Colonic Motility Disorders - · PDF file• Acute Diarrhea (UPDATED) ... • Pelvic floor musculature and the puborectalis ... prolonged pain lasting on average 3 days

Gastro Highlights 2012in honour of

Prof Dr Michael Fried Sept 8th 2012

Eamonn M M Quigley MD FRCP FACP FACG FRCPIAlimentary Pharmabiotic Centre

Department of MedicineUniversity College Cork

CorkIreland

Colonic Motility Disorders: what have we learned over the past 20 years?

Michael Fried; a

Global PerspectiveChair, Guidelines and Publications WGO

Member Executive Committee and Governing Council

Michael Fried: a Global Perspective

Guidelines with Cascades

• Acute Diarrhea (UPDATED)• Colorectal Cancer Screening• Constipation (UPDATED)• Endoscope Disinfection (UPDATED)• Esophageal Varices• Helicobacter pylori in developing countries

(UPDATED)• Hepatitis B• HCC: a global perspective• IBD: a global perspective• IBS: a global perspective• NAFLD-NASH• Obesity (UPDATED)• Radiation protection in the endoscopy suite


• Translated into multiple languages

• Published on line and in J Clin Gastro and elsewhere

• No 1 reason for web site hits

• Exponential rise in down-loads

• Have been used by national societies as their guidelines

• Ever-increasing citations

Guidelines

• Asymptomatic Gallstone Disease• Celiac Disease• Diverticular Disease• Dysphagia• Management of Acute Viral Hepatitis• Management of Strongyloidiasis• Needlestick injury and accidental exposure to blood

• Osteoporosis• Probiotics and Prebiotics(UPDATED)


• Numerous related publications in high-impact journals

Congratulations and

a very big thank you from WGO

Colonic Motility Disorders

•Motility of the Colon

•Diverticular disease

•IBS

•Constipation

•The microbiota

Colorectal Motility

Colon

• Changes in tone– Right colon– Serves to accommodate

• Segmenting contractions– Throughout the colon

• Power contractions (High Amplitude Propagating Contractions, HAPCs)– Propulsive along the colon

80 mmHg

8 cm/sec 2 cm/sec

30 sec

High Amplitude Propagated Contractions (HAPCs)

HAPC

Defecation

• Pelvic floor musculature and the puborectalis relaxes to straighten out the anal canal

• External sphincter relaxes

• Internal sphincter relaxes

• Diaphragm and abdominal wall muscles contract

Contracted Puborectalis Increases Ano-Rectal Angle

Relaxed Puborectalis Decreases Ano-Rectal Angle

Diverticula – easy to find but difficult to incriminate!

Burden of Disease

*Kang JY, et al. Aliment Pharmacol Ther 2003;17:1189-1195

• Inpatient admissions UK 1989-2000*

Perforated Diverticular Disease

Humes DJ, et al. Gastroenterology 2009;136:1198-1205.

Design Findings Comments RefCase control study: 100 (symptomatic) DD cases vs 80 age and sex matched controls

Dietary fiber intake higher amongst controls

Participants hospitalized due to diverticulosis; symptoms may have influenced diet

Manousos et al

Prevalence of DD in 189 non-vegetarians vs 55 vegetarians

Diverticular disease was higher in the non-vegetarians

"A potential confounder is a possible causative effect for meat”

Gear et al

Case control study:40 (symptomatic) DD vs 80 age/sex matched controls

Dietary fiber intake higher amongst controls

Symptoms may have influenced their diet

Brodribb et al

43 881 US men aged 40-75 followed over 6 years

Dietary fiber intake lower in cases

Presence of DD not defined at outset; cannot rule out effects of DD on dietary choices

Aldoori et al

Case control study:86 right-sided DD cases and 106 controls

No relationship between DD and fiber consumption

May indicate different etiology or right-sided DD has fewer effects ondiet

Lin et al

Commane DM, et al. World J Gastroenterol 2009;28:2479-88.

What happens to diverticulitis?• < 10% require surgery on first admission

• 15-25% develop complications leading to surgery.

• Among those managed conservatively recurrence rate: 7-45%.

PLACEBO (n=41)

5-ASA (n=40)

5-ASA + Probiotic

(n=36)Withdrew due to surgery

1 (2.4%) 2 (5.0%) 0 (0%)

Recurrent Diverticulitis

8 (20%) 5 (12.5%) 4 (11.8%)

Stollman N, et al. Am J Gastroenterol 2010;105:S139.

Stollman N, et al. Am J Gastroenterol 2010;105:S139.

Persistent Symptoms

Painful Diverticular Disease

• 170 patients with diverticula on BE followed from 1999-2006– 34% recurrent abdo pain

• Median of 3.5 days per month• Median duration 1 hour

– Predictors of recurrent pain• History of acute diverticulitis• High score on HAD scale

• 51/261 with diverticula on BE had episodes of prolonged pain lasting on average 3 days– Recurrence rate 71% for those treated with an antibiotic

vs 34% not

Humes DJ, et al. Br J Surg 2008;95:195-198.Simpson J, et al. Eur J Gastroenterol Hepatol 2003;15:1005-10.

Irritable Bowel Syndrome(IBS)

The Traditional View• A “nuisance” rather than a syndrome

• Not a “real” entity but brought on by stress or anxiety

• Main issue is to exclude important “real/organic” disease

• Does not merit serious scientific investigation

• No worthwhile treatments

Irritable Bowel Syndrome(IBS)

A Changed Perspective

• Common world wide

• Can be disabling

• Varying phenotype

• Etiology unclear but gut-brain axis thought to play a pivotal role and new avenues being explored

• Therapeutic options remain limited, but considerable progress and interest

Quigley E al. J Clin Gastro 2012

Do we investigate too much?Radiation exposure in GI disorders

Desmond et al, Clin Gastroenterol Hepatol 2011

Do we investigate too much?Radiation exposure in GI disorders

Desmond et al, Clin Gastroenterol Hepatol 2011

Variable Spontaneous abortion, n

Crude OR (95% CI), abortion

Adjusted OR (95%

CI), abortion

Ectopic pregnancy,

n

Crude OR (95% CI), ectopic

pregnancy

Adjusted OR (95%

CI), ectopic

pregnancy

No IBS 12,041 Reference Reference 1,296 Reference ReferenceIBS but no depression/anxiety

3,593 1.26(1.21, 1.31)

1.21(1.16, 1.26)

453 1.42(1.26, 1.61)

1.35(1.19, 1.52)

IBS and depression anxiety

1,803 1.40(1.32, 1.48)

1.26(1.19, 1.34)

254 1.74(1.50, 2.01)

1.51(1.30, 1.74)

IBS and Pregnancy Outcome

Khashan et al, Clin Gastroenterol Hepatol 2012 (in press)

IBS Pathophysiology

• Heredity; nature vs nurture

• Dysmotility, “spasm”

• Visceral Hypersensitivity

• Altered CNS perception of visceral events

• Psychopathology

• Infection/Inflammation

• Altered Microbiota

What factors precipitate symptoms in IBS?

•Food

•Stress

•Menstrual cycle (females)

Why does food provoke symptoms in IBS?

•Dietary components– Tryptophan

•Depletion/augmentation can influence anxiety and GI symptoms in IBS

•Food allergy•Food intolerance

– Gluten– FODMAPs

•Interaction with the gut flora

Evidence for a role for the Microbiota in IBS

• Direct evidence of an altered gut flora:– Post-Infectious IBS (PI-IBS)– Small Intestinal Bacterial Overgrowth (SIBO)– Altered Colonic Flora

• Evidence of physiological effects of an altered flora:– Changes in stool volume/consistency

•Bile salt deconjugation– Alterations in gas volume/composition

•Fermentation– Food-microbiota interactions

• Mediator of pro-inflammatory state

• Therapeutic impact of altering flora


• Direct evidence of an altered gut flora:– Post-Infectious IBS (PI-IBS)

Post-Infectious IBS

• 10-14% incidence following confirmed bacterial gastroenteritis

Dunlop, et al. 2003. Mearin, et al. 2005.

•Risk factors– Female– Severe illness– Pre-morbid psyche

• Depression– Persistent inflammation

• EC cells• T lymphocytes

Dunlop, et al. 2003.

300

200

100

0PI-IBS Patient

ControlsVolunteers

Lamina

Prop

ria

TLy

mph

ocyt

es P

er h

pf

**

75

50

25

0PI-IBS Patient

ControlsVolunteers

EC C

ells P

er h

pf

**

Lessons from PI-IBS

Disturbed Flora

Susceptible Host

Inflammatory Response

Myo-Neural DysfunctionSYMPTOMS


• Direct evidence of an altered gut flora:– Altered Colonic Flora

% s

imila

rity

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

H e a l t h y

I B S

Variability in Flora

Codling et al, 2010

Large overlap in the two populations

IBS, in generalHigh-throughput Sequencing of the Microbiota

Jeffery et al, Gut 2011

Correlation-based clustering of subjects by microbiota composition

Two IBS specific clusters Jeffery et al, Gut 2011

Revised Groupings

The two IBS specific clusters are similar


Clinical Associations


ImmuneActivation

Mast CellActivation

Luminal FactorsMicrobiota

A New Paradigm

Gut Barrier

Mucosal Immunology Quantitative RT-PCR

IBSControls

McSharry et al. Scand J Gastroenterol 2008

Chemokinein supernatant

followingEx vivo

biopsy culture

McSharry et al Scand J Gastroenterol 2008

McSharry et al. Scand J Gastroenterol 2008

Healthy IBS

CD3

CD4

CD8

T-Cell Subsets in the colonic mucosa

IP-10 (CXCL10)

IFNγ

Moloney et al, DDW 2012

Mucosal Compartment

• Increased mast cellsGuilarte et al, 2007

• More degranulating mast cells

Barbara et el, 2004

• Increased proteasesCenac 2007, Barbara 2008

A

Involved in crosstalk between mast cells and regulatory T cells.Induces release of histamine, proteases and IL-6 from mast cells

Effects on permeabilityInduces the expression of regulatory cytokines, such as IL-10

Beltran et al, DDW 2012

Early Life Events, Childhood Trauma, Visceral Hypersensitivity and IBS

Craig et al, DDW 2011

Early-Life Dysbiosis -Adult Visceral Hypersensitivity

O’Mahony et al DDW 2009

4 weeks 8 weeks

Microbiota at 4 and 8 weeks

4 weeks 8 weeks

Vehicl

e

10mg/kg

30mg/kg

100m

g/kg

0

20

40

60

*

***

Pres

sure

of d

iste

nsio

n (m

mH

g)

Vehicl

e

10mg/kg

30mg/kg

100m

g/kg

0

5

10

15

***

No

of p

ain

beha

viou

rs

Response to Colo-Rectal Distension at 9-12 weeks

Disruption of the Microbiota in early life leadsto a permanent change in enteric neurophysiology

Gut-Brain AxisCentral

Processing &Perception

Abnormal reflexesDisturbed perceptionAutonomic dysfunctionAberrant activation

http://www.gastrojournal.org/content/vol114/issue3/images/large/gast743azi10z.jpeg

0

50

100

150

200

250

300

B. infantis 35624 L. salivarius 4331 Placebo Healthyvolunteers

IL-1

0:IL

-12

ratio

Pre-treatmentPost-treatment

* p =.001

*

O’Mahony et al, Gastroenterology, 2005

Systemic CompartmentPeripheral Blood Mononuclear Cells

Systemic Immune Compartment in IBSSerum Cytokines

Dinan, et al. Gastroenterology. 2006.

* IL-6

IBS Controls

6

5

4

3

2

1

0

IL-6

(pg/

ml)

* sIL-6r

IBS Controls0

50000

100000

150000

sIL-

6r

IL-1β

Control IBS0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5 p = 0.3433

IL-1

β (p

g/m

l)

IL-6

Control IBS0

1

2

3

4

5

6

7p = 0.0068

**

IL-6

(pg/

ml)

IL-8

Control IBS0

5

10

15

20p = 0.0036

**

IL-8

(pg/

ml)

IL-10

Control IBS0

25

50

75

100 p = 0.0971

IL-1

0 (p

g/m

l)

“Pure”IBS

Scully et al, Am J Gastroenterol 2010

IL-12

Control IBS0

102030405060708090

100110

p = 0.2406

IL-1

2 (p

g/m

l)

IL-13

Control IBS0

25

50

75

100

125p = 0.1903

IL-1

3 (p

g/m

l)

TNFα

Control IBS0123456789

10111213 p = 0.56

TNF α

IFNγ

Control IBS0.02.55.07.5

10.012.515.017.520.022.5 p = 0.4692

IFN

γ (p

g/m

l)

“Pure”IBS


Extra-Intestinal Features of IBS(CFS, Fibromyalgia, PMS)


Extra-Intestinal Features of IBS(CFS, Fibromyalgia, PMS)


Microbiota(Dysbiosis)

Mucosa(Immune Dysfunction)

DysmotilityVisceral Hypersensitivity

Gut-Brain Axis Dysfunction

Immune Activation

Beyond the Gut?

IL6, IL8

IL1β, TNFα

Does this mean anything?

0.2

ratio

10 mins

HealthyPlasma (1:250)

IBSPlasma (1:250)

A

B

C

Healthy plasma

IBSplasma

-0.050

-0.025

0.000

0.025

0.050

0.075

0.100

0.125 ***

∆R

atio

IBS-AIBS-C IBS-D

0.4

ratio

10 minHlthy IBS-A IBS-C IBS-D

0.000

0.025

0.050

0.075

*

*

∆R

atio

p=0.06

Does this mean anything?

O’Malley et al, DDW 2011

ACTH Response to CRH

-15 0 15 30 45 60 90 1200

10

20

30Healthy subjectsIBS

** **

Time (min)

AC

TH(n

g/l)

Significant correlation between the ACTH response (ΔACTH)

and IL-6 levels (r= 0.61, df=40, p<0.05).Dinan et al, Gastroenterology 2006

Is IBS a form of IBD?

Controls IBS0

25

50

75100

125

150

175

200

Cal

prot

ectin

(mg/

kg s

tool

)

Keohane et al, Am J Gastroenterol 2010

CD + IBS (n=37) CD – IBS (n=25) p value

Age (years) 42 (21-65) 38.3 (20- 67) 0.30

Females/males 22/15 10/14 0.25

Duration of disease (range) 11.2 yrs (2-30) 11 yrs (1-30) 0.97

Surgery 67% 56% 0.15

Smokers 27% 8% 0.0008

Medications

5-ASA 62.2% 52% 0.2

Sulfasalazine 0% 4% 0.13

Steroids 0 0 ns

AZA/6MP 32% 37.8% 0.55

No meds 13.5% 20% 0.35

CDAI (mean +/- SD) 53.4 +/- 31.3 35.6 +/- 35.6 * 0.04

How about IBS symptoms in IBD?


CD + IBS (n=37) CD – IBS (n=25) p value

Age (years) 42 (21-65) 38.3 (20- 67) 0.30

Females/males 22/15 10/14 0.25

Duration of disease (range) 11.2 yrs (2-30) 11 yrs (1-30) 0.97

Surgery 67% 56% 0.15

Smokers 27% 8% 0.0008

Medications

5-ASA 62.2% 52% 0.2

Sulfasalazine 0% 4% 0.13

Steroids 0 0 ns

AZA/6MP 32% 37.8% 0.55

No meds 13.5% 20% 0.35

CDAI (mean +/- SD) 53.4 +/- 31.3 35.6 +/- 35.6 * 0.04

How about IBS symptoms in IBD?


p=0.01

CD+IBS CD-IBS Controls0

100

200

300

400

500

Cal

prot

ectin

(mg/

kg s

tool

, mea

n +

SE)

Crohn’s Disease


UC + IBS UC - IBS Controls0

100

200

300

400

500

600

700

800

Cal

prot

ectin

(mg/

kg s

tool

, mea

n +

SE)

Ulcerative Colitis


ImmuneActivation

Mast CellActivation

Microbiota

What is the Evidence for a Microbiome-Gut-Brain Axis?

A Probiotic can Reduce Stress Response

Bravo et al,PNAS 2011

Associated with altered levels of GABA in the brainEffects abolished by vagotomy

What is the Evidence for a role for the Microbiome-Gut-Brain

Axis in IBS?

Can we link the microbiota and inflammation in IBS?

• Anti-Flagellin antibodies (but not ANCA or ASCA)

• Increased levels of β-defensin

• Toll-like receptor (TLR) activation

TLR’s in IBS

0

1

2

3

TLR3

ddct

HC IBS

TLR7

HC IBS

ddct

P<0.0001

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

0

1

2

3

4

5

6

TLR8dd

ct

HC IBS

P=0.0019

0123456789 TLR4

ddct

HC IBS

P<0.0001

ImmuneActivation

Mast CellActivation

Microbiota

The Microbiota-Gut-Brain Axis

GutBarrier

Higher IL-6 and IL-8 levels in serumamong IBS patients

with Psychiatric

Co-morbidity

Fitzgerald et al, 2008

Immune Activation and Phenotype. Could this be Centrally Driven?

Craig et al, DDW 2012

Co-morbid Depression/Anxiety and IL-6 in IBS

Classical Approach to Constipation

Constipation

Colon TransitEvacuation

Delayed TransitNormal Evacuation

SLOW TRANSIT CONSTIPATION Normal TransitImpaired Evacuation

DEFECATORY DYSFUNCTIONDelayed Transit

Normal EvacuationIBS

Diagnostic tools for chronic constipation

Medical history

• Nature of symptoms- Duration of

constipation- Description of stool

movements• Frequency• Formation

• Current medications, including:- OTC laxatives- Prescription

agents• Health conditions

Rectal examination

• Perianal excoriation• Skin tags, hemorrhoids• Anocutaneous reflex• Anal fissure• Prolapse• Rectocele• Sphincter resting tone

Diagnostic testing

• Colonic transit• Balloon expulsion• Anorectal manometry• Dynamic pelvic

magnetic resonance imaging

• Defecography

Eoff JC, Lembo AJ. J Manag Care Pharm 2008;14:1–15

OTC: Over-the-counter

New Approaches

• Pro-secretory agents

• Prokinetics/Enterokinetics

Linaclotide

Binds to GC-C receptors on enterocytes

Elevation of CGMP levels: increase in anion efflux fluid secretion

Linaclotide:Increases intestinal secretionAccelerates intestinal transit Ameliorates visceral

hypersensitivity

Linaclotide in CC

Lembo et al Gastroenterology 2010

N = 310

Prucalopride

Quigley et al, APT 2009



Other approaches

Antibiotics*Rifaximin and methanogenic flora

Probiotics**Bifidobacterium lactis

Ileal Bile Acid Transporter Inhibitor A3309***Biofeedback and other behavioral approaches for “outlet” constipationSpinal stimulationSurgery

*Chmielewska and Szajewska, WJ Gastroenterol2010

**Quigley, Best Pract Clin Res Gastroenterol 2011***Simren et al, APT 2011

A3309 Phase IIB Study• A minimally absorbed

ileal bile acid transporter (IBAT) inhibitor

• 190 patients with CC (IBS and dysynergic defecation excluded)

• Primary outcome: change from baseline in number of spontaneous bowel movements per week

• Also saw improvements in stool consistency, CSBMs and bloating

Treatment Change from baseline in

weekly SBMsPlacebo 1.7

A3309 5 mg 2.5A3309 10 mg 4A3309 15 mg 5.4

• Lowered total and LDL Cholesterol

• Increased bile acid synthesis• Troublesome cramps and

diarrhea with 15 mg dose

Chey et al, Am J Gastroenterol 2011;106:1803-12

Sacral Nerve Stimulation

Summary

• Colonic motility remains poorly understood

• Diverticular disease represents a growing but relatively ignored public health issue

• IBS, a variable amalgam of common gastrointestinal symptoms, is an important global issue

• Alterations in the microbiota or in microbiota-host interactions could explain some symptoms in IBS or lead to immune activation which could, in turn, influence local and central pathways

• New therapeutic avenues are opening in IBS and chronic constipation

Supported by: Science Foundation Ireland, HRB, EU, Wellcome Trust, Enterprise Ireland, Higher Education Authority

Students, Trainees, Post-Docs, Scientists:• Clare O’Leary • Rodrigo Quera• John Keohane• Ahmed Abu-Shanab• Morcos Ashraf• Alan Desmond • Sebastian McWilliams• Katie Walsh• OJ O’Connor • Orla Craig • Zaid Heetun• Marianne Fraher • Paul Scully• Ian Jeffery• John McSharry• Caroll Beltran• Ger Clarke• Ger Moloney• Clare Codling• Declan McKernan• Peter Fitzgerald

Co-PI’s in APC:Gerald FitzgeraldMichael MaherPaul O’TooleJulian MarchesiKen NallySylvia MelgarLiam O’MahonyBeth BrintPaul RossCatherine StantonJohn CryanTed DinanNiall HylandSiobhain O’MahonyMichael MolloyDouwe van SinderenCharles Daly

Alimentary Health:Barry KielyEileen MurphyJenny RoperEileen MurphyCarmel Wycherly

COLONISTGeraldine GreelyAnne O’Neill

CUH/MUHPaula O’LearySeamus O’MahonyOrla CrosbieAli KhashanLouise KennyMartin BuckleyJane McCarthy

Director of APC and Chair, Dept of MedicineFergus Shanahan

Documents

Colonic Motility Disorders - · PDF file• Acute Diarrhea (UPDATED) ... • Pelvic floor musculature and the puborectalis ... prolonged pain lasting on average 3 days