small intestinal bacterial overgrowth -...
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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