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)

DeGaetani & Crowe, CGH, 8: 755, 2010Stapel 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

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

Stomach101–103 cfu/ml

Jejunum/Ileum104–107 cfu/ml

Ileal pH~7.6

Colon1011–1012 cfu/mlProximal pH~6.2

Distal pH~7.3

Most Common Bacteria

Anaerobic Genera Aerobic Genera

Bifidobacterium Escherichia

Clostridium Enterococcus

Bacteroides Streptococcus

Eubacterium Klebsiella

Duodenum101–103 cfu/ml

pH ~6.4

O’Hara AM, Shanahan F. EMBO Rep. 2006;7:688-693Kloetzer et al. Gastroenterol 2007;132 (suppl 2):A461

Factors Which Protect Against SIBO

O’Hara AM, Shanahan F. EMBO Rep. 2006;7:688-693, Kloetzer et al. Gastroenterol 2007;132 (suppl 2):A461

Gastric Acid

Migrating Motor Complex (MMC)

IC Valve

Pancreatic & Biliary Secretions

Mucosal Immune System

Disorders Commonly Associated with SIBOGastric acid secretion

Pancreatic enzymes

Motility Disorder Immune

Deficiency

GI Structural Defect

Potent acid suppressive drugs

Atrophic gastritis

Vagotomy

Chronic pancreatitis

Cirrhosis

Cystic fibrosis

Aging

Celiac sprue

Cirrhosis

Crohn’s disease

DM with AN

Pseudo-obstruction

Renal failure

Radiation enteritis

Scleroderma

Immuno- suppressive Rx

CVID

IgA deficiency

Fistula

IC valve resection

Bariatric surgery

JI bypass

Small bowel tics

Surgical blind loop

Maneeratanaporn, Chey. SIBO, 2009

Breath Testing for SIBO

Saad & Chey, Gastroenterol 2007;133:1763

Breath Testing for SIBO in IBS

Adapted from Lin HC. JAMA. 2004;292:852-858

Bacterial Concentration,Organisms/mL

<102

>105

Methods of Detection

Direct Aspiration and Culture

Glucose Breath Test

Lactulose Breath Test

Glucose

Lactulose

77 patients with suspected SIBO underwent: jejunal aspiration culture, gas chromatography of fatty acids,

H2BT— lactulose and – glucose

Test SensitivitySensitivity SpecificitySpecificityChromatography of fatty acids in aspirate 56% 100%

H2 breath test-lactulose 68% 44%

H2 breath test-glucose 62% 83%

Testing for SIBO

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

*Di Stefano M, et al. Aliment Pharm Ther. 2000;14(8):551-556.

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%*

Placebo Control Antibiotic Studies in IBS

Study Treatment % Improved*

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)

Vanner S. Gut.. 2008, 57:1315Lembo A, et al. DDW 2008. Abs T1390Pimentel M, et al. DDW 2010

Placebo, n ~600 32 %Pimentel, 2010 Rifaximin, n ~600 41 % (550 mg, TID) (p=0.0008)

ns

Dose-Finding Study of Rifaximin in SIBO Patients With IBS

Pat

ien

ts (

%)

•No significant differences in

adverse events among 3 groups

Lauritano EC, et al. Aliment Pharmacol Ther. 2005;22(1):31-35.

*p<0.001.†p<0.01.

*

†

n=90

Dosing duration, 7 days

0

20

40

60

80

100

Glucose Breath Test Normalization

600 mg/d

800 mg/d

1200 mg/d

Rifaximin for Non-Constipated IBS:Results from 2 phase III RCTs

* P < 0.0008NC-IBS with mild to moderate symptomsN = 1,260, Target 1 = 623, Target 2 = 637Rifaximin 550 mg tid x 14 daysPatients followed for an additional 10 wks

Pimentel, et al. DDW 2010

0

10

20

30

40

50

AR - IBS symptoms AR - Bloating

Placebo

Rifaximin

%

Res

po

nd

ers

* *

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

%Positive

LBT

Lauritano, et al. Am J Gastroenterol 2008; 103:2031

13

0

10

20

30

40

50

3 9

46

28

6Months of Follow-up61 consecutive IBS pts

Rifaximin 1.2 grams/day x 7 dPositive LBT associated with pain,bloating, flatus, diarrhea

What are the Options to Reduce IBS Symptom Relapse?

• Prokinetics• Probiotics• Rotating antibiotics• Dietary manipulation

– Low FODMAP– Gluten-free– Low fat– Others?

Brandtzaeg, Nat Rev Gastroenterol Hepatol, 7: 380-400, 2010

Biological Variables that Influence the Developing Immunophenotype of an Infant

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, 2005Leung & 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!