Small Intestinal Bacterial Overgrowth
Sheila E. Crowe, MD, FRCPC, FACP, FACG, AGAF
Department of Medicine
University of California, San Diego
An Everyday Case in My Clinic• A 29 yr old woman comes to see me for food intolerances and
gluten sensitivity. She reports that she has abdominal bloating and discomfort after eating various foods, abdominal cramping and loose stools ranging from 2 to 3 a day without blood for the past year. Symptoms are relieved by passage of stool. She also complains of fatigue.
• She went on a gluten free diet two months ago. She feels better but now finds that other foods are also leading to bloating, pain and loose stools. She is concerned about food allergies and if she has celiac disease. She also asks if her increasingly restrictive diet will cause nutritional problems. How do you address the patient’s concerns?
What is/are the Cause(s) of the Patient’s Adverse Reactions to Foods?
• Celiac disease• Non-celiac gluten sensitivity (NCGS)• Other food sensitivities• Food allergies• IBS or another FGID• Small intestinal bacterial overgrowth (SIBO)
DeGaetani & Crowe, CGH, 8: 755, 2010Stapel SO, et al, EAACI Task Force Report. Allergy, 63:793, 2008
Small Intestinal Bacterial Overgrowth: What is It?
• Definition of small intestinal bacterial overgrowth (SIBO):– Disruption of the normal small bowel bacterial population; may result in gas,
bloating, flatulence, altered bowel function, or malabsorption
– Widely accepted definition is >105 CFU/ml from the proximal jejunum
– Lower cut off may be appropriate for colonic type bacteria
• Wide array of effects– Direct injury, changes in function/sensation, gut immunology, permeability, and loss
of brush border enzymes
• Clinical manifestations from asymptomatic to bloating to frank malabsorption
The Gut Microflora in Health and GI Disease
• Bacteria exceed the number of host somatic cells by >one order of magnitude– Gut bacterial population ~100 trillion
– 500-1000 different species of bacteria
– 60% of fecal biomass is from bacteria
• Microflora exerts important effects on:– Structure, physiology, biochemistry, immunology, maturation of vasculature, and
gene expression
– Bidirectional effects on gut neuromotor function
– Role in IBD, SIBO, IBS, diverticular disease?
– Differences in microflora reported in IBS vs. healthy controls
Barbara et al. Am J Gastroenterol 2005;100:2560
Normal Intestinal Microflora & pH
Stomach101–103 cfu/ml
Jejunum/Ileum104–107 cfu/ml
Ileal pH~7.6
Colon1011–1012 cfu/mlProximal pH~6.2
Distal pH~7.3
Most Common Bacteria
Anaerobic Genera Aerobic Genera
Bifidobacterium Escherichia
Clostridium Enterococcus
Bacteroides Streptococcus
Eubacterium Klebsiella
Duodenum101–103 cfu/ml
pH ~6.4
O’Hara AM, Shanahan F. EMBO Rep. 2006;7:688-693Kloetzer et al. Gastroenterol 2007;132 (suppl 2):A461
Factors Which Protect Against SIBO
O’Hara AM, Shanahan F. EMBO Rep. 2006;7:688-693, Kloetzer et al. Gastroenterol 2007;132 (suppl 2):A461
Gastric Acid
Migrating Motor Complex (MMC)
IC Valve
Pancreatic & Biliary Secretions
Mucosal Immune System
Disorders Commonly Associated with SIBOGastric acid secretion
Pancreatic enzymes
Motility Disorder Immune
Deficiency
GI Structural Defect
Potent acid suppressive drugs
Atrophic gastritis
Vagotomy
Chronic pancreatitis
Cirrhosis
Cystic fibrosis
Aging
Celiac sprue
Cirrhosis
Crohn’s disease
DM with AN
Pseudo-obstruction
Renal failure
Radiation enteritis
Scleroderma
Immuno- suppressive Rx
CVID
IgA deficiency
Fistula
IC valve resection
Bariatric surgery
JI bypass
Small bowel tics
Surgical blind loop
Maneeratanaporn, Chey. SIBO, 2009
Breath Testing for SIBO
Saad & Chey, Gastroenterol 2007;133:1763
Breath Testing for SIBO in IBS
Adapted from Lin HC. JAMA. 2004;292:852-858
Bacterial Concentration,Organisms/mL
<102
>105
Methods of Detection
Direct Aspiration and Culture
Glucose Breath Test
Lactulose Breath Test
Glucose
Lactulose
77 patients with suspected SIBO underwent: jejunal aspiration culture, gas chromatography of fatty acids,
H2BT— lactulose and – glucose
Test SensitivitySensitivity SpecificitySpecificityChromatography of fatty acids in aspirate 56% 100%
H2 breath test-lactulose 68% 44%
H2 breath test-glucose 62% 83%
Testing for SIBO
Corazza GR, et al. Gastroenterology. 1990;98:302-309.
SIBO: Which test?• Aspiration and Culture
– Gold standard?– Difficult to perform, sampling error, costly
• Deconjugation of bile salts (SeHCAT, 23-seleno-25-homotaurocholic acid)• C14 - xylose breath test• Breath tests
– Lactulose• Sensitive but not specific - Likely leads to overtreatment
– Glucose• Specific but likely not as sensitive - May lead to under treatment
– Bottom line: Best choice of breath test remains to be determined
Saad & Chey, Gastroenterol 2007;133:1763
What is the Evidence to Support the Use of Antibiotics in IBS?
Efficacy of Antibiotics for SIBO
*Di Stefano M, et al. Aliment Pharm Ther. 2000;14(8):551-556.
Antibiotic Efficacy in SIBO
Metronidazole (250 mg TID) <20%
Neomycin (500 mg BID) 25%
Augmentin (250-875 mg TID/BID) or doxycycline (100 mg BID)
30%-40%
Rifaximin (400 mg TID) 70%*
Placebo Control Antibiotic Studies in IBS
Study Treatment % Improved*
Pimentel, 2003
Placebo, n = 44
Neomycin, n = 43
(500 mg, BID)
11%
35%
(p<0.05)
Sharara, 2006
Placebo, n=61
Rifaximin, n = 63
(400 mg, BID)
12%
29%
(p=0.03)
Pimentel, 2006
Placebo, n = 56
Rifaximin, n = 55
(400 mg, TID)
21%
36%
(p=0.026)
Lembo, 2008
Placebo, n = 197
Rifaximin, n = 191
(550 mg, BID)
44 %
52 %
(p=0.03)
Vanner S. Gut.. 2008, 57:1315Lembo A, et al. DDW 2008. Abs T1390Pimentel M, et al. DDW 2010
Placebo, n ~600 32 %Pimentel, 2010 Rifaximin, n ~600 41 % (550 mg, TID) (p=0.0008)
ns
Dose-Finding Study of Rifaximin in SIBO Patients With IBS
Pat
ien
ts (
%)
•No significant differences in
adverse events among 3 groups
Lauritano EC, et al. Aliment Pharmacol Ther. 2005;22(1):31-35.
*p<0.001.†p<0.01.
*
†
n=90
Dosing duration, 7 days
0
20
40
60
80
100
Glucose Breath Test Normalization
600 mg/d
800 mg/d
1200 mg/d
Rifaximin for Non-Constipated IBS:Results from 2 phase III RCTs
* P < 0.0008NC-IBS with mild to moderate symptomsN = 1,260, Target 1 = 623, Target 2 = 637Rifaximin 550 mg tid x 14 daysPatients followed for an additional 10 wks
Pimentel, et al. DDW 2010
0
10
20
30
40
50
AR - IBS symptoms AR - Bloating
Placebo
Rifaximin
%
Res
po
nd
ers
* *
Antibiotics & IBS: The Way Forward?• Reasons for symptom improvement unclear
– SIBO vs. alteration of colonic flora/fermentation?
• Optimal diagnostic test for SIBO unclear– Breath test results may not predict response to antibiotics
• Optimal antibiotic therapy unclear
• Benefits appear transient
– How can we increase the durability of response?
– How best to treat recurrent symptoms?
• Potential consequences of repeated, widespread antibiotic use?
Chey. AGA Perspectives 2009;4:5-8
Breath Test Recurrence After Treatment with Rifaximin
%Positive
LBT
Lauritano, et al. Am J Gastroenterol 2008; 103:2031
13
0
10
20
30
40
50
3 9
46
28
6Months of Follow-up61 consecutive IBS pts
Rifaximin 1.2 grams/day x 7 dPositive LBT associated with pain,bloating, flatus, diarrhea
What are the Options to Reduce IBS Symptom Relapse?
• Prokinetics• Probiotics• Rotating antibiotics• Dietary manipulation
– Low FODMAP– Gluten-free– Low fat– Others?
Brandtzaeg, Nat Rev Gastroenterol Hepatol, 7: 380-400, 2010
Biological Variables that Influence the Developing Immunophenotype of an Infant
Adverse Reactions to Food (ARF)
• Food allergy or hypersensitivity:– Immediate hypersensitivity– Allergic eosinophilic
gastroenteritis– Food protein induced
enterocolitis syndromes (FPIES)– Celiac disease
• Food sensitivities or intolerances (non-immune):– Food toxicity– Pharmacological– Metabolic– Physiological– Psychological– Idiosyncratic
Bischoff & Crowe, Gastroenterology, 128: 1089, 2005Leung & Crowe, Food intolerance and food allergy.
In: The Gastrointestinal Nutrition Desk Reference, 2011
Physiological Food Reactions
• Large volume meals (overeating) cause distension, promote regurgitation
• Fatty foods delay gastric emptying, alter motility• Legumes, cruciferous vegetables, garlic, onions, etc,
may lead to flatus (farts)• Non-absorbable or poorly absorbed sugars and
carbohydrates can cause diarrhea, bloating, flatulence, etc
• However, intestinal gas is NORMAL (14 X/day)
Summary of SIBO • The microbiome plays a critical role in normal development
and function of the human GI tract• Gastric acid, pancreaticobiliary secretions, the MMC, gut
immune system, permeability, and IC valve protect against the development of SIBO
• SIBO presents a clinical spectrum of disease• Differences in the distribution & composition of gut bacteria
make diagnosis difficult– All available tests have pros and cons
• Changes in gut flora may lead to IBS symptoms• Antibiotics offer short term benefits to a subset of IBS
sufferers
Between Celiac Disease & IBS:The “No Man’s Land” of Gluten Sensitivity
Summary: Food-Induced Symptoms in IBS• Food-induced symptoms are common in IBS and also
common of other FGID• CD can coexist with or mimic IBS, other FGID• Increased reporting of NCGS, actual prevalence? • Elimination of gluten OR wheat and other carbohydrates
(FODMAPs) can benefit IBS• Few studies to support a proven benefit
• SIBO may play a role in IBS and other FGID • How gluten and other food sensitivities contribute to FGID
remains unclear but multiple mechanisms are implicated • Additional research is needed!