ROME Update UEGW Rome Faculty Douglas Drossman, MD University of - - PowerPoint PPT Presentation

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

• f 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

20 40 60 80 100

Postprandial SBWC

Maltodextrin Psyllium

Postprandial SBWC, mL

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
• f 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

20 40 60 80

Response to SNS (ITT analysis)

OFF ON Stimulation period

Response rate, %

20 15 13.5

10 20 30 40

Baseline After temporary stimulation 1 year

Median Wexner Scores

Median Wexner 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

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

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

50 100 150 200 250

P<0.001

Sham diet Low FODMAP diet

Mean IBS-SSS Score

201.7 196.9

50 100 150 200 250

P=0.75

Placebo VSL #3

Mean IBS-SSS Score at Follow-Up*

Mean IBS-SSS 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

10 20 30 40 50 60

P<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
• n 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 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 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
• ral 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

1 2 3 Estimated mean change vs placebo (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

• 0.776

Soft stools by Rome II and III 0.798 Motility Index (baseline) 0.827 Motility Index (distension) 0.692 Motility Index (recovery) 0.816 AML Pain Threshold 0.939 AML Urge Threshold 0.934 Catastrophizing 0.659 RPSQ Somatization 0.621 BSI Depression (BSI-18) 0.838 BSI Anxiety (BSI-18) 0.838 Neuroticism (NEO-PI) 0.724

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.

2835

theromefoundation.org

Two Educational Models

Visiting Professorship  Top tier investigators and clinicians visit an academic medical center for 1-3 days :  Medical and gastroenterology grand rounds  Clinical case conferences with faculty and trainees  Individual advisory meetings with young aspiring faculty seeking careers in FGIDs  Workshops or other training programs as requested Visiting Lectureship  One day visit to a medical center, large clinical practice, GI club

• r community oriented educational venue

 Grand rounds to an academic program  Round table discussion, case conference or lecture

Rome Foundation Visiting Professorships and Lectureships

2838

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

2839

Industry Sponsors

Prometheus Laboratories Inc., Ferring Pharmaceuticals Inc., Salix, a division of Valeant Pharmaceuticals North America LLC., Ironwood Pharmaceuticals, Inc.