1. Brennan Spiegel, MD, MSHS
Bacterial Overgrowth and IBS: Causation, Association, or Neither?
Brennan Spiegel, MD, MSHS

3. The Brain-Gut Axis Higher brain activation in response to stress
Mayer E. et al; Gastroenterol 2010;139:48
Mayer E. et al; Gastroenterol 2011;140:1943
Higher brain activation in response to stress
Thinner grey matter density
Altered amygdala reactivity
Central nervous system (CNS)
Brain-gut axis
Dysbiosis
“Leaky” gut
Low-grade inflammation
Visceral hypersensitivity
Dysmotility
Enteric nervous system (ENS)

4. Evolving IBS Disease Model
Stress
Infection
Diet
Allergy
“Hit”
Susceptible Host
Disease Expression
Underlying dysfunction in:
Intestinal dysbiosis
Mast cell number and function
Serotonin trafficking
HPA Axis
Cortical pain processing

5. Existential Question: What Is IBS?
Dietary factors
High sorbitol diet
High-fiber diet
FODMAP Diet
Caffeine
Alcohol
Inflammation
Ulcerative colitis
Crohn’s disease
Microscopic colitis
Endocrine
Hyperthyroidism
Diabetes
Carcinoid
Gastrinoma
Psychological
Anxiety
Somatization
Depression
PTSD
Infection
SIBO
C. diff
Giardiasis
Malabsorption
Celiac sprue
Carb intolerance
Pancreatic disease
Bile acid malabsorption
IBS
** two patients with same physiological outcomes may have dramatically different responses to treatment

6. Is IBS an absence of other things?
** two patients with same physiological outcomes may have dramatically different responses to treatment
Or is it some thing… unto itself?

7. Proposed Pathophysiological Mechanisms Involved in IBS
Visceral hypersensitivity
Altered brain– gut interactions
Inflammation
IBS
Genetic factors
Bacterial-Host
Interactions
NACG running order – slide 40
Psychosocial factors

8. Diagnostic Battery is Extensive
IBS “Look-Alikes”
Bacterial overgrowth
Giardiasis
Hyperthyroidism
IBD
Lactose intolerance
Infectious colitis
Microscopic colitis
Celiac sprue
Performing the wrong tests can lead to excessive resource utilization and worsen patient outcomes
Diagnostic Battery
Breath-testing
Stool Ova & Parasites
Thyroid function testing
ESR / CRP / Colonoscopy
Stool leukocytes / C&S / C. diff
Colonoscopy / Flexsig
Sprue Serologies

9. Diagnostic Battery is Extensive
IBS “Look-Alikes”
Bacterial overgrowth
Giardiasis
Hyperthyroidism
IBD
Lactose intolerance
Infectious colitis
Microscopic colitis
Celiac sprue
Diagnostic Battery
Breath-testing
Stool Ova & Parasites
Thyroid function testing
ESR / CRP / Colonoscopy
Stool leukocytes / C&S / C. diff
Colonoscopy / Flexsig
Sprue Serologies

10. “I am convinced that the primary cause of IBS is bacterial overgrowth – ‘The New Culprit’”
“A revolutionary tool in the way irritable bowel syndrome is currently being treated”

11. Normal Distribution Intestinal Flora
100
103
106
1011
aerobes
aerobes
anaerobes
duodenum
jejunum
ileum
colon

12. Normal Distribution Intestinal Flora
Aspirate H2
breath
tests
glucose
lactulose
SIBO = >105 CFU/ml of “colonic type bacteria” in SI
duodenum
jejunum
ileum
colon
e.g. gram negatives, anaerobes, enterococci

13. Lactulose Hydrogen Breath Test
PPM 90
min H2
Lactulose
colonic
fermentation
cecum

14. LHBT criteria for diagnosing SIBO
colonic
fermentation
lactulose
jejunum
cecum
> 20 ppm H2 rise by 180 min
double peak 40 H2
PPM 30
rise H2 before 90 min 20 10
90 min
180 min

15. Pimentel M et al. New Engl J Med 2011;364:22-32

16. Rifaximin in IBS
Pimentel M et al. New Engl J Med 2011;364:22-32

17. 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 17

18. Question
The LHBT was used to promulgate the SIBO hypothesis of IBS. But how do we know it even tests for SIBO?

19. Yu et al. Gut :334

20. “These finding demonstrate that an abnormal rise in hydrogen measured in the LHBT can be explained by variations in oro-cecal 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.”

21. 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 :334
Camilleri et al. CGH 2008;6:772
Pimentel et al. DDs 2002;47:2639 21

22. 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 22

23. SIBO and IBS: Consistency among studies?

24. Prevalence of Abnormal* Lactulose Breath Tests in Rome I IBS
OR=26.2 (95% CI=4.7, 104)
100
84%
20% 50
IBS
Controls
N=111
N=15
*Single peak >20 ppm rise of H2 by 90 min
Pimentel et al. Am J Gastro 2003;98:412

25. IBS vs. Controls: H2 rise > 20 ppm by 180
<0.001 NS
Posserud et al
Gut 2006
N=204 NS
Walters et al
AJG 2005
N=126 NS
Bratten et al
AJG 2008
N=42 NS
NGM 2008
Grover et al
N=192
IBS
Control 90 80 70 60 50
% Positive 40 30 20 10
Pimentel et al
AJG 2003
N=126

26. Positive Lactulose Breath Test: Odds in IBS vs. Controls
Lupascu 2005
10.89 (3.33, 45.67)
Parodi 2007
14.00 (3.26, )
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, )
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

27. SIBO and IBS: Dose Response Relationship?

28. Clinical Relevance of Abnormal SI Bacterial Counts
“We found no clear association between symptoms and culture verified SIBO, mildly increased small bowel bacteria or abnormal LHBT. Thus, the clinical importance of abnormal small bowel bacterial counts in IBS patients is questionable.”
Comparison Group
Symptom Differences
>105 vs. <105 CFU/ml
No difference in IBS symptoms
>103 vs. <103 CFU/ml
LHBT double peak vs. no double peak
Posserud et al. DDW 2009 AB#1052

29. SIBO and IBS: Are treatments for SIBO more effective than treatments targeting other purported mechanisms of IBS?

30. Rifaximin in IBS
NNT = 11
Pimentel M et al. New Engl J Med 2011;364:22-32

31. Comparing NNTs of Available Pharmacotherapies for IBS
IBS Treatment
NNT vs. Placebo
Antidepressants 4
Antispasmodics 5
Linaclotide*
Alosetron* 8
Rifaximin* 11
Probiotics
Fiber
Lubiprostone* 13
* Higher quality studies available to support NNT calculation
Spiegel B. Clinic Gastroenterol Hep. 2011;9:461

32. 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.

33. NNT of “Placebo without Deception” in IBS?4
Kaptchuk et al. PLoS One 2010;22:5

34. SIBO and IBS: Lack of confounders?

35. 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?

36. SIBO Recurrence Following Rifaximin Predictors of SIBO Recurrence:50 40 30 20 10
44%
Predictors of SIBO Recurrence:
Older age (OR=1.09)
History of appendectomy (OR=5.9)
Use of proton pump inhibitors (OR=3.5)
28%
% Glc HBT Positive
13%
N=80
3 Months
6 Months
9 Months
Lauritano et al. Am J Gastroenterology 2008;103:2031

37. Relationship between PPI Use and Foregut Bacterial Counts
- randomized, double-blinded, prospective study comparing gastric and duodenal bacterial overgrowth in patients treated with omeprazole vs cimetidine
- 47 patients with dyspepsia randomly assigned to omeprazole 20 mg qd or cimetidine 800 mg qd for 4 weeks
- gastric and duodenal juice obtained via a double sheathed plastic wash pipe under sterile conditions - 10 ml from the stomach and 1 ml from 20 cm beyond pylorus and aspirates were plated quantitatively for anaerobes and aerobes
- bacterial overgrowth found in 53% of patients on ppi vs 17% on h2 blocker with sibo defined as total bacterial count >105 cfu/ml with p <.05 with a fairly close linear relationship between gastric pH and bacterial count: dotted line is >105 = sibo and plain line as linear correlation b/w pH and bacterial counts, which is higher in patients treated with ppi compared to h2 blocker
bacterial flora was mainly oral type flora - limitation of the study
- no antisecretory drugs or abx for 4 weeks prior to endoscopy.
- excluded those patients with diabetes
Thorens et al. Gut 1996; 35: 23-6.

38. Species Found in Foregut of Patients on PPIs
reproduced essentially the same study
40 patients underwent diagnostic endoscopy for suspected peptic ulcer disease
25 patient received ppi after endoscopy for 4-6 weeks with 20 or 40 mg omeprazole vs 15 patients in control group who had not been treated prior to endoscopy with either abx therapy or antisecretory therapy
no patient in the control had bacterial overgrowth compared to 56% of patients in ppi group and 1/2 of the patients with overgrowth had presence of fecal type bacteria
- sibo is defined as overgrowth of colonic type flora
Fried et al. Gut 1994; 35;23-6.

39. PPIs as the Confounder: Could IBS Be Linked to SIBO Through PPIs?
- 40% of IBS patients have comorbid GERD and 30-50% have overlapping dyspepsia
- 5% of chronic ppi users report abdominal pain, bloating, flatulence, constipation, diarrhea - symptoms similar to SIBO
- IBS patients more likely to receive ppi therapy
- chronic ppi therapy in IBS is extremely common - 44% of patients with IBS were receiving a ppi [much higher than non-IBS healthy controls]
- Therefore, PPI use is common in IBS patients and PPIs are associated with SIBO
- PPIs are bidirectionally associated with IBS - the risk factor and unidirectionally associated to SIBO - the outcome
Spiegel B, Chey W, Chang L. Am J Gastroenterol 2008;103

40. Causation? SIBO IBS Criteria for causation: Yes No
1. Biological plausibility?
Consistency?
Lack of confounding?
Removing X provides cure or robust improvement in Y?
Removing X is most effective treatment for Y?

42. 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.