Small Intestinal Bacterial OvergrowthThe old and the new

Jack A. Di Palma, M.D. University of South AlabamaMobile, Alabama

The “Old”

The ”New”

Microbiota GI tract consists of approximately 1015 /mL

(Million trillion) 30 genera and over 500 species Quantity and characteristics of bacteria vary depend

on 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 mucosaConserves energyMay play role in regulation of normal enteric flora

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

bacteria

GI Bacterial Presence

Stomach < 103/ml Jejunum < 103/ml Ileum < 108 /ml Colon < 1010/mlHealth:

Gram-positive, aerobicOvergrowth:

Gram-negative, anerobic

Physiological Suppression of Overgrowth Low gastric pH Secretory IgA Defensins/ other Paneth cell products Gastric and small bowel motility

Migrating motor complex during fasting

Ileocecal valve

Small Bowel Bacterial Overgrowth

Malabsorption due to bile acid deconjugation

Low B12Iron deficiencyHigh folate

Abnormal small bowel mucosa

Clinical Presentation Steatorrhea, weight loss,

malabsorption, malnutrition Metabolic bone disease Nutritional deficiencies Low B12, high folate Diarrhea, bloating cramps

Bacterial Overgrowth

Accounts for 20-43% of chronic diarrhea in diabetes

Results from UGI surgery 50% of neonatal diarrhea Probably significant in the elderly and in IBS and constipation

Prevalence of SIBO*

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

(Including renal failure)

Diabetes with diarrhea 43% Chronic alcohol 90%

*varying by testing method used

Prevalence of SIBO*

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

*varying by testing method used

Clinical Predictors of SIBOChoung, Aliment Pharm Ther 2011

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

Older age SteatorrheaNarcotic use IBDSB diverticula Pancreatitis

Setting for IBS Hypochlorhydria

Gastric disease or drugs Immunodeficiency

IgA Dysmotility

Diabetes, Scleroderma, Pseudo-obstruction Structure

Blind Loop

Diverticulosis, stricture, fistula

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

What are the diagnostic options?

Diagnostic Options Jejunal aspiration for bacterial colony

counts and strain identification Schilling’s test Nuclide tests

14C-glycocholic acid14C-D-xylose14C-sorbitol

Hydrogen and methane testing after glucose or lactulose challenge

Limitations of Culture Testing

Invasive Oral flora contamination Culture transport difficulties Miss distal overgrowth Unclear relevance of increased

bacterial colonization in the elderly

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 beforecolon cleansing for colonoscopy (or 30d afterwards)

SIBO test results vary greatly by methodology

Positivity criteria % positive testsFasting 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

Performance Characteristics of Breath Tests Highly variable Few careful studies of hydrogen vs.

quantitative cultures Glucose

Sensitivity 27-93%Specificity 30-86%

LactuloseSensitivity 17-89%Specificity 44-100%

SmartPill Capsule

Senses and records pH, pressure and temperature data

Wirelessly transmits data to the SmartPill Data Receiver

pH SENSOR

PRESSURE SENSOR

BATTERIES

TRANSMITTER

MICROPROCESSOR

Diagnostic Options Jejunal aspiration for bacterial colony counts

and strain identification Schilling’s test Nuclide tests

14C-glycocholic acid14C-D-xylose14C-sorbitol

Hydrogen and methane testing after glucose or lactulose challenge

Empiric Treatment

What are the treatment options?

Treatment for Bacterial Overgrowth

Correct the underlying conditionSurgeryProkinetic agents

NutritionLactose-restricted, low residue dietIncrease caloriesMicronutrient supplementation(B12, fat soluble vitamins, trace elements)

Antibiotics

Which antibiotic?

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

RifaximinDi Stefano, Aliment Pharmacol 2000

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

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

What about probiotics?

Probiotics in SIBO 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

Irritable Bowel Syndrome?

Prevalence of SIBO in IBSbased on lactulose breath test

Author Type of Breath test

GasesMeasured

# 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

Act

ive

Trea

tmen

t

05

101520253035404550

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

Per

cent

Glo

bal I

mpr

ovem

ent

Weeks after Rifaximin

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

Sustained reliefPimental, TARGET 1 and 2 DDW 2010

Rifaximin Placebo

Adequate relief of IBS symptoms

40.7% 31.7%

Adequate relief of IBS bloating

40.2% 30.3%

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

Irritable Bowel Syndrome

70

60

50

40

30% a

nsw

erin

g “y

es”

at W

eek

4 80

B. infantis 1x106B. infantis 1X1010 B. infantis 1X108 placebo

P=0.0118

Global Assessment of Symptom Relief

70

60

50

40

30% a

nsw

erin

g “y

es”

at W

eek

4 80

B. infantis 1x106B. 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 SIBO?Long, DiPalma DDW 2015

Lactulose challenge test, n=100Clinical Response

No criteria 67%One 76%Three 85%Four 77%Overall 73%Criteria-Fasting elevation, early rise in 20 or 60 minutes, second, colon peak

Constipation?

Methane revisited in IBS subjects

0102030405060708090

100

H2 CH4 and H2 CH4

% o

f pat

ient

s

ConstipationDiarrhea

Chi-square=16.6, p<0.001

Pimentel, DDS 2003

Rifaximin and Neomycin for Methane IBS Low, Am J Gastro 2010

Design:Retrospective

Subjects:Methane producing IBS patients

Interventions:Neomycin 500mg BID for 10d,Rifaximin 400mg TID for 10 days,or both

Rifaximin and Neomycin for Methane IBS Low, Am J Gastro 2010

nClinical

ResponseMethane

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

Proton Pump Inhibitors

SIBO and PPILombardo CG and H 2010

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

Take Away Message SIBO is clinically significant Underdiagnosed

ElderlyMedications (Motility, PPI)Chronic diarrhea IBSConstipation

Diagnostic testing options limited Antibiotic choices