Small Intestinal Bacterial Overgrowth Sheila E Crowe MD

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? • • • Celiac disease Non-celiac gluten sensitivity (NCGS) Other food sensitivities Food allergies IBS or another FGID Small intestinal bacterial overgrowth (SIBO) De. Gaetani & 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 & p. H Duodenum 101– 103 cfu/ml p. H ~6. 4 Colon 11 10 – 1012 cfu/ml Proximal p. H~6. 2 Distal p. H~7. 3 Stomach 101– 103 cfu/ml Jejunum/Ileum 104– 107 cfu/ml Ileal p. H~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): A 461

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, 2): A 461 Kloetzer et al. Gastroenterol 2007; 132 (suppl

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 Atrophic gastritis Cirrhosis Vagotomy Cystic fibrosis Celiac sprue Cirrhosis Crohn’s disease CVID Ig. A deficiency IC valve resection Bariatric surgery 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 Breath Test Lactulose Breath Test Bacterial Concentration, Organisms/m. L <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, H 2 BT— lactulose and – glucose Test Sensitivity Specificity Chromatography of fatty acids in aspirate 56% 100% H 2 breath test-lactulose 68% 44% H 2 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 (Se. HCAT, 23 -seleno-25 -homotaurocholic acid) • C 14 - 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 Placebo, n ~600 Rifaximin, n ~600 (550 mg, TID) 32 % 41 % (p=0. 0008) Vanner S. Gut. . 2008, 57: 1315 Lembo A, et al. DDW 2008. Abs T 1390 Pimentel M, et al. DDW 2010 % Improved*

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 % Responders * * * 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 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? • • Prokinetics Probiotics Rotating antibiotics Dietary manipulation – – 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): – – – 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!