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
Michael Fried: a Global Perspective
• 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)
Colonic Motility Disorders
•Motility of the Colon
•Diverticular disease
•IBS
•Constipation
•The microbiota
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
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
Burden of Disease
*Kang JY, et al. Aliment Pharmacol Ther 2003;17:1189-1195
• Inpatient admissions UK 1989-2000*
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.
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
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
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
Evidence for a role for the Microbiota in IBS
• 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
Evidence for a role for the Microbiota in IBS
• 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
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
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
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
Scully et al, Am J Gastroenterol 2010
Microbiota(Dysbiosis)
Mucosa(Immune Dysfunction)
DysmotilityVisceral Hypersensitivity
Gut-Brain Axis Dysfunction
Immune Activation
Beyond the Gut?
IL6, IL8
IL1β, TNFα
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
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?
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?
Keohane et al, Am J Gastroenterol 2010
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
Keohane et al, Am J Gastroenterol 2010
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
Keohane et al, Am J Gastroenterol 2010
A Probiotic can Reduce Stress Response
Bravo et al,PNAS 2011
Associated with altered levels of GABA in the brainEffects abolished by vagotomy
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
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?
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
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
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
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