1. Small Intestinal Bacterial Overgrowth
Sheila E. Crowe, MD, FRCPC, FACP, FACG, AGAF
Department of Medicine
University of California, San Diego

2. 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?

3. 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, 2010
Stapel SO, et al, EAACI Task Force Report. Allergy, 63:793, 2008

4. 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
SIBO is a condition we are all familiar with and treat with antibiotics
- Definition: Increase (ie, disruption) in normal concentration of bacteria in small intestine
- Symptoms include gas, bloating, flatulence, altered bowel function, and nutrient malabsorption – similar to the symptoms of IBS
This connection between IBS and SIBO is not necessarily new. The 6th edition of Sleisenger & Fordtran quotes data that dysmotility disorders (IBS, gastroparesis, pancreatitis) account for up to 90% of individuals with SIBO and should be considered in patients with these conditions
Sleisenger & Fordtran’s. Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management;

5. 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
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

6. Normal Intestinal Microflora & pH
Duodenum
101–103 cfu/ml
pH ~6.4
Stomach
101–103 cfu/ml
Most Common Bacteria
Anaerobic Genera
Aerobic Genera
Bifidobacterium
Escherichia
Clostridium
Enterococcus
Bacteroides
Streptococcus
Eubacterium
Klebsiella
Colon
1011–1012 cfu/ml
Proximal pH~6.2
Distal pH~7.3
Jejunum/Ileum
104–107 cfu/ml
Ileal pH~7.6
O’Hara AM, Shanahan F. EMBO Rep. 2006;7:
Kloetzer et al. Gastroenterol 2007;132 (suppl 2):A461 6

7. Factors Which Protect Against SIBO
Gastric Acid
Migrating Motor Complex (MMC)
IC Valve
Pancreatic &
Biliary Secretions
Mucosal Immune System
O’Hara AM, Shanahan F. EMBO Rep. 2006;7: , Kloetzer et al. Gastroenterol 2007;132 (suppl 2):A461 7

8. Disorders Commonly Associated with SIBO
Gastric 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
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

9. Breath Testing for SIBO Saad & Chey, Gastroenterol 2007;133:1763

10. Breath Testing for SIBO in IBS
Methods of Detection
Direct Aspiration and Culture
Glucose Breath Test
Lactulose Breath Test
Glucose
Lactulose
Bacterial Concentration, Organisms/mL
<102
>105
Adapted from Lin HC. JAMA. 2004;292: 10

11. 77 patients with suspected SIBO underwent:
Testing for SIBO
77 patients with suspected SIBO underwent:
jejunal aspiration culture, gas chromatography of fatty acids, H2BT— lactulose and – glucose
Test
Sensitivity
Specificity
Chromatography of fatty acids in aspirate
56%
100%
H2 breath test-lactulose
68%
44%
H2 breath test-glucose
62%
83%
Corazza GR, et al. Gastroenterology. 1990;98:

12. Saad & Chey, Gastroenterol 2007;133:1763
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

13. What is the Evidence to Support the Use of Antibiotics in IBS?

14. Efficacy of Antibiotics for SIBO
Efficacy in SIBO
Metronidazole (250 mg TID)
<20%
Neomycin (500 mg BID)
25%
Augmentin ( mg TID/BID) or doxycycline (100 mg BID)
30%-40%
Rifaximin (400 mg TID)
70%*
Summary of published studies evaluating therapeutic efficacy of antibiotics in eradication of SIBO
- Di Stefano et al studied the efficacy of rifaximin compared to chlortetracycline in 21 patients affected by SIBO
Fasting, peak, and total H2 excretion were measured after ingestion of 50 g glucose
10 patients were administered rifaximin 1200 mg/day (400 mg TID) and 11 patients were administered chlortetracycline 1 g/day (333 mg TID) for 7 days
H2 breath testing was normalized in 70% of patients receiving rifaximin compared to 27% of patients receiving chlortetracycline (p<0.01)
Improvement in symptoms was significantly higher in patients treated with rifaximin (mean cumulative score, p<0.01)
Findings from this study suggest rifaximin may be an appropriate and more effective therapy in treatment of SIBO
*Di Stefano M, et al. Aliment Pharm Ther. 2000;14(8):

15. 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 %
Placebo, n ~ %
Pimentel, Rifaximin, n ~ %
(550 mg, TID) (p=0.0008)
Vanner S. Gut , 57:1315
Lembo A, et al. DDW Abs T1390
Pimentel M, et al. DDW 2010

16. Dose-Finding Study of Rifaximin in SIBO Patients With IBS20 40 60 80
100
Glucose Breath Test Normalization
600 mg/d
800 mg/d
1200 mg/d
n=90 * †
Dosing duration, 7 days
Patients (%) ns
No significant differences in adverse events among 3 groups
Present study assessed efficacy, safety, and tolerability of rifaximin for treatment of IBS
Prospective, parallel-group, randomized study of 90 ROME II IBS patients diagnosed with IBS
- SIBO defined by glucose breath test (increase in hydrogen values >12 ppm above basal value after 50 g glucose ingestion)
- 3 treatment groups (30 patients/group)
Rifaximin 600 mg daily for 7 days
Rifaximin 800 mg daily for 7 days
Rifaximin 1200 mg daily for 7 days
- Primary efficacy variable was SIBO eradication rate measured by glucose breath test 1 month after rifaximin therapy
- Secondary variables were patient compliance and incidence of adverse events
Rifaximin 1200 mg daily resulted in significantly higher glucose breath test normalization rate (60%; 18 of 30 patients) compared with 600 mg/d (17%; 5 of 30 patients; p<0.001) or 800 mg/d (27%; 8 of 30 patients; p<0.01)
Higher doses of rifaximin therapeutically effective in eradication of SIBO without increasing incidence of adverse effects
*p<0.001.
†p<0.01.
Lauritano EC, et al. Aliment Pharmacol Ther. 2005;22(1):31-35.

17. Rifaximin for Non-Constipated IBS: Results from 2 phase III RCTs* *
% Responders
* P <
NC-IBS with mild to moderate symptoms
N = 1,260, Target 1 = 623, Target 2 = 637
Rifaximin 550 mg tid x 14 days
Patients followed for an additional 10 wks
Pimentel, et al. DDW 2010

18. 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?
Points regarding rifaximin in IBS
Unequal recruitment between centers
Unusual endpoint and analysis
Is the difference clinically meaningful?
None of the usual secondary clinical endpoints (except bloating) significant
Breath test results not provided
Drossman, Ann Int Med, 2006; 145:626
Chey. AGA Perspectives 2009;4:5-8

19. Breath Test Recurrence After Treatment with Rifaximin46 50 40 %
Positive
LBT 28 30 20 13
Double-blind, placebo controlled
study of 87 IBS pts randomized to
Rifaximin 1.2 grms/d or placebo x 10d
SD for rifaximin is and is for placebo 10 3 6 9
61 consecutive IBS pts
Rifaximin 1.2 grams/day x 7 d
Positive LBT associated with pain,bloating,
flatus, diarrhea
Months of Follow-up
Lauritano, et al. Am J Gastroenterol 2008; 103:2031

20. What are the Options to Reduce IBS Symptom Relapse?
Prokinetics
Probiotics
Rotating antibiotics
Dietary manipulation
Low FODMAP
Gluten-free
Low fat
Others?
Retrospective chart review of 84 patients who received one course of rifaximin (10 days of 400 mg TID)
Time in clinical treatment was 11 months (range months)
Other antibiotics included neomycin, doxycycline, amoxicillin/clavulanate, and ciprofloxacin

21. Biological Variables that Influence
the Developing Immunophenotype of an Infant
Brandtzaeg, Nat Rev Gastroenterol Hepatol, 7: , 2010

22. 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, 2005
Leung & Crowe, Food intolerance and food allergy.
In: The Gastrointestinal Nutrition Desk Reference, 2011

23. 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)

24. 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
NOTE FROM PHIL: WE NEED TO LIMIT PRESENTATION TO 20 DATA SLIDES. 24

25. Between Celiac Disease & IBS: The “No Man’s Land” of Gluten Sensitivity

26. 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!