Role of Bacteria in IBSMark Pimentel, MD, FRCP(C)

Director, GI Motility ProgramCedars-Sinai Medical Center

Los Angeles, California

IBS PrevalenceIBS Prevalence

Irritable bowel syndrome (IBS) is the most common chronic medical condition worldwide. 15-20% of all populations suffer from IBSThe cause has remained unknownAccounts for 30% of all health related costs (direct and indirect) in gastroenterology

How are we treating IBS?How are we treating IBS?

STRATEGY 1: Symptom based therapyPain

BloatingDiarrhea

Constipation

STRATEGY 2:STRATEGY 2: HypothesisHypothesis--basedbased

DYSMOTILITY

ACUTEGASTROENTERITIS

SIBO

SEROTONIN

IBS

BRAIN-GUT AXIS

Salmonella, E. coli, Campylobacter, …

Agonist/Antagonist

What is the evidence for What is the evidence for altered gut bacteria in IBS?altered gut bacteria in IBS?

Breath Testing in IBSBreath Testing in IBS

0 20 40 60 80 100

Galatola, 1995

Pimentel, 2000

Pimentel, 2003

Nucera, 2004

Nucera, 2005

Walters, 2005

Esposito, 2007

Madrid, 2007

Carrara, 2008

Bratten, 2008

Lupascu, 2005

Cuoco, 2006

McCallum, 2007

Majewski, 2007

Grover, 2008LA

CTU

LOS

E

GLU

CO

SE

SU

CR

OS

E

Review of SIBO DiagnosticsReview of SIBO Diagnostics

1

10

100

1000

10000

100000

1000000

Healthy Celiac IBD IBS Billroth II

Col

ony

Cou

nts

in S

B/m

L

Koshini, et al. ACG, 2007

SIBO?>105 is diagnostic of Billroth II

Culture of Jejunum/DuodenumCulture of Jejunum/Duodenum

05

101520253035404550

>10,000 coliforms >5,000 coliforms

Perc

ent o

f Sub

ject

s

ControlIBS

4%

24%

12%

43%

N=165 IBS, 26 controls Posserud, et al, Gut, 2007

P<0.05 P<0.001

Effect of LBT Normalization on Global ImprovementEffect of LBT Normalization on Global Improvement

0

10

20

30

40

50

60

70

80

Placebo Neo-Abn LBT Neo-Normal LBT

Perc

ent I

mpr

ovem

ent p<0.000001*

*One-way ANOVA

10%

32%

75%

Pimentel, et al, Am J Gastro, 2003

What role does bacteria What role does bacteria play in health and disease?play in health and disease?

Accredited by:

Supported by: Abbott Laboratories and Centocor, Inc.

Summary:Summary: Probiotic StudiesProbiotic Studies

Study Probiotic Primary Endpoint Met

Other Benefits

Bausserman, et al Lactobacillus GG No Distension

Sen, et al L. plantarum No None

Nobaek, et al L. plantarum No Flatulence and pain

Kim, et al VSL#3 No Bloating

O’Sullivan, et al Lactobacillus GG No None

O’Mahoney, et al L. salivarius orB. infantis

Only for B. infantis

Pain, bloating

L. salivarius L. salivarius oror B. infantisB. infantis

• DBRCT (n=80)

• Adults Rome II IBS

• PRIMARY OUTCOME-Composite score

• DOSE:1010/dayin malted milk

O’Mahony,et al Gastro, 2005.

012345678

-2 1 3 5 7 9 11

Week

Com

posi

te L

iker

t

Placebo L. salivarius B. infantis

Treatment Period

B. Infantis 35624B. Infantis 35624

• DBRCT (n=330 completed)

• Adults Rome II IBS

• PRIMARY OUTCOME-Pain/discomfort at 4 week mark only

• DOSE: 3 doses-encapsulated

Whorwell,et al Am J Gastro, 2006.

11.21.41.61.8

22.22.42.6

0 1 2 3 4 5 6

Week

Com

posi

te L

iker

t

Placebo 106 108 1010

Treatment Period

Explanation for Failure of 10Explanation for Failure of 101010

How do you diagnose How do you diagnose SIBO?SIBO?

Accredited by:

Supported by: Abbott Laboratories and Centocor, Inc.

Normal distribution of floraNormal distribution of flora

ColonColon101099--10101111

DistalDistalIleumIleum

101033

Proximal Proximal IleumIleum<10<1011

Distribution of flora in SIBODistribution of flora in SIBO

Breath Testing for SIBOBreath Testing for SIBO

GLUCOSE

LACTULOSE

QuinTron Model SCQuinTron Model SC

-H2, CH4 and CO2

-~$12000

BREATH TESTING AND BLOATINGBREATH TESTING AND BLOATING

BACTERIAL OVERGROWTH

• Lactulose Breath Test• Glucose Breath Test• Sorbitol Breath Test• 13C-Xylose Breath

Test

CHO MALDIGESTION

• Fructose Breath Test• Lactose Breath Test

NONE ARE PROPERLY VALIDATED!!

GASES PRODUCED IN GUTGASES PRODUCED IN GUT

Carbon Dioxide (CO2)Hydrogen (H2)Methane (CH4)Hydrogen Sulfide (H2S)

0

10

20

30

40

50

60

70

0 15 30 45 60 75 90 105 120 135 150 165 180

Time (Minutes)

Part

s Pe

r Mill

ion

Lactulose Breath TestLactulose Breath Test

0

10

20

30

40

50

60

70

0 15 30 45 60 75 90 105 120 135 150 165 180

Time (Minutes)

Part

s Pe

r Mill

ion

Complexities of Gas ProductionComplexities of Gas Production

Hydrogen Producers

H2S Producers5H2→1H2S

Methane Producers4H2→1CH4

010203040506070

0 15 30 45 60 75 90 105 120 135 150 165 180

Time (Minutes)

Part

sPe

rMill

ion

Methane Hydrogen

0

10

20

30

40

50

60

70

0 15 30 45 60 75 90 105 120 135 150 165 180

Time (Minutes)

Part

sPe

rMill

ion

H2

H2

Impact of Gas TypeImpact of Gas TypeIBS Subgroup (n=65)*

Hydrogen Methane

Diarrhea 34 0

Constipation 19 12

OR=∞, CI=3.7-∞, p<0.0001.*After excluding normal (n=17), no gas on LBT (n=4) and subjects where C=D (n=15).

Pimentel, et al. Am J Gastroenterol 2003Pimentel, et al. Am J Gastroenterol 2003

100 % of methane producers

Methane in IBS subjectsMethane in IBS subjects

0102030405060708090

100

H2 CH4 and H2 CH4

% o

f pat

ient

s

ConstipationDiarrhea

ChiChi--square=16.6, p<0.001square=16.6, p<0.001

Pimentel, et al. DDS, 2003.Pimentel, et al. DDS, 2003.

Methane and transitMethane and transit

Transit TimeTransit Time

No early No early methane on methane on

LBTLBT

EarlyEarly methane methane on LBTon LBT

Cloarec, et alCloarec, et al(Orocecal(Orocecal-- min)min)

6868 110110

Stephan, et alStephan, et al(whole gut(whole gut--hours)hours)

4848 8585

Cloarec D, et al Gut 1990;31:300-4.Stephen AM. Br J Nutr 1986;56:349-61.

0

20

40

60

80

Room Air Methane

% M

arke

r Rec

over

y

Intestinal transit is slowed by methaneIntestinal transit is slowed by methane

Pimentel, et al. Am J Physiol, 2006.

n=5, p<0.0001

69% mean slowing of transit with CH4

What is the role of What is the role of bacteria in bloating?bacteria in bloating?

Accredited by:

Supported by: Abbott Laboratories and Centocor, Inc.

GAS?GAS?

If you say If you say ““gasgas”” clinically what clinically what does it mean?does it mean?

Flatus?Flatus?Bloating?Bloating?Distension?Distension?Belching?Belching?Dyspepsia?Dyspepsia?

BLOATINGBLOATING

What is bloating to the patient?What is bloating to the patient?Distension?Distension?Fullness?Fullness?Nausea?Nausea?OrOr……just feel bloated but not really distended just feel bloated but not really distended (visceral hypersensitivity)(visceral hypersensitivity)

How does the bowel accumulate gas?How does the bowel accumulate gas?

SUBSTRATE

SLOW TRANSIT SWALLOWED

FERMENTATION

SUBSTRATESUBSTRATELegumesFiberAdditives (Olestra)Non-digestible carbohydrates

SucraloseSucraloseSorbitolSorbitolMaltitolMaltitolLactoseLactoseFructosevvFructosevv

SLOW TRANSITSLOW TRANSIT

Mechanical (bowel obstruction, adhesions)Small bowel dysmotilityColonic dysmotilityDrugs (e.g. narcotics)Poor gas clearance by motility

FERMENTATIONFERMENTATION

Substrate category is through fermentationAccelerated transit of nutrients to the bacteria (food moving to the colon bacteria)Poor digestion (e.g. pancreatic insufficiency)Bacteria moving up to food.

How do you manage gut How do you manage gut bacteria in IBS?bacteria in IBS?

Comparison of AntibioticsComparison of Antibiotics

ANTIBIOTICANTIBIOTIC EFFICACY IN SIBOEFFICACY IN SIBO

FlagylFlagyl <20%<20%

NeomycinNeomycin 25%25%

Augmentin or Augmentin or DoxycyclineDoxycycline

3030--40%40%

RifaximinRifaximin 70%*70%*

DiStefano M, Aliment Pharm Ther, 2000.

Rifaximin in Abdominal Bloating & Flatulence Rifaximin in Abdominal Bloating & Flatulence Trial (RAFT): ResultsTrial (RAFT): Results

Results Rifaximin n=56

Placebo n=54 p

Symptomatic relief at day 20

37.5% (21/56)

20.4% (11/54) 0.038

Symptomatic relief at day 30

28.6% (16/56)

11.1% (6/54) 0.019

Sharara et al. Am J Gastro, 2006.

MSOffice1

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MSOffice1 New slide , 12/10/2004

Act

ive

Trea

tmen

t

05

101520253035404550

1 2 3 4 5 6 7 8 9 10

Placebo Rifaximin

RIFAXIMIN IN IBSRIFAXIMIN IN IBS

*P=0.02 Mixed Longitudinal Model for 10-week difference

No Active Treatment

Per

cent

Glo

bal I

mpr

ovem

ent

Weeks after Rifaximin

Pimentel, et al, Ann Intern Med, Oct., 2006

0 10 20 30 40 50 60

Bloating

IBS Symptoms

Percent with Adequate Relief

Placebo (n = 197) Rifaximin (n = 191)

P=0.03

P=0.04

Ringel Y et al. Gastroenterology 2008; 134: 1411 Lembo A et al. Gastroenterology 2008; 134: 1390

52.4

44.2

46.1

39.6

ResultsResults

202530354045505560

1 2 3 4

Week

Perc

ent w

ith A

dequ

ate

Rel

ief

Placebo Rifaximin

P=0.019 P=0.010

Duration of ImprovementDuration of Improvement

Ringel Y et al. Gastroenterology 2008; 134: 1411 Lembo A et al. Gastroenterology 2008; 134: 1390

Rifaximin Retreatment for IBSRifaximin Retreatment for IBS

Retrospective chart review.69% of 84 subjects treated with rifaximin felt better.16 patients had recurrence of SIBO and needed retreatment (all patients improved).4 patients needed another treatment (all improved again).All other antibiotics had only 25% chance of working more than once.Conclusion: There does not appear to be bacterial resistance issues so far.

Lee, et al. ACG Meeting, Oct., 2006

Methane and Double Blind StudyMethane and Double Blind Study

0

20

40

60

80

Per

cent

Glo

bal I

mpr

ovem

ent

Hydrogen producersreceiving neomycin

Methane producersreceiving neomycin

p<0.01

Pimentel, et al. Dig Dis Sci in press, 2006.

0

10

20

30

40

50

60

70

80

90

100

Neomycin Rifaximin Neo+Rifax

Perc

ent e

radi

catin

g C

H4

Treating MethaneTreating Methane

0

10

20

30

40

50

60

70

80

90

Neomycin Rifaximin Neo+Rifax

Perc

ent w

ith C

linic

al R

espo

nse

CH4 Eradication Clinical Response

Low, et al. ACG P1074

P=0.001 P=0.01

Protection against SIBOProtection against SIBO

Mucosal Mucosal immunityimmunity

Small Small intestinal intestinal motilitymotilityIleocecalIleocecal

ValveValve

GastricGastricAcidityAcidity

Biliary and Biliary and Pancreatic secretionsPancreatic secretions

Phase III of Interdigestive MotilityPhase III of Interdigestive Motility

Phase III frequency in IBS with SIBOPhase III frequency in IBS with SIBO

ControlsControls(n=30)(n=30)

IBS with IBS with SIBOSIBO(n=68)(n=68)

pp--valuevalue

# of phase # of phase IIIIII

2.22.2±±1.01.0 0.70.7±±0.80.8 <0.00001<0.00001

Duration of Duration of phase IIIphase III

428428±±173173 305305±±123123 <0.001<0.001

Pimentel, et al. Dig Dis Sci, 2002.

68% less frequent

Drugs that stimulate phase IIIDrugs that stimulate phase III

Low dose erythromycinTegaserod

Prokinetics and SIBOProkinetics and SIBO

0

50

100

150

200

250

300

No Tx Erythromycin Tegaserod

Tim

e in

rem

issi

on (d

ays)

P<0.05

P<0.05P<0.01

Yang, et al. ACG, 2007

SIBO Treatment StrategySIBO Treatment StrategyIBS SYMPTOMS

LACTULOSE BREATH TEST

Rifaximin

Hydrogen Positive

Prokinetic

Symptom Re-evaluation/Retest

Methane Positive

Rifaximin+Neomycin

What is postWhat is post--infectious infectious IBS?IBS?

Accredited by:

Supported by: Abbott Laboratories and Centocor, Inc.

AuthorAuthor Follow UpFollow Up PIPI--IBSIBS %%

McKendrick et al 1994McKendrick et al 1994 12m12m 12/3812/38 3131

Gwee et al 1999Gwee et al 1999 3m3m 22/10022/100 2222

Neal et al, 1997 & 2003Neal et al, 1997 & 2003 6m6m6yr6yr

23/35723/35714/19214/192

777.37.3

Thornley et al 2000Thornley et al 2000 6m6m 9/939/93 99Okhuysen, et al 2004Okhuysen, et al 2004 6m6m 6/606/60 1010

Mearin, et al, 2005Mearin, et al, 2005 12m12m 24/27124/271 1010

Incidence of PIIncidence of PI--IBS (Acute gastroenteritis)IBS (Acute gastroenteritis)

MetaMeta--analysis of PIanalysis of PI--IBS studiesIBS studies

Included 8 studies due to qualityAverage rate of IBS after gastroenteritis was 9.8%No evidence of publication bias

Halvorson HA, et al. Am J Gastro, 2006

Prevalence and StabilityPrevalence and Stability

6-17% of IBS sufferers recall acute gastroenteritis as a herald of IBSLongstreth, et al, Gastro 2000 (abstract)

69% of patients with IBS (not PI-IBS) still symptomatic at 6 years whereas 57% with PI-IBS still symptomatic 6 years later.Neal KR, et al Gut, 2002.

Risk Factors for PIRisk Factors for PI--IBSIBS

Female (Neale, et al Gut, 2002).Increased diarrhea during acute infectionYounger patient with acute diarrheaAbsence of vomiting (Neal, 1997)Psychology (Gwee, et al Gut, 1999. Dunlop, Gastro, 2003.)

PostPost--infectious IBSinfectious IBS

Percent with Percent with IBS at 1 yearIBS at 1 year

Relative Risk Relative Risk (CI)(CI)

Irritable BowelIrritable Bowel 12%12% 5.2 (2.75.2 (2.7--9.8)9.8)

NonNon--ulcer ulcer dyspepsiadyspepsia

15%15% 7.8 (3.17.8 (3.1--19.7)19.7)

Mearin, et al. Gastro, 2006

Nausea was a risk factor for NUD

NORMALNORMAL

ACUTE GASTROENTERITISACUTE GASTROENTERITIS

COMPLETECOMPLETERECOVERYRECOVERY

~~GENETIC SUSCEPTIBILIITYGENETIC SUSCEPTIBILIITY~~ABNORMAL HOST RESPONSEABNORMAL HOST RESPONSE~~TOXIN INTENSITYTOXIN INTENSITY

POSTPOST--INFECTIOUS IBSINFECTIOUS IBSFUNCTIONAL GI DISEASES?FUNCTIONAL GI DISEASES?

90% 10%