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Irritable Bowel Syndrome:

What’s the Latest?

Tim Burke, DO

Pacific Digestive Associates

Clackamas, OR

Rome III Criteria for IBS

Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with ≥ 2

of the following:

Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with ≥ 2

of the following:

Improvement with defecationImprovement

with defecation

Onset associated with a change in

frequency of stool

Onset associated with a change in

frequency of stool

Onset associated with change in form of stool

Onset associated with 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

IBS: What’s the Latest?

• IBS subtypes: patients aren’t stagnant

• Distinguishing IBS-C from CC

• Utility of testing

• Methane

• Antibiotics

• Probiotics

• Celiac disease

• Diet

• Osmotic agents

• Secretagogues

In Clinical Practice Patients Move from

Group to Group

IBS-MIBS-M

CCCCIBS-CIBS-C

IBS-C: IBS with constipation

CC: Chronic Constipation

IBS-M: mixed or alternating

symptoms of constipation and

diarrhea

Simren M, et al. Scand J Gastroenterol 2001; 36(5):545-52

Tillisch K, et al. Am J Gastroenterol 2005; 100(4):896-904

Simren M, et al. Eur J Gastroenterol Hepatol 2003; 15(2):165-72

Simren M, et al. Gastroenterology 2005; 128(3):580-9

Simren M, et al. Am J Gastroenterol 2010; 105:2228-2234

Distinguishing IBS-C from CC

• No firm rationale to distinguish IBS-C from CC

by the Rome committee

• Treatments are often similar

– Tegaserod (no longer available in N.A.)

– Lubiprostone

– Prucalopride (available in the EU)

– Linaclotide

Distinguishing IBS-C from CC

• Symptom-based criteria for CC and IBS overlap

– Abdominal pain/discomfort and gas/bloating

creates a spectrum between CC and IBS

CC IBS-C

- PAIN/DISCOMFORT & GAS/BLOATING +

Brandt LJ, et al. Am J Gastroenterol 2005; 100(suppl 1): S5

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Utility of Testing:

Yield of Colonoscopy in IBSHistologic Findings in IBS Patients and Controls;

Populations Not Matched for Age and Gender

Lesion IBS Patients

n=466

(%)

Controls

n=451

(%)

P Value

Adenomas 36 (7.7) 118 (26.1) <0.0001

Hyperplastic Polyps 39 (8.4) 52 (11.5) NS

Colorectal adenocarcinoma 0 (0.0) 1 (0.2) NS

IBD 2 (0.4) 0 (0.0) NS

Microscopic colitis 7 (1.5) N/A N/A

Microscopic colitis was more common in a subset of patients

with IBS-D who were ≥ 45 years (2.3%).

IBD, inflammatory bowel disease; IBS-D, irritable bowel syndrome diarrhea-predominant; N/A,

not applicable; NS, not significant.

Chey WD, et al. Am J Gastroenterol 2010; 105:859-865

Pretest Probability of Organic Disease1

Organic DiseaseIBS Patients

(%)

Control/Population

(%)

Colitis/IBD 0.51-0.98 0.3-1.2

Colorectal cancer 0-0.51 0-6 (varies with age)

Lactose malabsorption 38 26

Thyroid dysfunction 4.2 5-9

Celiac Disease 3.6 0.7

Celiac disease: antibodies2 7.3 4.8

Celiac disease: confirmed2 0.41 0.44

1. American College of Gastroenterology Task Force on Irritable Bowel Syndrome, et al. Am J Gastroenterol

2009; 104(suppl 1): S1-S35.

2. Cash BD, et al. Gastroenterology 2011; 141:1187-1193

Methane & Constipation

• About 1/3rd of the population

produces CH4

• Predominant organism is

Methanobrevibacter smithii

• Thought to be present in 60%

of humans in left colon

• 107-1010 per g dry weight

Methane and Constipation

Prevalence of CH4 in slow transit

ConstipationAUC of methane on breath test

Attaluri, et al. Am J Gastro, 2010;105, 1407.

Methane Gas Infusion Slows Transit

69% mean slowing of transit

Pimentel, et al. AJPGI. 290;1089,2006.

Rifaximin: Most Extensively Studied

Antibiotic for IBS

• Gut-directed antibiotic

• Not systemically absorbed

• Doses studied for IBS: 400 mg BID to 550 mg

TID

• Generally well tolerated

• Adverse effects include: headache, abdominal

pain, and upper respiratory tract infection

*This agent is not currently FDA approved for IBS

Ford AC, et al. Clin Gastroenterol Hepatol 2009;7:1279-1286. Pimentel M, et al. N Engl J Med 2011; 364:22-32

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Rifaximin Trials: Global Relief of IBS

Without Constipation

• 2 Phase 3 randomized

controlled trials; n=1260

patients

• Rifaximin 550 mg TID x 2

weeks; patients followed

additional 10 weeks

• 40.7% vs. 31.7% with

adequate relief of global

symptoms (p<0.001)

T-I, TARGET 1 trial; T-II, TARGET 2 trial; Comb, Combination of both trials.

*Rifaximin is not currently FDA-pproved for IBS Pimentel M, et al. N Engl J Med 2011;364:22-32

Probiotics

• What about Probiotics? Could some

methane-producing bacteria respond to

probiotics?

Probiotics for IBS

• Lactobacilli – anaerobic, gram (+) rods– casei

– plantarum

– acidophilus

– reuteri

• Bifidobacteria – anaerobic, gram (+) rods

• VSL #3 (8 separate organisms: 3 Bifidobacteria, 1 Stretococcus, 4 Lactobacilli)

• Enterococcus

• Streptococcus salivarius

• Saccharomyces

Moayyedi P, et al. GUT 2010:59:325-332. Epub 2008 Dec 17

Probiotics: Mechanisms of Action

• Competitive inhibition

• Barrier protection

• Immune effects

• Anti-inflammatory effects

• Production of various substances (enzymes, SCFA, bacteriocidal agents)

• Ability to alter local pH and physiology

• Provides nutrition to colonocytes

Camilleri. J Clin Gastroenterol 2006;40,264.

Bifidobacteria Infantis 35624 for IBS

Global Assessment of Relief

SGA: (Subjects’ Global Assessment) a yes/no response to the following question:

“Please consider how your felt in the past week in regard to your IBS, in particular your general

well being, and symptoms of abdominal discomfort or pain, bloating or distention, and altered

bowel habit. Compared with the way you felt before beginning the medication, have you had

adequate relief of your IBS symptoms?”

Whorwell PJ, et al. Am J Gastroenterol 2006;101:1581-1590

B Infantis B Infantis B Infantis Placebo

1 x 1010 1 x 108 1 x 106

Wheat & IBS

• Gluten-related disorders

– Celiac disease

– Dermatitis herpetiformis

– Gluten Ataxia

– Non-celiac gluten sensitivity

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Gluten

• A storage protein in wheat, barley, and rye

• Genetically susceptible individuals (HLA-DQ2 and HLA-DQ8) develop an immune response

• Worldwide prevalence of celiac disease in IBS patients = 4%1

• US prevalence of celiac disease in IBS patients = 0.41%2

• KEY POINT: The vast majority of IBS patients do not have celiac disease

1Green. Lancet 362; 383:2003; 2Cash et al. Gastroenterology 141;1187:2011

IBS & Diet

• Low carbohydrate

• Low fructose/fructan

• Low gluten

• Low FODMAP

– (Fermentable Oligosaccharides, Disaccharides,

Monosaccarides, and Polyol)

Low Carbohydrate Diet

• Prospective, randomized, controlled study

• 17 moderate-severe IBS-D patients

• 4-week very low carbohydrate diet (VLCD)

– 51% fat; 45% protein; 4% carbohydrate

• Endpoint: adequate relief for > 2 weeks

• 13 completed the study

• All 13 met the responder definition

• 10 experienced adequate relief for all 4 weeks

Austin et al, Clin Gastro & Hepatol 7;706:2009

Low Carbohydrate Diet

• Secondary Endpoints also improved

– Decrease in stool frequency

– Improvement in stool consistency

– Decreased abdominal pain

– Improvement in quality-of-life

IBS & Low Fructose/Fructan Diet

• 26 IBS patients with fructose malabsorption(Rome II; + breath test; mean age = 38)

• Prior response to low fructose/low fructandiet

• Randomly re-challenged with offending foods

• 70% of those receiving fructose, 77% receiving fructans, and 79% receiving a mixture noted return/worsening of symptoms compared to glucose (14%; p < 0.002)

Sheperd et al, Clin Gastroenterol Hepatol 2008; 6:765-771.

IBS & Low Gluten

• R, DB, PC, re-challenge study

• 34 IBS patients (Rome III); celiac excluded

• Prior improvement in Sx on gluten-free diet

• 16 gm of non-fermentable gluten/day vs. 16

grams of gluten

• Primary endpoint: adequate symptom relief

• Gluten-group had less improvement in Sx than

those on gluten-free (68% vs. 40%; p = .001)

Biesiekierski et al, Am J Gastro 2011;106:508.

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IBS & Low Gluten Diet

Biesiekierski et al, Am J Gastro, 2011; 106:508.

IBS and Gluten-free Diet

• 45 Pts with ISB-D (43 women); 4-weeks

• Gluten-free diet (23) vs. Gluten-diet (22)

• Genotype analysis performed

• Stool frequency, intestinal transit and

intestinal permeability measured

• Results: Gluten diet was associated with

increased SB permeability, especially in HLA-

DQ2/8 positive patients

Vazquez-Roque et al, Gastroenterology 2013; 144:903-911

What Are FODMAPs?

Fermentable Oligo-, Di-, Monosaccharides And Polyols

Shepherd SJ, et al. J Am Diet Assoc. 2006;106:1631-1639.

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

Gibson PR, et al. J Gastroenterol Hepatol 2010;25:252-258.

Excess Fructose

Honey, apples, pears,

peaches, mangos, fruit

juice, dried fruit

Fructans

Wheat (large amounts), rye

(large amounts), onions,

leeks, zucchini

Sorbitol

Apricots, peaches, artificial

sweeteners, artificially

sweetened gums

Raffinose

Lentils, cabbage, brussel

sprouts, asparagus, green

beans, legumes

IBS & Low FODMAP Diet:

Or, what is there left to eat?

• Lean proteins

• Gluten-free breads, rolls, pasta

• Rice, corn, oat products

• Quinoa

• Safe fruits and vegetables:

– Snow peas, bok choy, mangarin oranges

IBS & Low FODMAP Diet:

Some Problems Exist

• What is the cut-off for FODMAP content?

• Resources differ on low FODMAP diets

• Total meal FODMAPs should be counted, not

individual FODMAPs

IBS: Prospective study to Evaluate Low

FODMAP diet

• 82 consecutive IBS patients (NICE criteria)

• Detailed symptom and dietary evaluation

• 9 month evaluation – performed in UK

• Individual symptoms and global IBS symptoms

measured

• 39 in the standard diet group

• 42 in the low FODMAP diet group

Staudacher et al, J Hum Nutr Diet, 2011, 24, 487.

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Improvements in IBS Symptom Scores:

Low FODMAP vs. Control Diet

Staudacher HM, et al. J Hum Nutr Diet 2011;24:487-495

*

*p ≤ 0.001

¥p < 0.05

IBS Symptom Improvement:

Low FODMAP Diet vs. Standard Diet

• Bloating (82% vs. 49%)

• Abdominal pain (85% vs. 61%)

• Flatulence (87% vs. 50%)

• Nausea (67% vs. 29%)

• Diarrhea (83% vs. 62%; ns)

• Composite symptom score (86% vs. 49%)

Osmotic Agents: PEG for IBS-C

• 27 adolescents: PEG

improved number of

BMs (p < 0.05) but not

pain in IBS-C patients

SMs, bowel movements; PEG, polyethylene glycol

Khoshoo V, et al. Aliment Pharmacol Ther 2006;23:191-196

Osmotic Agents: PEG for IBS-C

• Prospective, multi-center, R, DB, PC

• Rome III criteria

• 139 patients (mean age = 41; 83% women)

• 28 day study; 13.8 gm/sachet;

• 1-3 sachets/day vs. placebo

• Primary endpoint: mean # of SBM/day

• Results: At week 4, 4.4 SBM/week vs. 3.1 SBM/week (PEG vs. placebo; p < .0001)

Chapman. Am J Gastroenterol 2013;108,1508

PEG 3350 for IBS-CEfficacy of Linaclotide in Patients with

IBS-C

ANCOVA, analysis of convariance; RW, randomized withdrawl *p < 0.0001 for linaclotide patients vs. placebo patients (ANCOVA)

¥p < 0.001 for linaclotide/linaclotide patients vs. linaclotide/placebo

patients (ANCOVA)

Treatment Period* RW Period¥

Treatment Period RW Treatment Sequence

Rao S, et al. Am J Gastroenterol 2012;107:1714-1724.

n = 800

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Linaclotide Phase 3 IBS-C Trial:

Adbominal Pain Over 26 Weeks

ITT population, observed cases, LS-mean presented: p-values basted on ANCOVA at each

week. Bars represent 95% CI

n = 804ITT, intention to treat; LS, least squares

Chey WD, et al. Am J Gastroenterol 2012;107:1702-1712.

p = 0.0007 for week 1

P < 0.0001 for weeks 2-26

Summary

• IBS is a constantly evolving field

• Rome IV 2015 – expect changes in the

definition

• Our understanding of IBS physiology continues

to expand

• Expect new treatment options within the next

few years