH SENSOR PRESSURE SENSOR BATTERIES TRANSMITTER MICROPROCESSOR

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Diagnostic Options

 Jejunal aspiration for bacterial colony counts and strain identification  Schilling’s test  Nuclide tests

14C-glycocholic acid 14C-D-xylose 14C-sorbitol

 Hydrogen and methane testing after glucose

• r lactulose challenge

 Em piric Treatm ent

W hat are the treatm ent options?

Treatm ent for Bacterial Overgrow th

 Correct the underlying condition Surgery Prokinetic agents  Nutrition Lactose-restricted, low residue diet Increase calories Micronutrient supplementation (B12, fat soluble vitamins, trace elements)  Antibiotics

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W hich antibiotic? Antibiotic choices

 Tetracyclines  Amoxicillin/ clavulanic acid  Cephalexin and metronidazole  Trimethoprim/ sulfamethoxazole  Quinolones  Chloramphenicol

Rifaxim in

Di Stefano, Alim ent Pharm acol 2 0 0 0

 Non-absorbable rifamycin derivative  Design: Randomized, blinded  Study subjects: 21 defined by H2 responses to 50g glucose  Methods: Received rifaximin 1200mg or chlortetracycline 1g for 7d  Results: H2 normalized in 70% after rifaximin and 27% after chlortetracycline

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Comparison of Antibiotics

ANTIBIOTIC EFFICACY IN SIBO Flagyl <20% Neomycin 25% Augmentin or Doxycycline 30-40% Rifaximin 70%*

DiStefano M, Aliment Pharm Ther, 2000.

Do prokinetics help? Prokinetics

 Stasis and outflow  No proven benefit of metoclopramide, cisapride  Erythromycin in small reports  Low dose octreotide 50ug daily in scleroderma  Optimism for 5HT3, 5HT4 agents

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W hat about probiotics? Probiotics in SI BO

 Experimental studies in animals suggest that probiotics enhance the mucosal barrier, inhibit bacterial growth, modulate immune system and have anti-inflammatory effects that might benefit patients with SBBO  Human studies suggest benefit with some agents, but no large studies reported yet

Quigley EMM, Gastroenterology 2006 LR Schiller

I rritable Bow el Syndrom e?

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Prevalence of SI BO in I BS based on lactulose breath test

Author Type of Breath test Gases Measured # subjects Prevalence (% ) Galatola, 1995 Xylose H2 80 56 Pimentel, 2000 Lactulose H2/ CH4 202 76 Pimentel, 2003 Lactulose H2/ CH4 111 57-84 Nucera, 2004 Lactulose H2/ CH4 200 75 Nucera, 2005 Lactulose H2/ CH4 98 65 Walters, 2005 Lactulose H2 39 10

Active Treatment 5 10 15 20 25 30 35 40 45 50 1 2 3 4 5 6 7 8 9 10 Placebo Rifaximin

RIFAXIMIN IN IBS

*P=0.02 Mixed Longitudinal Model for 10-week difference

No Active Treatment Percent Global Improvement

Weeks after Rifaximin

Pimentel, et al, Ann Intern Med, Oct., 2006

Sustained relief

Pim ental, TARGET 1 and 2 DDW 2 0 1 0

Rifaxim in Placebo Adequate relief of I BS sym ptom s 40.7% 31.7% Adequate relief of I BS bloating 40.2% 30.3%

Rifaximin 500mg TID, n=1260, 12w response after 2w treatment

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I rritable Bow el Syndrom e

70 60 50 40 30

% answering “yes” at Week 4

80

• B. infantis 1x106
• B. infantis 1X1010
• B. infantis 1X108

placebo

P=0.0118

Global Assessment of Symptom Relief

70 60 50 40 30

% answering “yes” at Week 4

80

• B. infantis 1x106
• B. infantis 1X1010
• B. infantis 1X108

placebo

P=0.0118

Global Assessment of Symptom Relief

N=90 N=92

Whorwell, Am J Gastroenterol 2006 LR Schiller

Does CHO Testing Predict Clinical Response in SI BO?

Long, DiPalm a DDW 2 0 1 5

Lactulose challenge test, n= 100 Clinical Response No criteria 67% One 76% Three 85% Four 77% Overall 73%

Criteria-Fasting elevation, early rise in 2 0 or 6 0 m inutes, second, colon peak

Constipation?

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Methane revisited in IBS subjects

10 20 30 40 50 60 70 80 90 100 H2 CH4 and H2 CH4 % of patients Constipation Diarrhea

Chi-square=16.6, p<0.001 Pimentel, DDS 2003

Rifaxim in and Neom ycin for Methane I BS

Low , Am J Gastro 2 0 1 0

 Design: Retrospective  Subjects: Methane producing IBS patients  I nterventions: Neomycin 500mg BID for 10d, Rifaximin 400mg TID for 10 days,

• r both

Rifaxim in and Neom ycin for Methane I BS

Low , Am J Gastro 2 0 1 0

n Clinical Response Methane Eradication Neomycin 8 63% 33% Rifaximin 39 56% 28%* Both 27 85% 87% *Of these who did not eradicate methane, 66% who had subsequent treatment with both drugs normalized their breath test

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Proton Pum p I nhibitors SI BO and PPI

Lom bardo CG and H 2 0 1 0

PPI n=200, IBS n=200, controls n=50

Take Aw ay Message

 SIBO is clinically significant  Underdiagnosed Elderly Medications (Motility, PPI) Chronic diarrhea IBS Constipation  Diagnostic testing options limited  Antibiotic choices