Transcript Document

Bacterial Overgrowth and IBS:
Causation, Association, or Neither?
Brennan Spiegel, MD, MSHS
The Brain-Gut Axis
Central nervous
system (CNS)
Higher brain activation in
response to stress
Thinner grey matter density
Altered amygdala reactivity
Brain-gut axis
Enteric nervous
system (ENS)
Mayer E. et al; Gastroenterol 2010;139:48
Mayer E. et al; Gastroenterol 2011;140:1943
Dysbiosis
“Leaky” gut
Low-grade inflammation
Visceral hypersensitivity
Dysmotility
Evolving IBS Disease Model
“Hit”
Susceptible
Host
Underlying dysfunction in:
•
•
•
•
•
Intestinal dysbiosis
Mast cell number and function
Serotonin trafficking
HPA Axis
Cortical pain processing
Stress
Infection
Diet
Allergy
Disease
Expression
Existential Question: What Is IBS?
Malabsorption
Dietary factors
High sorbitol diet
High-fiber diet
FODMAP Diet
Caffeine
Alcohol
Celiac sprue
Carb intolerance
Pancreatic disease
Bile acid malabsorption
Inflammation
Ulcerative colitis
Crohn’s disease
Microscopic colitis
IBS
Psychological
Infection
SIBO
C. diff
Giardiasis
Endocrine
Hyperthyroidism
Diabetes
Carcinoid
Gastrinoma
Anxiety
Somatization
Depression
PTSD
Is IBS an absence of other things?
IBS
Or is it some thing… unto itself?
Proposed Pathophysiological Mechanisms
Involved in IBS
Visceral
hypersensitivity
Altered brain–
gut interactions
Inflammation
IBS
Bacterial-Host
Interactions
Genetic
factors
Psychosocial
factors
Diagnostic Battery is Extensive
IBS “Look-Alikes”
Performing the wrong tests
Bacterial overgrowth
Breath-testing
can leadGiardiasis
to excessive
resource
Stool Ova & Parasites
Hyperthyroidism
Thyroid function
testing
utilization
and worsen
patient
IBD
ESR / CRP / Colonoscopy
outcomes
Lactose intolerance
Breath-testing
Infectious colitis
Microscopic colitis
Celiac sprue
Diagnostic Battery
Stool leukocytes / C&S / C. diff
Colonoscopy / Flexsig
Sprue Serologies
Diagnostic Battery is Extensive
IBS “Look-Alikes”
Bacterial overgrowth
Giardiasis
Diagnostic Battery
Breath-testing
Stool Ova & Parasites
Hyperthyroidism
Thyroid function testing
IBD
ESR / CRP / Colonoscopy
Lactose intolerance
Infectious colitis
Microscopic colitis
Celiac sprue
Breath-testing
Stool leukocytes / C&S / C. diff
Colonoscopy / Flexsig
Sprue Serologies
“Aam
revolutionary
toolthe
in the
way
“I
convinced that
primary
irritable
syndrome
is currently–
cause
of bowel
IBS is bacterial
overgrowth
being
treated”
‘The
New
Culprit’”
Normal Distribution Intestinal Flora
100
103
106
aerobes
anaerobes
aerobes
duodenum
jejunum
1011
ileum
colon
Normal Distribution Intestinal Flora
Aspirate
H2
breath
tests
duodenum
glucose
lactulose
jejunum
ileum
colon
SIBO = >105 CFU/ml of “colonic type bacteria” in SI
e.g. gram negatives, anaerobes, enterococci
Lactulose Hydrogen Breath Test
H2
H2
PPM
0
90
min
H2
Lactulose
colonic
fermentation
cecum
LHBT criteria for diagnosing SIBO
colonic
fermentation
lactulose
jejunum
cecum
0
> 20 ppm H2 rise by
180 min
double peak
40
H2
PPM
rise H2 before 90 min
30
20
10
90 min
180 min
Pimentel M et al. New Engl J Med 2011;364:22-32
Rifaximin in IBS
Pimentel M et al. New Engl J Med 2011;364:22-32
Does X Cause Y?
Criteria for Causation
• It’s sensible that X could cause Y (biological plausibility)
• Competing mechanisms are less plausible (coherence)
• Most studies show X and Y are related (consistency)
• X comes before Y (temporal relationship)
• Removal of X removes or improves Y
• Therapies targeting X are most effective for Y (effect size)
• Nothing gets between X and Y (lack of confounding)
Hill, B. Proc R Soc Med 1965;58:295
Question
The LHBT was used to promulgate the
SIBO hypothesis of IBS. But how do
we know it even tests for SIBO?
Yu et al. Gut 2011 60:334
“These finding demonstrate that an abnormal rise in hydrogen
measured in the LHBT can be explained by variations in orocecal transit time in patients with IBS and therefore do not
support the diagnosis of SIBO.”
“It seems probable that antibiotics reduce bloating in IBS by
suppressing species of bacteria in the colon, not the small
intestine. Altering colonic flora using alternative strategies to
antibiotics, such as pre or probiotics, may prove advantageous.”
SIBO and IBS: Biological Plausibility?
• The test used to promulgate the SIBO hypothesis may not have
measured SIBO in the first place.
• LHBT is probably a measure of colonic bacteria that are not
displaced from the colon itself.
• LHBT data may simply indicate that dysmotility underlies IBS –
something long established.
Yu et al. Gut 2011 60:334
Camilleri et al. CGH 2008;6:772
Pimentel et al. DDs 2002;47:2639
SIBO and IBS: Biological Plausibility?
• In order for a risk factor to be the predominant cause
of a disease, we should expect that competing
hypotheses are less plausible.
• A causal theory is strongest when it does not conflict
with other facts and there are no plausible competing
theories.
Hill, B. Proc R Soc Med 1965;58:295
SIBO and IBS:
Consistency among studies?
Prevalence of Abnormal* Lactulose Breath
Tests in Rome I IBS
OR=26.2 (95% CI=4.7, 104)
100
84%
50
20%
0
IBS
N=111
*Single peak >20 ppm rise of H2 by 90 min
Controls
N=15
Pimentel et al. Am J Gastro 2003;98:412
IBS vs. Controls: H2 rise > 20 ppm by 180
<0.001
NS
NS
NS
NS
90
Control
80
70
% Positive
IBS
60
50
40
30
20
10
0
N=126
N=204
N=126
N=42
N=192
Positive Lactulose Breath Test:
Odds in IBS vs. Controls
Lupascu 2005
10.89 (3.33, 45.67)
Parodi 2007
14.00 (3.26, 124.54)
Posserud 2007
1.13 (0.14, 52.89)
Bratten 2008
0.45 (0.18, 1.23)
Grover 2008
2.29 (0.86, 7.16)
Rana 2008
12.38 (1.96, 513.13)
Pooled OR (95% CI)
3.45 (0.94, 12.72)
0.1 0.2
0.5
1
2
5
10
100
1000
Ford, Talley, Spiegel, Moayeddi . Clin Gastro Hep 2009
SIBO and IBS:
Dose Response Relationship?
Clinical Relevance of Abnormal SI
Bacterial Counts
Comparison
Symptom
Differences
“We found
no clearGroup
association between
symptoms
and
culture verified SIBO, mildly increased
small bowel
No difference in IBS symptoms
>105 vs. <105 CFU/ml
bacteria
abnormal
3 vs. <10or
3 CFU/ml
>10
LHBT. Thus,Nothe
clinical
difference
in IBS symptoms
importance
of abnormal
small
bacterial
No difference
in IBS counts
symptoms
LHBT
double peak
vs. no double
peak bowel
in IBS patients is questionable.”
Posserud et al. DDW 2009 AB#1052
SIBO and IBS:
Are treatments for SIBO more effective
than treatments targeting other
purported mechanisms of IBS?
Rifaximin in IBS
NNT = 11
Pimentel M et al. New Engl J Med 2011;364:22-32
Comparing NNTs of Available
Pharmacotherapies for IBS
IBS Treatment
NNT vs. Placebo
Antidepressants
Antispasmodics
4
5
Linaclotide*
Alosetron*
5
8
Rifaximin*
Probiotics
Fiber
11
11
11
Lubiprostone*
13
*
Higher quality studies available to support NNT calculation
Spiegel B. Clinic Gastroenterol Hep. 2011;9:461
Even Peppermint Oil Looks Good in IBS
NNT = 2.5
Ford A, Talley N, Spiegel B et al. Am J Gastroentrol 2008 Nov 13;337:a2313.
NNT of “Placebo without
Deception” in IBS?
4
Kaptchuk et al. PLoS One 2010;22:5
SIBO and IBS:
Lack of confounders?
Question
I plan to use antibiotics regardless of the
HBT or jejunal aspirate. In fact, I don’t
check the HBT anyway. Will clearing SIBO
with rifaximin lead to a long-term cure?
Or will the SIBO just come back?
SIBO Recurrence Following Rifaximin
44%
Predictors of SIBO Recurrence:
50
% Glc HBT Positive
40
Older age
30 (OR=1.09)
28%
20
13%
History of appendectomy
(OR=5.9)
10
N=80
0
Use of proton
pump inhibitors (OR=3.5)
3 Months
6 Months
9 Months
Lauritano et al. Am J Gastroenterology 2008;103:2031
Relationship between PPI Use and Foregut
Bacterial Counts
Thorens et al. Gut 1996; 35: 23-6.
Species Found in Foregut of Patients on PPIs
Fried et al. Gut 1994; 35;23-6.
PPIs as the Confounder: Could IBS Be Linked to
SIBO Through PPIs?
Spiegel B, Chey W, Chang L. Am J Gastroenterol 2008;103
Causation?
SIBO
IBS
Criteria for causation:
Yes
1. Biological plausibility?
2. Consistency?
3. Lack of confounding?
4. Removing X provides cure or robust
improvement in Y?
5. Removing X is most effective
treatment for Y?
No
Take-Away Messages
• Test used to promulgate SIBO hypothesis may not have measured
SIBO in the first place
• A dose-response effect between intestinal microbiota and IBS
symptoms is lacking
• The relationship between SIBO and IBS is inconsistent
• Therapies that do not address SIBO often outperform antibiotics –
even “placebo without deception”
• PPIs confound the relationship between SIBO and IBS
• Bottom line: Bacteria may play a role in some symptoms in some
patients, but are unlikely to be the predominant cause of IBS.