ROME Update UEGW - Focus · patients with IBS and to study the underlying mechanisms Methods •...
Transcript of ROME Update UEGW - Focus · patients with IBS and to study the underlying mechanisms Methods •...
ROME Update UEGW
Rome Faculty
Lin Chang, MD David Geffen School of Medicine at UCLA
Los Angeles, CA
Douglas Drossman, MD University of North Carolina
Drossman Gastroenterology PLLC
Chapel Hill, NC
William Chey, MD University of Michigan
Ann Arbor, MI
Rome Faculty Disclosures
Lin Chang, MD Advisory Board Membership: Salix, QOL Medical, Takeda, Ironwood, Allergan,
Commonwealth Labs, Astra Zeneca, Ardelyx
Douglas Drossman, MD Nothing to disclose
William Chey, MD
Grants/Research Support: Ironwood, Perrigo, Prometheus, Nestle Consultant/Speaker Bureau: Ardelyx, Astra-Zeneca, Albivro, Actoris, Ironwood
Honorarium Recipient: Ardelyx, Astra-Zeneca, Albivro, Actoris, Ironwood
Planning Committee
Julie Messick Nothing to disclose
5
This Program is Supported by Educational Grants from:
Prometheus Laboratories Inc., Ferring Pharmaceuticals Inc., Salix, a division
of Valeant Pharmaceuticals North America LLC., Ironwood
Pharmaceuticals, Inc.
3013
theromefoundation.org
3012
How Does Psyllium Really Work in
Constipation?
A Double-Blind Crossover Study to Evaluate
Its Impact on Magnetic Resonance Imaging
Biomarkers
K. Murray, G. Major, C. Hoad1, A. Nowak, L. Marciani,
A. Silos-Santiago, C. Kurtz, J. Johnston, P. Gowland,
R. Spiller, on behalf of the
University of Nottingham GI MRI Research Group
Aims and Methods
Aims
• To assess the effect of psyllium on MRI imaging biomarkers
Methods
• Double-blind crossover study of adults with functional constipation or IBS-C by
Rome III criteria
• Patients randomized to Metamucil Original Coarse Fiber 14 g TID (21 g/day) or
placebo comparator (maltodextrin 14 g TID)
– Treatment periods were preceded by 10 days of usual laxatives, then 8 days
without therapy
• Patients swallowed 5 MRI transit markers at 0800 on Day 5 of treatment
• On Day 6, MRI scans were taken fasting and serially after a standard test meal for 7
hours, with a final fasting scan on Day 7 of treatment
• Primary endpoint was the Weighted Average Position Score of transit markers 24
hours after ingestion (WAPS24) (score increases with longer whole gut transit)
• Secondary endpoints
– Free water content of the small bowel (SBWC) and ascending colon (ACWC)
– T1 and T2 values of the chyme in the ascending colon (AC) and descending colon (DC)
– Colonic volume (CV)
Murray K et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP059.
Results
*All analyses by paired t-test.
Murray K et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP059.
32.9
81.5
0
20
40
60
80
100
Postprandial SBWC
Maltodextrin Psyllium Postp
randia
l S
BW
C, m
L
P<0.001*
AC, ascending colon; CV, colonic volume; DC, descending colon; SBWC, small bowel water content; WAPS, Weighted Average Position Score of
transit markers 24 hours after ingestion.
• 16 subjects completed both treatment
periods
• Psyllium accelerated WGT such that
WAPS24 decreased by mean 0.8 (1.8,
P=0.05, 1-tailed), or 24%
• Increase in SBWC was followed by a
smaller increase in ACWC (P<0.05)
• Fasting T1 values were lower than
previously reported in healthy volunteers,
but increased on psyllium in both the AC
(P<0.001) and DC (P<0.01) to values
within the normal range
• CV increased by 332mL (95%CI 214–
451, P<0.001), or 48%
Results
Effect of Psyllium on Key MRI Parameters
*Values from previous studies of healthy volunteers.
AC, ascending colon; CV, colonic volume; DC, descending colon; SBWC, small bowel water content; WAPS, Weighted
Average Position Score of transit markers 24 hours after ingestion.
Healthy volunteers*
Patients with
constipation on
maltodextrin
Patients with
constipation on
psyllium
WAPS24 0.8 (0–1.6) 3.4 (1.6-4.8) 2.2 (1.5-3.0)
Colonic volume (mL) 561 (239) 690 (218) 1022 (240)
T1 AC (secs) 0.77 (0.64-0.92) 0.55 (0.49-0.61) 0.82 (0.44-1.14)
T1 DC (secs) 0.55 (0.39-0.85) 0.23 (0.19-0.55) 0.57 (0.32-0.78)
Murray K et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP059.
Conclusions
• Psyllium decreased WGT while both CV and fluidity of the colonic chyme (T1)
increased
– These measures were different on placebo than prior data in healthy volunteers
and demonstrated a significant response to therapy
• The sequences used are readily translatable to any MRI scanner in clinical
use and are promising as non-invasive biomarkers for the assessment of
constipation and the effect of gut modulators
Murray K et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP059.
CV, colonic volume; WGT, whole gut transit.
Sacral Nerve Stimulation for Refractory
Constipation: Preliminary Results of a
Multicenter Randomized Cross-over Double-
blind Study
F. Zerbib, L. Siproudhis, P.-A. Lehur, C. Germain,
F. Mion, A.-M. Leroi, B. Coffin, A. Le Sidaner, V. Vitton,
C. Bouyssou-Cellier, G. Chene
Aim/Methods
Aim
• To assess the efficacy of sacral nerve stimulation (SNS) in a multicenter randomized
cross-over double blind study
Methods
• Patients with severe constipation refractory to conservative therapy were included if they
had ≥ 2 of the following: i) < 3 BMs/week, ii) straining to evacuate on >25% of attempts,
iii) sensation of incomplete evacuation on >25% of occasions
• Permanent neurostimulator implantation offered to responders to 3-week temporary
stimulation (response defined by number of BMs ≥3/week and/or >50% improvement in
symptoms
• After 2-week washout, patients were randomized in a crossover design to two, 8-week
periods of active (ON) or sham (OFF) stimulation separated by 2-week washouts
– Patients and investigators were blinded to the stimulation sequence
• At the end of the 2 trial periods, all patients were offered active stimulation until the last
evaluation at 1 year
• Symptoms (Wexner score, Visual Analogic Scale), Quality of Life scale, and
tolerability/side effects were assessed before and at the end of each period
• Colonic transit time and anorectalmanometry were performed at inclusion and at the end
of follow-up
Zerbib F et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP060.
Results
• 36 patients underwent temporary stimulation
– Mean age (SD) 45 (14) years, 33 female
– Most (77.8%) had predominant dyschesia
• Of 21 (58.3%) responders, 20 received permanent stimulation
– Mean age (SD) 44 years (15), 19 female
• Stimulator explanted in 3 patients during the study period*
• After 1-year follow-up, 55% of implanted patients (n=11) remained responders
55 60
0
20
40
60
80
Response to SNS
(ITT analysis)
OFF ON
Stimulation period
Response r
ate
, %
20
15 13.5
0
10
20
30
40
Baseline After temporary stimulation
1 year
Median Wexner Scores
Media
n W
exner
score
Zerbib F et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP060.
* Reasons for explantation included infection of the stimulator site (n=2) and lack of efficacy/consent withdrawal (n=1).
Conclusions
• In patients with refractory constipation who responded to temporary SNS,
this randomized double-blind study could not demonstrate any significant
effect of active stimulation (ON) compared to absence of stimulation (OFF)
• SNS may be a therapeutic option in a small subgroup of patients
– Positive response remained 1 year after permanent implantation of the stimulator in
30% of initially-tested patients
Zerbib F et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP060.
Bifidobacterium Longum NCC3001 Improves
Depression and Reduces Brain Emotional
Reactivity in Patients with Irritable Bowel
Syndrome (IBS): A Randomized
Double-blind, Placebo-controlled Trial
M. I. Pinto-Sanchez, G. B. Hall, K. Ghajar, A. Nardelli,
C. Bolino, C. Welsh, A. Rieder, J. Traynor, C. Gregory,
J. Lau, A. C. Ford, G.E. Bergonzelli, M. Surette,
S. Collins, P. Moayyedi, P. Bercik
Aim/Methods
Aim
• To evaluate the effects of B. longum NCC3001 on anxiety and depression in
patients with IBS and to study the underlying mechanisms
Methods
• Randomized, double-blind, placebo-controlled, single center study in adult
patients with IBS with diarrhea or mixed stool pattern (Rome III criteria) and mild
to moderate anxiety and/or depression
• B. longum or placebo (maltodextrin) was administered daily for 6 weeks
• Validated questionnaires were used to assess anxiety and depression (HAD
score, STAI), IBS symptoms (adequate relief question, IBS Birmingham and
Bristol scale), quality of life (SF-36) and somatization (PHQ-15) before, at the
end and 1 month after the treatment (follow-up)
• Brain activation patterns assessed with backward masked fear paradigm (fMRI),
cognitive function (memory and concentration), serum BDNF and inflammatory
markers, and gut microbiota profiles (16S rRNA Illumina)
Pinto-Sanchez MI et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP162.
Results
• 38 of 44 patients randomized completed the study (B. longum=18, placebo=20)
• Compared with placebo, treatment with B. longum was associated with
– Improved depression scores at 6 weeks (RR 2.94, 95% CI 1.05-8.23, P=0.01)
and through follow-up
– Higher percentage of patients reporting adequate relief of overall IBS symptoms (RR 2.1,
95% CI 1.15-3.83, P=0.02)
– No statistically significant changes in IBS Birmingham scores
– Improved physical subdomain of quality of life (P=0.03, Mann–Whitney U=228.5), with
trends for improvement in the mental subdomains of vitality and emotional role functioning
– Significant reductions from baseline via functional MRI in response to negative emotional
stimuli in multiple brain areas involved in emotion processing, including amygdala, frontal
and temporal brain regions (P<0.001)
• No statistically significant differences were observed in anxiety, cognitive function,
inflammatory markers, serum BDNF levels or gut microbiota profiles in B. longum-
treated patients compared to placebo
Pinto-Sanchez MI et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP162.
Conclusions
• Our results demonstrate that 6-week treatment with B. longum
NCC3001 improves comorbid depression, overall gastrointestinal
symptoms and quality of life in patients with IBS
• This is associated with changes in the brain activation patterns in the
amygdala and fronto-limbic regions, suggesting that reduction in
limbic reactivity may underlie the beneficial effect of this probiotic
Pinto-Sanchez MI et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP162.
The Impact of Low FODMAP Dietary Advice
and Probiotics on Symptoms In Irritable
Bowel Syndrome: A Randomized, Placebo-
controlled 2 x 2 Factorial Trial
H. Staudacher, M. C. Lomer, J. Lindsay, P. Irving, K. Whelan
Aim/Methods
Aim
• To investigate the effect of low-FODMAP dietary advice with a probiotic on
symptom response compared with a sham diet in patients with IBS
Methods
• Adults with IBS referred to a secondary care dietetic service were randomised
to low FODMAP or sham (placebo) dietary advice and the multistrain probiotic
VSL #3 or placebo for 4 weeks in a 2 x 2 factorial design
– Sham (placebo) diet was designed to be equivalent in nutrients and FODMAP content
to habitual diet
• Outcome measures included the global symptom question (‘did you have
adequate relief of your IBS symptoms over the last 7 days?) and the validated
IBS symptom severity scale (IBS-SSS, maximum score 500) at baseline and
follow up
• Statistical analysis performed using logistic and linear regression
Staudacher H et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP163.
Results
• 104 patients were recruited and 95 completed the study (63 females, 66%)
– 8 withdrawals (4 low FODMAP, 4 sham) and 1 loss to follow up (sham)
• There was no significant interaction between diet (LFD/sham) and probiotic
(VSL#3/placebo) for adequate relief or IBS-SSS
Staudacher H et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP163.
38
57
0
20
40
60
80
RR 1.51
(95% CI,0.99, 2.29)
P=0.05
Proportion of Patients Achieving Adequate Relief at Follow-Up
(ITT population)
Sham diet Low FODMAP
diet
Responders
, %
37
57
0
20
40
60
80
Placebo VSL #3
Responders
, %
RR 1.52
(95% CI,0.99, 2.33)
P=0.05
Results
Staudacher H et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP163.
231.8
165.5
0
50
100
150
200
250
P<0.001
Sham diet Low
FODMAP
diet
Mean IB
S-S
SS
Score
201.7 196.9
0
50
100
150
200
250
P=0.75
Placebo VSL #3
Mean IBS-SSS Score at Follow-Up*
Mean IB
S-S
SS
Score
*Adjusted for baseline values.
Results
Staudacher H et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP163.
44.7 41.6
54.5
28.6 27.3
40.7
0
10
20
30
40
50
60P<0.001
Pain Distension Satisfaction with
bowel habit
Days
IBS-SSS Subscores (Number of Days with
Symptom)at Follow-Up
P=0.001
P<0.001
Results/Conclusions
Conclusion
• This is the first randomiszd placebo-controlled trial evaluating the effect of low
FODMAP dietary advice which demonstrates greater effectiveness compared
with sham advice for IBS symptoms
• The effectiveness of this probiotic is equivocal
• Whether concomitant probiotic treatment is able to prevent the impact of LFD
on the microbiota will be investigated
Staudacher H et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP163.
Consistency In Efficacy Outcomes of
Eluxadoline Treated Patients with Irritable
Bowel Syndrome With Diarrhea Using
Recent and Traditional Endpoints
M. J. Zuckerman, L. S. Dove, D. A. Andrae,
J. M. Davenport, L. Turner,
R. Lopez, P. S. Covington
Aim and Methods
Aim
• To examine the consistency of eluxadoline (ELX) efficacy outcomes in two
26-week, double-blind, placebo-controlled Phase 3 trials by comparing the daily
composite response endpoint with Global Symptom Score (GSS) and the patient-
friendly, traditional adequate relief (AR) endpoint
Methods
• Patients meeting Rome III criteria for IBS-D were randomized to ELX (75 or 100 mg)
BID or placebo
• Primary endpoint was composite response (based on simultaneous improvement in
daily worst abdominal pain [0–10 scale] and stool consistency [Bristol Stool Scale 1–7]
with 50% of days demonstrating a response) evaluated over Wks 1–12 and 1–26 (with
≥60/84 or ≥110/182 days of diary compliance, respectively)
• Patients indicated whether they had AR from IBS symptoms over the past week and
rated their daily IBS symptoms over the past 24 h (0=none, 4=very severe)
• Efficacy assessments included CMH analysis requiring AR response of ≥ 6/12 or
≥13/26 weeks
– For assessment of GSS, CMH analysis of ≥50% of days with either daily GSS <2 or GSS
improved by ≥2 compared with baseline average
• Change from baseline in GSS assessed using ANCOVA of pooled data
ANCOVA, analysis of covariance; CMH, Cocrhane-Mantel-Haenzel.
Zuckerman MJ et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP168.
Results
• N=2428 patients with IBS-D across both trials
• Average GSS scores decreased in all groups and in both studies from
baseline through Week 26
• Significantly more patients receiving ELX were composite responders
compared with placebo-treated patients (P≤0.014), with the exception of
patients receiving ELX 75 mg in IBS-3001 over Weeks 1–26
• Comparable results were seen for GSS and AR endpoints with ELX 75 and
100 mg
• Efficacy in the ELX 100 mg group was more robust than in the 75 mg group
in both trials, and results from IBS-3002 were generally more robust than
those from IBS-3001
• Pooled data for ANCOVA change from baseline for GSS also demonstrated
superiority over PBO at Weeks 12 and 26 (P≤0.008)
Zuckerman MJ et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP168.
Results
Zuckerman MJ et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP168.
17.1 19
28.8 32.3
43.8 40
23.9 23.4
35.1 36.3
52.9 45.7
25.1 29.3 34.7 37.1
54.2 49.5
0
10
20
30
40
50
60
70
Responders
, %
Study 3001
P=0.014
Weeks 1–12 Weeks 1–26 Weeks 1–12 Weeks 1–26 Weeks 1–12 Weeks 1–26
Daily composite endpoint GSS Adequate relief
P=0.004 P<0.001
P=0.112
P=0.063
P=0.048
P=0.144
P=0.002 P=0.005
P=0.221
P=0.008 P=0.097
Efficacy Outcomes
Placebo Eluxadoline 75 mg Eluxadoline 100 mg
Results
Zuckerman MJ et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP168.
16.2 20.2
29.6 34.3
49.2 43.7
28.9 30.4
43.6 45.1
60.1 52.8
29.6 32.7
42.4 43.2
58.4 53.7
0
10
20
30
40
50
60
70
Responders
, %
Study 3002
P<0.001
Weeks 1–12 Weeks 1–26 Weeks 1–12 Weeks 1–26 Weeks 1–12 Weeks 1–26
Daily composite endpoint GSS Adequate relief
P<0.001 P<0.001
P=0.001
P<0.001
P<0.001
P=0.012
P=0.011 P=0.006
P=0.002
P=0.003 P=0.013
Efficacy Outcomes
Placebo Eluxadoline 75 mg Eluxadoline 100 mg
Conclusions
• Individual studies and pooled data demonstrated that ELX was superior to
PBO in relieving IBS-D symptoms
• Efficacy outcomes for the GSS endpoint and the more patient-friendly,
traditional AR endpoint were consistent with the primary efficacy composite
endpoint over 12 and 26 weeks
Zuckerman MJ et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP168.
Efficacy of Oral Ibodutant in IBS-D Female
Patients Measured by Urgency Score: An
IRIS-2 Exploratory Analysis
J. Tack, K. Schumacher, S. Scartoni, G. Tonini, K. Ott,
I. Otranto, F. Masciopinto, M. Bertolotti, A. Capriati,
C. A. Maggi
Aim and Methods
Aim
• To evaluate the benefit of ibodutant in a female IBS-D population exposed to
oral daily ibodutant doses of 1, 3 and 10 mg over 8 weeks of treatment and
2 weeks of treatment withdrawal in terms of the mean stool urgency score
changes versus baseline
Methods
• Among data collected through the IVRS/IWRS diary to characterize the
efficacy profile of ibodutant, stool urgency was assessed as measure of
IBS-D severity
• Mean change after 4 weeks, 8 weeks of treatment, and after 2 weeks of
treatment withdrawal vs baseline (daily IVRS/IWRS diary records) were
recorded according to a 5-point scale
– Scale ranged from from 0=no symptoms, 1=mild, 2=moderate, 3=severe to 4=very
severe
– Urgency response defined as intensity reduction of 1-score point (on 5-point scale)
compared to baseline
• Pre-specified analysis of variance (ANOVA) by gender
Tack J et al. UEGW 2015. October 24-2008, 2005; Barcelona, Spain: Abstract OP170.
Results
• At baseline, female patients (59.57% of total patients) reported a moderate
urgency intensity with a mean score value of 2.4 (0.7)
– No relevant differences between treatment groups
• Ibodutant was superior to placebo in improving stool urgency scores
measured after treatment
– LS Means: -33.71 in placebo, -34.86 in 1 mg, -38.34 in 3 mg, -38.17 in 10 mg
treatment arm
– Mean estimated score reduction was -4.47 (P=0.007) in the 10 mg treatment arm
vs baseline and 2 weeks after treatment withdrawal
• Mean score reduction of -4.63 (P=0.004) demonstrated in females
at 3 mg dose
– No statistically significant change in males
Tack J et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP170.
Results
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
Estim
ate
d m
ean c
hange v
s p
lacebo (
SE
) Ibodutant Dose
1 mg 3 mg 10 mg
Stool Urgency Score Mean Change During Treatment and
Withdrawal Period in IBS-D Female Population (N=333)
P=0.475
P=0.004 P=0.007
-1.15
(1, 617)
-4.63
(1, 623) -4.47
(1, 655)
Tack J et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP170.
Conclusions
• Ibodutant doses of 10 mg and 3 mg given once daily over 8 weeks of
treatment significantly improved mean stool urgency scores in female
IBS-D patients
• This decrease of stool urgency scores was maintained also over the ensuing
2-week treatment-free withdrawal phase
Tack J et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP170.
Principal Component Analysis (PCA) with
Replication Confirms Four Independent
Etiological Factors in Irritable Bowel
Syndrome (IBS)
M. van Tilburg, O. S. Palsson, W. Whitehead
Aim and Methods
Aim
• To determine whether the variables discriminating a large sample of IBS
patients from a demographically similar group of healthy individuals cluster
together in distinct patterns that suggest independent pathophysiological
factors in IBS
Methods
• Subjects with physician-diagnosed IBS (Rome II or III) and control subjects
without GI problems completed psychological and GI symptom
questionnaires
• Barostat tests performed in all IBS subjects and a subset of control subjects
to measure bowel sensory thresholds with the ascending method of limits
(AML) method and the colonic motility index
– Testing performed at rest, after the AML, after recovery, and after a standard meal
• Variables that significantly (P<0.05) differentiated IBS and control subjects
(were entered into PCA analysis with varimax rotation
• PCA was run twice, on randomly divided equal-size halves of the total IBS
sample, to examine stability of the generated model
van Tilburg M et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP270.
Results
• 530 IBS patients (79.4% females; mean age=35.8 years) and 337 controls
(78.7% females; mean age=34.7 years)
• Significant differences between IBS and control subjects found on all test
variables except motility post-meal, which was excluded from the PCAs
• Initial PCA, on half the total IBS sample, yielded 4 factors that were easily
identifiable as representing psychological functioning, motility, visceral
sensitivity, and abnormal stool consistency
– These factors collectively explained 63.9% of the total variance
• Replication PCA conducted with the other half of the IBS sample yielded the
same 4 factors with similar loadings, confirming the IBS factor structure
– Explained 63.4% of the variance
van Tilburg M et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP270.
Results
Psychological Functioning Motility
Visceral
Sensitivity
Abnormal Stool
Consistency
Hard stools by Rome II and III 0 0 0 -0.776
Soft stools by Rome II and III 0 0 0 0.798
Motility Index (baseline) 0 0.827 0 0
Motility Index (distension) 0 0.692 0 0
Motility Index (recovery) 0 0.816 0 0
AML Pain Threshold 0 0 0.939 0
AML Urge Threshold 0 0 0.934 0
Catastrophizing 0.659 0 0 0
RPSQ Somatization 0.621 0 0 0
BSI Depression (BSI-18) 0.838 0 0 0
BSI Anxiety (BSI-18) 0.838 0 0 0
Neuroticism (NEO-PI) 0.724 0 0 0
Factor Loadings of Factors That Significantly
Differentiated IBS and Control Subjects*
van Tilburg M et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP270.
*Factors scoring ≤0.35 set to 0 for clarity.
Conclusions
• These findings of f4 robust and replicable factors in our large IBS sample
confirm that psychological variables, motility, visceral sensitivity and stool
consistency abnormalities are all independent and prominent etiological
contributors to IBS
van Tilburg M et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP270.
Identification of a Gut Microbial Signature
Linked to Severity or Irritable Bowel
Syndrome
J. Tap, M. Derrien, L. Öhman, R. Brazeilles,
S. Cools-Portier, J. Doré´,
B. Le Nevé´, H. Törnblom, M. Simren
Aim and Methods
Aim
• To explore the role of altered gut microbiota in the heterogeneity of IBS
pathophysiology
Methods
• Subjects with IBS (ROME III, all subtypes) and healthy controls were characterized for
symptom severity (IBS-SSS, GSRS), psychological comorbidities (HAD, FIS, PHQ-15,
VSI) and quality of life (IBSQoL)
• Combined nutrient and lactulose challenge test with symptom assessment and
measurement of exhaled H2 and CH4 was performed
• Unprepared sigmoid colon biopsies and stool samples were obtained
– Paired fecal and mucosal microbiota were analyzed by 16S rRNA targeted
pyrosequencing with LOTUS v1.32 to identify Operational Taxonomical Units and
Green Genes database
– Microbial enterotype stratification was identified with the Dirichlet multinomial
bayesian statistics
• Microbial IBS signature was identified using machine learning procedure and L1
regularized logistic regression and validated through a 10-fold independent cross-
validation
• Quantitative PCR was used to detect archaea methanogens in stool samples
Tap J et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP404.
Results
• 130 subjects (95 IBS, n=78 severe IBS) and 35 healthy controls
• 16S rRNA microbiota OTU-based data complexity was reduced using a
machine-learning procedure into a ‘‘species-specific IBS severe signature’’,
consisting of 100 bacterial OTUs linked to IBS severity (assessed by IBS-SSS)
– This IBS severity microbial signature has been further confirmed in sigmoid
mucosal microbiota (n=57, AUC=0.80) and an external validation stool set
(n=46, AUC=0.68), allowing discrimination of severe IBS from mild/moderate
IBS patients and healthy controls
• Using this signature, IBS symptom severity score was significantly and
negatively associated with
1) exhaled CH4
2) presence of Archaea methanogens
3) microbial species richness
4) enterotypes enriched either with Clostridiales or Prevotella species
• This IBS severity signature was independent from age, gender, BMI and
exhaled H2
Tap J et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP404.
Conclusions
• These results indicate that IBS symptom severity is associated with a distinct
signature at the fecal microbiota level
• Exhaled CH4, enterotypes stratification and mucosal microbiota are linked
with this signature
• Whether this indicates a causal role of gut microbiota alteration in the
genesis of IBS symptoms remains to be investigated
Tap J et al. UEGW 2015. October 24-28, 2015; Barcelona, Spain: Abstract OP404.
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Visiting Lectureship
One day visit to a medical center, large clinical practice, GI club or community oriented educational venue
Grand rounds to an academic program
Round table discussion, case conference or lecture
Rome Foundation Visiting Professorships and Lectureships
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Year One
Completed
Year Two March 1 – December 31, 2015 Call for Year Two applications
December 1– December 31, 2015 Grant review, speaker and site selection
January 1 – December 31, 2016 Grant award period – year two
Rome Foundation Visiting Professorships and Lectureships
Selection Committee William D. Chey, MD USA (co-chair) Jan Tack, MD PhD Belgium (co-chair)
Douglas A. Drossman MD USA Magnus Simren, MD, PhD Sweden
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Industry Sponsors Prometheus Laboratories Inc., Ferring Pharmaceuticals Inc., Salix, a
division of Valeant Pharmaceuticals North America LLC., Ironwood
Pharmaceuticals, Inc.