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

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)

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

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

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?

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

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

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

“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”

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

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

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

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

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 17

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 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.”

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 21

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

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% 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

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

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 “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

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 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

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 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

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.

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.

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

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?

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.