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New Insights in Irritable Bowel Syndrome

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Christopher Chang, MD, PhDDivision of Gastroenterology/Hepatology

University of New Mexico School of Medicine

And

New Mexico VA Health Care System

April 22, 2017

National Conference for Nurse Practitioners

Nashville, TN

Overview

• Irritable bowel syndrome: definitions and

assessment

• Pathophysiology: no shortage of mechanisms

• Bacterial hypothesis of IBS

• Small Intestinal Bacterial Overgrowth (SIBO)

• Post-infectious IBS

• Dietary modification to treat IBS

Irritable Bowel Syndrome

• Irritable bowel syndrome (IBS) is the most common

chronic medical condition worldwide.

• 15-20% of all populations suffer from IBS

• The cause has remained unknown: “diagnosis of

exclusion”

• Accounts for 30% of all health related costs (direct

and indirect) in gastroenterology; >$50B estimated

costs.

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Recurrent abdominal pain or discomfort at least 3

days/month in the last 3 months associated with 2 or

more of the following:

Improvement with

defecation

Onset associated

with a change in

frequency of stool

Onset associated

with a change in

form of stool

*Criteria fulfilled for the last 3 months with symptom

onset at least 6 months prior to diagnosis

Longstreth GF et al. Gastroenterology. 2006;130:1480-1491.

Definition of IBS?

IBS: Rome III Criteria

Longstreth GF et al. Gastroenterology. 2006;130:1480-1491.

Still a diagnosis of exclusion

Hot off the press:

Rome IV IBS criteria

• Recurrent abdominal pain, ave > 1 day per

week in the last 3 months, associated with 2

or more of the following:

– Related to defecation

– Associated with change in frequency of stool

– Associated with a change in form or appearance

of stool

• Criteria fulfilled for the last 3 months with

symptom onset 6 months before diagnosis

Lacy ’16 Gastroenterol 150: 1393

GI Conditions

• Functional abdominal pain

• Functional constipation or

diarrhea

• Functional dyspepsia

• Celiac disease

• IBD

• Microscopic colitis

• Infectious colitis

• Ischemic colitis

• Colon cancer

• Food intolerances

• Bile malabsorption

Non-GI Conditions

• Food intolerances

• Endocrinologic conditions

– Thyroid disease

– Diabetes

• Gynecologic conditions

– Endometriosis

– Ovarian cancer

• Neurologic conditions

– Parkinson’s

• Medications

Potential Differential Diagnoses for IBS

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• Age ≥50 years old

• Blood in stools

• Nocturnal symptoms

• Weight loss

(unintentional)

• Change in symptoms

• Recent antibiotics

• Family history of organic GI disease

If alarm features are present,

investigate and treat appropriately

Alarm Features for Organic Disorders

1. Vanner SJ et al. Am J Gastroenterol. 1999;94:2912-2917;

2. Hammer J et al. Gut. 2004;53:666-672.

Proposed pathophysiology of

IBS-FBD

IBS-FBD

DietVisceral

hyperalgesia

Inflammation

Altered

Brain-gut

interactionsPsychological

factors

Genetics

Bacterial-host

interactions

Consultation

Symptoms

Acute

Gastroenteritis

Abuse

History

Other

Precipitating

Factors

Food

Stress

• Enteric Neuropathy

• Gastrointestinal (GI)

Motor Disturbances

• Visceral

Hypersensitivity

• Abnormal Central

Processing of

Sensations

• Psychological

Disturbances

GeneticFactors

Environment

Pathophysiology of IBS

Adapted from Rome Foundation Functional GI Disorders Specialty Modules.

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Sensory Thresholds are Altered in Patients

With IBS

****50

40

30

20

10

0IBS Control subjects

Pe

rce

ive

d in

ten

sity (

VA

S,m

m)

IBS Control subjects

****70

60

50

40

30

20

10

0

Pa

in th

resh

old

(mm

Hg

)

****P<.0001

Posserud I et al. Gastroenterology. 2007;133:1113-1123.

Brain-gut-enteric microbiota

axis

Altered bowel

function

Abdominal

pain/

discomfort

Bloating

and

distension

Bloating

• Probiotics

• Antibiotics

• Tegaserod

Diarrhea

• Loperamide

• Alosetron

• Antibiotics

• Probiotics

•Eluxadoline

Abdominal pain/

discomfort

• Antispasmodics

• Antidepressants

• Alosetron

• Tegaserod

Constipation

• Ispagula/psyllium

• Lubiprostone

•Linaclotide

• Osmotic laxatives

• Tegaserod

Pharmacologic Management of IBS

1. Brandt LJ et al. Am J Gastroenterol. 2009;104 Suppl 1:S1-35;

2. Brandt LJ et al. Am J Gastroenterol. 2002;97:S7-26;

3. Drossman DA et al. Gastroenterology. 2002;123:2108-2131.

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DYSMOTILITY

ACUTE

GASTROENTERITIS

S

I

B

O

SEROTONIN

IBS

BRAIN-GUT AXIS

Salmonella, E. coli,

Campylobacter, …

Agonist/Antagonist

STRATEGY : Treat the CAUSE

Model: Integrating gut microbiota into

IBS-FBD pathophysiology

Bacterial Hypotheses in IBS

S

I

B

O

IBS

ACUTE

GASTROENTERITIS ?

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1011cfu/mL

103 cfu/mL

102 cfu/mL

Colon

Small Bowel

101 cfu/mL

~ 0 cfu/mLDuodenum

Cecum

Jejunum

Ileum

SIBO- What is it?

Type of Test Specific Test

Breath testing Lactulose Breath Test

13C Xylose Breath Test

Glucose Breath Test

Sucrose Breath Test

Sorbitol Breath Test

Culture Small bowel aspirate and

culture

Empiric Approach Test, treat and re-evaluate

Diagnosing SIBO

Carbohydrate Breath Testing for SIBO

Saad RJ, Chey WD. Gastroenterology. 2007;133:1763-1766.

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Lactulose Hydrogen Breath Test

NOT E: Weights are f rom random ef fects analysis

Overall (I-squared = 67.9%, p = 0.008)

Pa rodi

Scarpellini

Lupascu

Au thor

Collin

Pimentel

Grover

glucose

lactulose

glucose

Breath Test

lactulose

Type of

lactulose

sucrose

9.64 (4.26, 21.82)

4.30 (1.24, 14.98)

24.27 (7.35, 80.15)

10.89 (3.52, 33.71)

OR (95% CI)

18.04 (6.55, 49.71)

20.67 (5.29, 80.69)

2.29 (0.89, 5.87)

100.00

15.71

16.20

16.82

Weight

17.94

%

14.68

18.65

9.64 (4.26, 21.82)

4.30 (1.24, 14.98)

24.27 (7.35, 80.15 )

10.89 (3.52, 33.71 )

OR (95% CI)

18.04 (6.55, 49.71 )

20.67 (5.29, 80.69 )

2.29 (0.89, 5.87)

100.00

15.71

16.20

16.82

We ight

17.94

%

14.68

18.65

1.1 .2 .5 1 2 5 10 20

Breath Testing in IBS

Shah, et al Dig Dis Sci, 2010;55:241-9

Forest plot of all age-sex matched studies

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>10,000 coliforms >5,000 coliforms

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ub

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ts

Control

IBS

4%

24%

12%

43%

P<0.05 P<0.001

N=165 IBS, 26 controls Posserud, et al, Gut, 2007;56:802-8

Small Bowel Culture in IBS vs. controls

Where to set

the bar?

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Placebo Neo-Abn LBT Neo-Normal LBT

Percen

t Im

prov

em

en

t

75%

32%

10%

Expectation: Antibiotics should

improve SIBO-IBS

*One-way ANOVA Pimentel, et al, Am J Gastro, 2003

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50

1 2 3 4 5 6 7 8 9 10

Placebo Rifaximin

Pe

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nt G

lob

al Im

pro

ve

me

nt

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

Pimentel, et al, Ann Intern Med, 2006

Rifaximin improves symptoms in

non-selected IBS

TARGET 1 and 2: Primary and Key Secondary End Points for Entire 3-Month Study Period

Pimentel M et al for the TARGET study group. N Engl J Med. 2011;364:22-32.

Efficacy Outcome

Primary end point

Weekly global IBS symptoms

TARGET 1

TARGET 2

Combined

TARGET 1

TARGET 2

Combined

Key secondary end point

Weekly IBS-related bloating

Odds Ratio (95% CI) P for

Treatment

Effect

1.35 (1.00-1.82)

1.52 (1.13-2.03)

1.44 (1.17-1.77)

1.28 (0.95-1.73)

1.56 (1.16-2.09)

1.42 (1.15-1.75)

.05

.005

<.001

.10

.003

.001

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Target 1 and 2: Daily Adequate Relief of Global IBS Symptoms for Non-C IBS Patients

• 1260 patients

from 179 sites

• NNT ~11

Meta-Analysis of Rifaximin Efficacy

on Global IBS Symptoms2

Menees SB, et al. Am J Gastroenterol. 2012;107:28.

• NNT 11.0 – 11.4

• Pooled safety analysis (vs placebo)

– No serious TEAE

– No GI TEAE

– No infectious TEAE

– No C. difficile colitis

• High concentration to GI tract

(<0.4% systemic absorption)

• In vitro activity against

Gram-positive and Gram-negative

aerobic and anaerobic bacteria

Meta-Analysis: Rifaximin Achieves Global IBS Symptom and Bloating Improvement

0

20

40

60

80

Room Air Methane

% M

ark

er

Reco

very

n=5, p<0.0001

69% mean slowing

of transit with CH4

Hydrogen Producing IBS Stool Methane Producing IBS Stool

Methane Produced by Gut Methanogen Methanobrevibacter smithii

Is Associated with Constipation and Slows Gut Motility

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• 32 C-IBS patients with positive methane breath test

• Randomized to either neomycin 500 mg BID ± rifaximin 550 mg TID x 7 d

• Rifax + neo subjects who eradicated methane (<3 ppm) had lower

constipation severity score 4 weeks after treatment, compared to those who

did not (p = 0.02)

Constipation Bloating

Pimentel, et al. Dig Dis Sci. 2014;59:1278.

Symptom Severity 7-Days after Antibiotic Treatment

Bacterial Hypotheses in IBS

S

I

B

O

IBS

ACUTE

GASTROENTERITIS ?

Marshall, et. al. '06, Gastro 131:

445

IBS after waterborne outbreak of AGE

• Livestock fecal contamination of water supply in Walkerton, Ontario in 2000

• AGE affecting >2000 locals

• Campylobacter jejuni and E. coli 0157:H7 most common

• Questionnaires administered 2 years later

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• S. enteritidis outbreak in Catalonia village, 2002

• 1243 persons affected

• Self administered questionnaires every 3 months by affected and cohort from same county

• 1 year RR for having IBS symptoms: 7.8 (3.1-19.7)

IBS after Salmonella outbreak

Mearin, et. al. '05, Gastroenterology 129:98

Travelers with diarrhea

• Is traveler’s diarrhea (TD) associated with new onset

IBS (PI-IBS)?

– Travelers visiting Israeli clinic enrolled before trip abroad

– Questionnaires before, during and after (6-7 months) trip

– 405 subjects finished study

• Results:

– 118 travelers with TD 13.6% developed IBS

– 287 travelers with no diarrhea 2.4% developed IBS

– Relative risk of developing PI-IBS = 5.7

Stermer '06, CID 43:898

Risk of PI-IBS in young, healthy population

• Reviewed records of Defense Dept Medical

Surveillance System (all medical encounters of active

duty US military personnel)

• Follow acute gastroenteritis patients who grew out

Campylobacter, Salmonella, Shigella, or Yersinia

• Match each patient with 4 healthy controls

– 1,753 pathogen-specific gastroenteritis cases followed for

median of 3.8 years

– Incidence (per 100,000 peron-years) of PI-IBS was 3.0,

compared to 1.0 for control group

Porter '13, BMC Gastro 13:46

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Prevalence:

9.8% IBS in

cases

vs

1.2% IBS in

controls

2.8 (1.0-7.5)

8.7 (3.3-22.6)

10.7 (2.5-45.6)

10.1 (0.6-181.4)

6.6 (2.0-22.3)

2.7 (0.2-30.2)

9.9 (3.2-30.0)

11.3 (6.3-20.1)

7.3 (4.8-11.1)

OR

0.1 0.5 1 10 50

Protective Effect Increased Risk

OR (95% Cl) Study (year/bacteria)

Ji (2005/Shigella)

Mearin (2005/Salmonella)

Wang (2004/Unspecified)

Okhuysen (2004/Unspecified)

Cumberland (2003/Unspecified)

llnyckyj (2003/Unspecified)

Parry (2003/Bacterial NOS)

Rodriguez (1999/Bacterial NOS)

Pooled estimate

Meta-analysis: Risk of PI-IBS increases 7-fold after AGE

*Systematic review of 8 studies involving 588,061 subjects; follow-up ranged from 3 to 12 months.

Halvorsen HA et al. Am J Gastroenterol. 2006;101:1894-1899.

Impact of foodborne illness

US foodborne pathogens per year cause:

•48 million illnesses

•> 100,000 hospitalizations

•3000 deaths

• Unreported

• Underappreciated

• Further sequelae

Increasing globalization of our food supply

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Treatment options for PI-IBS

Treatment trials specifically for PI-IBS are lacking.

Gradual recovery seen in pooled studies, over several years.

Consider:

• Test for SIBO: treat accordingly, e.g. Rifaximin

• 5-ASA: small RCT reported at DDW 2008

• Cholestyramine: BA malabsorption from pathogen damage to TI and

R-colon

• Probiotics: adjunctive therapy

• Standard IBS treatment:

– General dietary laxative avoidance

– Loperamide

– Low dose TCA

– Serotonin antagonists

• No improvement in IBS sx or enteroendocrine cell # after

prednisolone 30mg/d x 3 weeks (Dunlop, et. al. ‘03, APT 18:77)

Neal R, BMJ, 1997; 314:779Gwee et al, Gut 1999; 44:400

Duration of

abdominal pain

Duration and

intensity of

diarrhea

Females Factors Predicting

PI-IBS

Younger

age

Psychologic

distress

Gwee, et. al. '99 Gut 44:400, and

Spence et. al. '07, Gut 56:1066

Psychological factors in PI-IBS

• More “life events” and

hypochondriasis

independently predictive of

PI-IBS

• Scores for somatisation,

neuroticism and anxiety

also significantly elevated

• Higher levels of perceived

stress, somatisation,

anxiety, and negative

illness beliefs

• Higher likelihood of

reporting acute

gastroenteritis?

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Spiller, et. al. '00, Gut 47: 804

Elevated intra-epithelial T-cells in rectal mucosa

following C. jejuni infection and PI-IBS

Similar trends in immune cells of the lamina propria

Spiller, et. al. '00, Gut 47: 804

Increased serotonin-positive enteroendocrine cells

in PI-IBS rectal biopsies

• Serotonin (5-TH) predicted to increase frequency of loose stools, may promote hyperalgesia and homing of inflammatory cells

• Elevated serotonin release after a test meal in PI-IBS (Dunlop, et.al. ‘05, CGH 3:349)

Dichromate staining --> brown

Acute GI infection: the most important risk factor for IBS

Diet Visceral hyperalgesia

AlteredBrain-gut

interactions

PsychologicalFactors and Stress

Genetics

Neuromotordisturbances

IBS

Acute GI Infection

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The new paradigm?

IBD

Microscopic

colitis

IBS

Normal

Incre

asin

g inflam

mation

NORMAL

ACUTE GASTROENTERITIS

COMPLETE

RECOVERY~GENETIC SUSCEPTIBILIITY

~ABNORMAL HOST RESPONSE

~TOXIN INTENSITY

POST-INFECTIOUS IBSFUNCTIONAL GI DISEASES?

90% 10%

Food

Poisoning

Bacterial

Toxin AutoimmunityGut Nerve

Damage

Bacterial

Overgrowth IBS

IBS

Mechanism/Sequence/Main

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Could all IBS be post-infectious?

Take home points…so far

• IBS is currently a symptom-based disorder: Abdominal discomfort +

bowel irregularity

• IBS is probably not a single disease entity, but rather likely consists of

several different disease states and pathophysiology. Established data

suggests alterations in

– Gastrointestinal motility

– Visceral sensitivity

– Brain-gut regulation

• More recent evidence indicates that excess bacteria in the small bowel (SIBO) may underlie a significant fraction of IBS cases. Alterations in the normal balance of gut microbes may also underly IBS. Treatment with antibiotics often leads to symptom resolution in select patients.

• Post-infectious IBS occurs in susceptible individuals with a prevalence of ~10% after acute gastroenteritis.

• IBS may be associated with immune activation and an autoimmune mechanism secondary to gut infections.

• Alterations in the gut microbiome may play an increasingly recognized role in IBS

Food and IBS: lots of confusion

• >60% of IBS patients report worsened sx after meals

• Common suspects: wheat, corn, dairy, coffee, tea, and citrus fruits

• Swedish study (Bohn’14, AJG)

• Incompletely absorb carbs: dairy, beans, lentils, apple, flour, plum

• Biogenic amines: beer/wine, salami, cheese

• Histamine-releasing: beer/wine, milk, pork

• Fried and fatty foods

• Norwegian study (Monsbakken ‘06, Eur J Clin Nutr)

• 70% had sx related to food intake

• 62% limited or excluded food from diet

• 12% had inadequate diet

• Mayo survey of IBS or dyspepsia pts (Saito ‘05, AJG) vs HC

• No differences in consumption of frequently implicated “culprit” foods

• E.g. wheat, dairy, caffeine, fructose beverages

• ACG IBS guidelines 2009: “insufficient evidence that food allergy testing or exclusion diets are efficacious” (grade 2C)

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What are FODMAPs?

Lentils, cabbage, brussels

sprouts, asparagus,

green beans, legumes

Sorbitol

Raffinose

Honey, apples, pears,

peaches, mangos, fruit

juice, dried fruit

Apricots, peaches, artificial

sweeteners, artificially

sweetened gums

Wheat (large amounts), rye

(large amounts), onions,

leeks, zucchini

Excess

Fructose

Fructans

Fermentable oligo-, di-, monosaccharides and polyols

1. Shepherd SJ, et al. Clin Gastroenterol Hepatol. 2008;6:765-771;

2. Shepherd SJ, Gibson PR. J Am Diet Assoc. 2006;106:1631-1639.

Absorptive patterns of different FODMAPs

How FODMAPs Can Lead to GI Symptoms

Diarrhea

Distention

Shepherd et al '13, AJG 108:707

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Improved symptoms after 4 weeks of low FODMAP diet

• (Not shown) ITT analysis: more low FODMAP pts (13/19, 68%) reported adequate sx control compared to control diet (5/22, 23%), P= 0.005.

• Low FODMAP pts had better reduction in mean daily sx score (incidence + severity) for bloating, borborygmi, urgency and overall

Staudacher et al '12 J Nutrition

142:1510

Overall GI symptoms improve in IBS cohort on low FODMAP

• Randomized, controlled cross over study. 30 IBS, 8 HC subjects

• 21 days low FODMAP or “typical” Australian diet. > 21d washout period before crossing

over to other diet.

• Almost all food provided during intervention diet period. (< 0.5 gm FODMAP per meal goal

on LFD)

• Daily symptoms rated on 0-100mm VAS. Ave score last 14 d in red.

• 70% IBS subjects had sx improvement >10 mm.

22.8 vs 44.9, P< 0.001

No change in symptoms

With either diet

Halmos et al '14, Gastro 146

Specific symptoms and satisfaction with stool

consistency improved on low FODMAP

• Abdominal pain, bloating, and flatus had similar improvements as overall GI sx in IBS.

• Dissatisfaction with stool consistency improved in both IBS-D and IBS-C subjects (47.8 vs 25.9, typical vs LFD)

• Fecal characteristics including water content, did not change significantly with diet.

Halmos et al '14, Gastro 146

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Downloaded from

www.ibsgroup.org

Strategy to implement low FODMAP diet

Test for SIBO

Treat if positive

Review

response in

6-8 weeks

Rechallenge to:

Determine tolerance level

Increase variety in diet

Implementing low FODMAP diet trial

• Empiric strategy to eliminate or significantly restrict the most

likely offending foods

• Limits false positives from bias or placebo effect seen in single

food sequential ellimination strategies; limits false negatives if

patient has multiple food reactions/intolerances.

• Full elimination of FODMAPs not the goal

• If available, trained dietician is important partner

• Rechallenge examples:

• Mannitol: ½ cup mushrooms

• Sorbitol: 4 dried apricot halves

• Lactose: 250 cc milk or 200 gm yogurt

• Fructose: 2 teaspoons honey

• Fructans: 2 slices wheat bread or 1 clove garlic

• GOS: ½ cup lentils or legumes

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Additional recommendations for

implementing dietary changes

• Food and symptom diary may help identify trigger foods.

• Food reactions usually occur within 3 days of eating the food,

and should occur consistently on > 3 separate occasions.

• Specificity important in multi-component foods (e.g. pizza)

• Assessment of diet change should take at least 2 weeks; if no

clear benefit, it didn’t work or try repeating.

• Elimination/exclusion of identified foods need not be permanent.

Attempt to re-introduce the food should be made after 3-6

months.

Parting thoughts to chew on…

• Dietary manipulation keeps pts engaged

in improving their sx. Added placebo

effect?

• Most IBS pts attribute sx to specific

foods. Testing or blinded challenges

often contradict pt perceptions.

• Likely multiple mechanisms: poorly

absorbed molecules? Microbiota

changes?

• Low FODMAP diet improves IBS sx in

several recent studies.

• Non-celiac wheat/gluten sensitivity

overlaps with IBS. May have features

of CD and/or food allergy

• Referral to knowledgeable dietician is

helpful.