Transcript Local Immune and Inflammatory Responses Following infection with

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?
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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
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
Sleisenger & Fordtran’s. Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management;
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
Duodenum
101–103
cfu/ml
pH ~6.4
Colon
11
10 –1012 cfu/ml
Proximal pH~6.2
Distal pH~7.3
Stomach
101–103 cfu/ml
Jejunum/Ileum
104–107 cfu/ml
Ileal pH~7.6
Most Common Bacteria
Anaerobic Genera
Aerobic Genera
Bifidobacterium
Escherichia
Clostridium
Enterococcus
Bacteroides
Streptococcus
Eubacterium
Klebsiella
O’Hara AM, Shanahan F. EMBO Rep. 2006;7:688-693
Kloetzer et al. Gastroenterol 2007;132 (suppl 2):A461
Factors Which Protect Against SIBO
Pancreatic &
Biliary Secretions
Gastric Acid
Mucosal Immune
System
Migrating Motor
Complex (MMC)
IC Valve
O’Hara AM, Shanahan F. EMBO Rep. 2006;7:688-693,
Kloetzer et al. Gastroenterol 2007;132 (suppl 2):A461
Disorders Commonly Associated with SIBO
Gastric acid
secretion
Pancreatic
enzymes
Motility Disorder
Immune
Deficiency
GI Structural
Defect
Potent acid
suppressive drugs
Chronic
pancreatitis
Aging
Immunosuppressive Rx
Fistula
Celiac sprue
Atrophic gastritis
Cirrhosis
IC valve resection
CVID
Cirrhosis
Vagotomy
Cystic fibrosis
Crohn’s disease
Bariatric surgery
IgA deficiency
JI bypass
DM with AN
Small bowel tics
Pseudoobstruction
Surgical blind loop
Renal failure
Radiation enteritis
Scleroderma
Maneeratanaporn, Chey. SIBO, 2009
Breath Testing for SIBO
Saad & Chey, Gastroenterol 2007;133:1763
Breath Testing for SIBO in IBS
Methods of Detection
Direct Aspiration and Culture
Glucose
Glucose Breath Test
Lactulose
Lactulose Breath Test
Bacterial Concentration,
Organisms/mL
<102
>105
Adapted from Lin HC. JAMA. 2004;292:852-858
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;98:302-309.
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
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%*
*Di Stefano M, et al. Aliment Pharm Ther. 2000;14(8):551-556.
Placebo Control Antibiotic
Studies in IBS
Study
Treatment
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)
Pimentel, 2010
Vanner S. Gut.. 2008, 57:1315
Lembo A, et al. DDW 2008. Abs T1390
Pimentel M, et al. DDW 2010
Placebo, n ~600
Rifaximin, n ~600
(550 mg, TID)
% Improved*
32 %
41 %
(p=0.0008)
Dose-Finding Study of Rifaximin
in SIBO Patients With IBS
100
*
n=90
Patients (%)
80
600 mg/d
†
800 mg/d
1200 mg/d
60
40
Dosing duration, 7 days
ns
• No significant
differences in
adverse events
among 3 groups
20
0
Glucose Breath Test Normalization
*p<0.001.
†p<0.01.
Lauritano EC, et al. Aliment Pharmacol Ther. 2005;22(1):31-35.
Rifaximin for Non-Constipated IBS:
Results from 2 phase III RCTs
50
% Responders
40
*
*
Placebo
Rifaximin
30
* P < 0.0008
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
20
10
0
AR - IBS symptoms
AR - Bloating
Pimentel, et al. DDW 2010
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
46
50
40
%
Positive
LBT
28
30
20
13
10
0
3
61 consecutive IBS pts
Rifaximin 1.2 grams/day x 7 d
Positive LBT associated with pain,bloating,
flatus, diarrhea
6
Months of Follow-up
9
Lauritano, et al. Am J Gastroenterol 2008; 103:2031
What are the Options to Reduce IBS
Symptom Relapse?
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Prokinetics
Probiotics
Rotating antibiotics
Dietary manipulation
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Low FODMAP
Gluten-free
Low fat
Others?
Biological Variables that Influence
the Developing Immunophenotype of an Infant
Brandtzaeg, Nat Rev Gastroenterol Hepatol, 7: 380-400, 2010
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):
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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
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!