1. La Sindrome Digestiva Funzionale:
non solo colon irritabile
Cesare Cremon
Policlinico S.Orsola – Malpighi
Azienda Ospedaliero - Universitaria di Bologna
(1088 – 2013)

2. Disordini Funzionali Gastro-Intestinali
>40% popolazione generale lamenta sintomi digestivi
Ho la pancia gonfia
Ho la pancia gonfia
eemi fa male
mi fa male
Ho mal di pancia
Ho mal di pancia
Mi sento piena
Mi sento piena
Mi brucia ililpetto
Mi brucia petto
Ho mal di stomaco
Ho mal di stomaco
Sono stitica
Sono stitica
Ho spesso diarrea
Ho spesso diarrea

3. The FGID and the Rome III Process
A. Functional esophageal disorders
A1. Functional heartburn
A2. Functional chest pain of presumed esophageal origin
A3. Functional dysphagia
A4. Globus
–
–
B1. Functional dyspepsia
• B1a. Postprandial distress syndrome
• B1b. Epigastric pain syndrome
B2. Belching disorders
• B2a. Aerophagia
• B2b. Unspecified excessive belching
B3. nausea and vomiting disorders
• B3a. Chronic idiopathic nausea
• B3b. Functional vomiting
• B3c. Cyclic vomiting syndrome
B4. Rumination syndrome in adults
–
–
–
–
–
C1. Irritable bowel syndrome
C2. Functional bloating
C3. Functional constipation
C4. Functional diarrhea
C5. Unspecified functional bowel disorder
–
–
–
E1. Functional gallbladder disorder
E2. Functional biliary SO disorder
E3. Functional pancreatic SO disorder
–
–
Symptom-based diagnostic criteria
not explained
by other pathologically based disorders
–
–
–
–
F1. Functional fecal incontinence
F2. Functional anorectal pain
• F2a. Chronic proctalgia
– F2a1. Levator ani syndrome
– F2a2. Unspecified functional anorectal pain
• F2b. Proctalgia fugax
F3. Functional defecation disorders
• F3a. Dyssynergic defecation
• F3b. Inadequate defecatory propulsion
B. Functional gastroduodenal disorders
–
–
C. Functional bowel disorders
D. Functional abdominal pain syndrome
E. Functional gallgallbladder and Sphincter of Oddi disorders
F. Functional anorectal disorders
FGIDs:
6 major domains for adults
28 disorders
–
Drossman DA. Gastroenterology 2006;130:1377–90

4. The Challenge of Functional Gastrointestinal Disorders (FGID)
Variable combination of chronic or recurrent gastrointestinal symptoms
Variable combination of chronic or recurrent gastrointestinal symptoms
not explained by structural //biochemical abnormalities
not explained by structural biochemical abnormalities
• Highly prevalent conditions (female-to-male ratios of 2-3:1)
• Significant burden on health-care systems
• Economic impact (direct and indirect costs: work absenteism x3)
• Reduced patient’s QoL
• Pathophysiology poorly understood
• Poorly effective therapy

5. FGID – Conceptual Model
Early Life
•Genetics
•Environment
Psychosocial
Factors
•Life stress
•Psychologic state
•Coping
•Social support
Brain
CNS
Physiology
Gut
ENS
FGID
•Symptoms
•Behavior
Outcome
•Medications
•MD visits
•Daily function
•Quality of life
•Motility
•Sensation
•Inflammation
•Altered bacterial flora
Drossman DA. Gastroenterology 2006;130:1377–90

6. New pathophysiologic aspects in FGID
Stress (CRF)
anxiety, depression
Genetic polymorphisms
(IL-10, TGF-β, TNF-α, IL-6, SERT, TNFSF15 )
Gene expression
Increased mucosal
permeability (↓ ZO-1)
Mucosal
immune
activation
Altered enteroendocrine
metabolism
(serotonin)
Neuroplasticity
(SP, NGF)
Food hypersensitivity (gluten? FODMAP?)
BAM
Transient infection
Altered microbiota (dysbiosis?)
Barbara G and Stanghellini V. Gut 2009;58:1571-5

7. Prevalence of FGIDs (Rome III criteria)
in a randomized population-based study
Prevalence of FGIDs (%)
one-year recall time
25
A community random sample:
900 residents of Olmsted Country, Minnesota
20
15
10
5
0
IBS
Chronic
constipation
Functional
dyspepsia
PDS
EPS
Rey E et al., Aliment Pharmacol Ther 2010;31:1237-47

8. Functional Gastro-Intestinal Disorders
the old days…
”a young anxious woman”, “an exclusion diagnosis”
the present…
”a positive diagnosis”

9. The FGID and the Rome III Process
A. Functional esophageal disorders
Symptom-based diagnostic criteria
not explained
by other pathologically based disorders
–
–
–
–
A1. Functional heartburn
A2. Functional chest pain of presumed esophageal origin
A3. Functional dysphagia
A4. Globus
B. Functional gastroduodenal disorders
– B1. Functional dyspepsia
–
• B1a. Postprandial distress syndrome
• B1b. Epigastric pain syndrome
B2. Belching disorders
• B2a. Aerophagia
• B2b. Unspecified excessive belching
B3. nausea and vomiting disorders
• B3a. Chronic idiopathic nausea
• B3b. Functional vomiting
• B3c. Cyclic vomiting syndrome
B4. Rumination syndrome in adults
–
–
–
–
C2. Functional bloating
C3. Functional constipation
C4. Functional diarrhea
C5. Unspecified functional bowel disorder
–
–
–
E1. Functional gallbladder disorder
E2. Functional biliary SO disorder
E3. Functional pancreatic SO disorder
–
–
F1. Functional fecal incontinence
F2. Functional anorectal pain
• F2a. Chronic proctalgia
– F2a1. Levator ani syndrome
– F2a2. Unspecified functional anorectal pain
• F2b. Proctalgia fugax
F3. Functional defecation disorders
• F3a. Dyssynergic defecation
• F3b. Inadequate defecatory propulsion
–
–
C. Functional bowel disorders
– C1. Irritable bowel syndrome
D. Functional abdominal pain syndrome
E. Functional gallgallbladder and Sphincter of Oddi disorders
F. Functional anorectal disorders
FGIDs:
6 major domains for adults
28 disorders
–
Drossman DA. Gastroenterology 2006;130:1377–90

10. Rome III Criteria* for Functional Dyspepsia
One or more (at least several times per week) of:
• Bothersome postprandial fullness
• Early satiation
• Epigastric pain
• Epigastric burning
No evidence of structural disease (upper endoscopy)
Postprandial
Distress Syndrome
Epigastric Pain
Syndrome
*Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis
Tack J et al., Gastroenterology 2006;130:1466–79

11. Pathophysiology complicated …
Psychsocial factors
Visceral hypersensitivity
Delayed gastric emptying
Decreased fundic
accommodation
Gastric acid
Overdistended antrum
Mild inflammation
(Helicobacter pylori)
… or poorly understood ?
Tack J et al., Gastroenterology 2006;130:1466–79

12. Risk indicators of delayed gastric emptying of solids
in patients with functional dyspepsia
Odds ratio
Delayed gastric emptying: 33.5% of dyspeptics
30
15
0
Female sex
Postprandial fullness
Vomiting
*
*
*
*
*
*
Stanghellini V et al., Gastroenterology 1996;110:1036-42

13. Diagnostic Algorithm for Functional Dyspepsia
*
*Alarm features include age, unintentional weight loss, symptoms that awaken the patient
at night, dysphagia, lymphadenopathy, abdominal mass, and signs of anemia
Tack J and Talley NJ. Am J Gastroenterol 2010; 105:757–63

14. Rome III Criteria* for IBS
Recurrent abdominal pain or discomfort at least 3
days per month in the last 3 months associated
with 2 or more of the following:
Improvement with
defecation
Onset associated
with change in
frequency of stool
Onset associated
with change in
form of stool
*Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis
Longstreth et al., Gastroenterology 2006;130:1480-91

15. Localization of abdominal pain in IBS
Back pain
68-81%
52%
20%
31%
58%
Agreus et al., Gastroenterology 1995;109:671-80
Maxton et al., Gut 1991;32:784-6

16. Pain Comorbidity in IBS
 Frequent overlap
Migraine
Other GI
 Prevalence in female
IBS
Fibromyalgia
Dyspareunia
Interstitial
Cystitis
 Similar epidemiology
 Psychiatric co-morbidity
 Common pathophysiological aspects
Barsky AJ et al., Ann Intern Med 1999;130:910-21

17. Overlap between IBS, functional dyspepsia and GERD
144 patients with IBS
IBS
Dyspepsia
GERD
IBS
22.9%
22.9%
8.3%
IBS
GERD
45.8%
IBS
Dyspepsia
Cremon et al., Am J Gastroenterol 2009;104:392-400
Cremon et al., DDW 2013

18. IBS diagnosis
Positive diagnosis
(Rome III Criteria)

Recurrent abdominal pain or discomfort* at least 3
days per month in the last 3 months with symptoms
onset at least 6 months prior to diagnosis
*unconfortable sensation not described as pain

Associated with 2 or more of the following
1. Improvement with defecation
2. Onset associated with a change in
frequency of stool
3. Onset associated with a change in form
(appearance) of stool
Exclusion of alarm features
(red flags)
Age (> 50 yrs)
Family history of CR- ca., IBD, CD
Rectal bleeding
Anemia
Fever, ↑ ESR
Weight loss
Major change in symptoms
Abdominal mass
Longstreth et al., Gastroenterology 2006;130:1480-91
Mayer EA. N Engl J Med 2008;358:1692-9

19. Probability of organic disease
in patients with symptom-based diagnosis of IBS
Organic Disease
IBS (%)
General Popul. (%)
Colitis / IBD
0.5 - 1.0
0.3 - 1.2
Colon Cancer
0 - 0.5
4-6
Celiac Disease
4. 7
0.2 - 0.5
0 - 1.7
n.v.
6
5–9
GI Infections
Thyroid Dysfunction
Cash BD et al., Am J Gastroenterol 2002;97:2812–289

20. Diagnostic Algorithm for IBS
Spiller RC and Thompson WG. Am J Gastroenterol 2010;105:775-785

21. Take Home Messages
• Oltre il 40% della popolazione lamenta sintomi digestivi (in larga parte di natura
funzionale)
• FGIDs: combinazione variabile di sintomi gastrointestinali cronici o ricorrenti, in
assenza di anomalie strutturali o biochimiche
• Sfida per il MMG e il Gastroenterologo (alta prevalenza, enorme impatto sulla QoL ed
economico per la società)
• I tre più comuni sono: la sindrome dell’intestino irritabile, la dispepsia funzionale e la
stipsi cronica (>90% di tutti i FGIDs)
• Criteri di Roma → diagnosi positiva (non più diagnosi di esclusione) → segni e/o
sintomi di allarme

22. Take Home Messages
• La dispepsia funzionale è distinta in 2 sottogruppi: “Postprandial Distress Syndrome”
(forma “simil-motoria”) e “Epigastric Pain Syndrome” (forma “simil-ulcerosa”)
• Distinti meccanismi fisiopatologici e distinti trattamenti
• Il dolore/fastidio addominale è il sintomo cardine della sindrome dell’intestino
irritabile
• “Grande mimo” e frequente overlap con altri disordini funzionali
• L’assenza di segni/sintomi di allarme dovrebbe rassicurare il clinico che la diagnosi è
corretta → necessità di limitati accertamenti diagnostici (escludere malattia celiaca)

24. Breath test
• Breath test: test del respiro
• Esami non invasivi → diagnosi di:
intolleranze alimentari (ad es. lattosio,
fruttosio), la presenza di Helicobacter
pylori o la presenza di batteri in esubero
nel piccolo intestino (SIBO)
• Parte dei gas prodotti dalla fermentazione
batterica diffonde nel sangue ed è escreta
con il respiro

25. Small Intestinal Bacterial Overgrowth (SIBO)
• Presenza microbiologica di almeno 105
unità formanti colonie (CFU) per millilitro
(mL) nell’aspirato digiunale
• Tipo 1: batteri Gram+ del tratto
respiratorio superiore
• Tipo 2: incremento in batteri colici
• Diagnosi
– Test invasivi: aspirato di succo digiunale
ed esame colturale (gold standard)
– Test non-invasivi: misure di prodotti del
metabolismo batterico
Lin. JAMA 2004;292:852-8

26. Gasbarrini et al., Aliment Pharmacol Ther 2009;29 (Suppl 1):1-49

27. Diagnostic value of breath test in detecting SIBO
Lactulose BT
- sensitivity
- specificity
- +ve predictive value
- -ve predictive value
- diagnostic accuracy
52.4%
85.7%
61.5%
53.6%
55.1%
Glucose BT
- sensitivity
- specificity
- +ve predictive value
- -ve predictive value
- diagnostic accuracy
62.5%
81.8%
80.0%
65.5%
71.7%
Role, indication and
methodology of H2BT in
Digestive Disorders
Consensus conference
Rome, December 2007
Gasbarrini et al., Aliment Pharmacol Ther 2009;29 (Suppl 1):1-49

28. Gasbarrini et al., Aliment Pharmacol Ther 2009;29 (Suppl 1):1-49

30. Current Management of IBS
IBS Symptoms
Constipation
• Reassurance/diet
• Increase fiber (20 g)
• Osmotic laxative
Diarrhea
Gas/Bloating
First Line
• Reassurance/diet
• Loperamide
• Diphenoxylate
• Reassurance/diet • Reassurance/diet
• Treat the
• Treat constipation/diarrhea
• Antispasmodics
constipation
(e.g. PEG)
• Stool softener
• Bisacodyl
• Prokinetics
• Tegaserod*
• Prucalopride**
• Secretory stimulators
• Lubiprostone*
• Linaclotide*
Pain
(e.g. otilonium bromide,
trimebutine, peppermint oil)
Second Line
• Alosetron*
• Bile acid
sequestran
• Antibiotics
• Probiotics
*Not available in Europe
**Approved in Europe for the symptomatic treatment of chronic constipation
in women in whom laxatives fail to provide adequate relief
• Antibiotics
• Probiotics
• Antibiotics
• Probiotics
• Tricyclic antidepressants
• Selective serotonin
reuptake inhibitors
Adapted from Mayer EA. N Engl J Med 2008;358:1692-9

31. Major claims of probiotics in IBS
•
•
•
•
•
Restore intestinal dysbiosis
Modulate gastrointestinal motility
Reduce visceral hypersensitivity
Reduce low grade mucosal immune activation
Improve epithelial permeability
All these claims are based on convincing experimental evidence from preclinical studies

32. Major claims of probiotics in IBS
•
•
•
•
•
Restore intestinal dysbiosis
Modulate gastrointestinal motility
Reduce visceral hypersensitivity
Reduce low grade mucosal immune activation
Improve epithelial permeability
All these claims are based on convincing experimental evidence from preclinical studies

34. The efficacy of probiotics in the treatment
of irritable bowel syndrome: a systematic review
• 185 trials screened (RCT, adults patients, any
definition of IBS, probiotics versus placebo for at least 7
days)
• 18 trials eligible for inclusion
• Lactobacilli = 6
• Bifidiobacteria = 3
• Streptococci = 1
• Combination = 9
Moayyedi et al., Gut 2010;59:325-332

35. Forest plot of trials comparing probiotics with placebo on
overall IBS symptoms (dichotomous outcome)
10 studies with 918 participants
NNT = 4
High heterogeneity X2 = 28.3
No differences between different type
of probiotic, all showing small benefit
Moayyedi et al., Gut 2010;59:325-32

36. Placebo controlled clinical trials of probiotics in IBS
Simren M, Barbara G, et al., Gut 2013;62:159-76

37. Drawbacks of probiotics in IBS
• Several different formulations have been tested
• Strain, dose, and mechanism of action are not fully clarified
• Same formulation gave contraddictory results
• Different patient populations included in studies (eg, IBS definition, bowel
habit, source), frequently not controlled for concomitant therapies
• Long-term studies are not currently available
• Safety-data are not fully established

39. New pathophysiologic aspects in FGID
Stress (CRF)
anxiety, depression
Genetic polymorphisms
(IL-10, TGF-β, TNF-α, IL-6, SERT)
Gene expression
Increased mucosal
permeability (↓ ZO-1)
Mucosal
immune
activation
Altered enteroendocrine
metabolism
(serotonin)
Neuroplasticity
(SP, NGF)
Food hypersensitivity (gluten?)
BAM
Transient infection
Altered microbiota (dysbiosis?)
Barbara and Stanghellini Gut 2009;58:1571-5

40. New pathophysiologic aspects in IBS
• IBS is a multifactorial disease
• Application of novel thechniques discovers the
participation of cellular and molecular mechanisms
in IBS pathophysiology
• During the last years, the role of the intestinal
microbiota in IBS pathophysiology has received
great interest
• Microbiota committee evaluating the role of the
intestinal microbiota in functional gastrointestinal
disorders
• Evidence of microbiota changes (dysbiosis) in IBS?

41. Post-Infectious IBS
Gastrointestinal infection
• Campylobacter
• Shigella
• Salmonella
•…
1.4 episodes/yr
Acute
Symptoms
Dysbiosis
Recovery
Post-Infectious IBS
(6-17%)
Persistent dysbiosis?
Spiller et al., Gastroenterology 2009;136:1979-88

42. Salmonella outbreak in Bologna
(October 19, 1994)
•
Tuna sauce contaminated with Salmonella enteritidis D
•
Delivered for lunch to 36 schools in the Bologna area
– 1770 subjects infected (acute symptoms)
• 1684 pupils (95%) – children 3-10 yrs
• 86 teachers or other school employees (5%) – adults 19-59 yrs
•
1543 (87.2%) completed a symptom questionnaire and underwent repeated
stool cultures (every 3 wks for 3 months)
•
Positive fecal cultures decreased from 100% to 1.5% at 3 months post-infection
•
6% of patients complained of PI symptoms (vomiting, abdominal pain,
diarrhea) at 3 months (negative culture in all cases)
Barbara et al., Aliment Pharmacol Ther 2000;14:1127-31

43. Salmonella outbreak in Bologna
(…16 years later)
Non-exposed
Exposed
IBS
50
*P = 0.007
OR = 2.05
(95% C.I.= 1.22-3.42)
*
Prevalence of IBS (%)
40
58/151
(38.4%)
30
20
32/137
(23.4%)
10
0
Cremon et al., DDW 2013; submitted

44. Microbiological revolution: What have we learned?
Agar plate
culture
• Long time to culture
• 60-80% unculturable
• Molecular biology
• 16S rRNA
• Number of microbiota genes > 100 time of human genome
• 1000-1150 bacterial species identified
• Each individual harbours >160 species
• “A silent organ” with high metabolic activity (biomass ≈ liver)
Gill SR, et al. Science 2006;312:1355–1359

45. 1.5
Different composition of fecal microbiota in IBS vs healthy
Multivariate analysis (RDA)
• 62 primary care IBS (Rome II), 46 HC
HC
IBS
• Deep molecular analysis
Axis2 (20.3%)
• 2-fold ↑ Firmicutes/Bacteroidetes ratio
• Multivariate analysis identifies 2 distinct
enterotypes
-1.5
C
V
-1.5
Axis1 (50%)
• IBS symptoms correlated with 18
phylogenetic groups (R = 0.29-0.43)
1.5
Rajilić-Stojanović et al., Gastroenterology 2011;141:1792-801

46. Irritable bowel syndrome subtype defined by
species-specific alterations in faecal microbiota
Sequenced 30.000 16S rRNA gene V4 region
amplicons per subjects
High Firmicutes:Bacteroidetes ratio IBS (red)
Normal Firmicutes:Bacteroidetes ratio IBS (blu)
↑HAD depression score in normal-like IBS group
Jerrery IB et al., Gut 2012,61:997-1006

48. New pathophysiologic aspects in FGID
Stress (CRF)
anxiety, depression
Genetic polymorphisms
(IL-10, TGF-β, TNF-α, IL-6, SERT)
Gene expression
Increased mucosal
permeability (↓ ZO-1)
Mucosal
immune
activation
Altered enteroendocrine
metabolism
(serotonin)
Neuroplasticity
(SP, NGF)
Food hypersensitivity (gluten?)
BAM
Transient infection
Altered microbiota (dysbiosis?)
Barbara and Stanghellini Gut 2009;58:1571-5

49. A low fermentable oligosaccharides, disaccharides,
monosaccharides and polyols (FODMAPs) diet is more effective
than standard dietary advice for symptom control in IBS
Standard diet (NICE guidelines)
Low FODMAP
100
80
% of IBS patients
with symptom improvement
*
*
*
*
*
*
*
60
40
IBS?
20
0
Bloating
Abdominal
pain
Flatulence
Diarrhoea
Constipation
Nausea
Composite
score
Staudacher et al., J Hum Nutr Diet 2011;24:487-95

50. FODMAP Diet

51. Between Celiac Disease and Irritable Bowel Syndrome:
The Gluten Sensitivity
Genetic suscetibility
Factors that alter
barrier function
Immune tolerance to gluten
Gluten sensitivity (HLA-DQ2/DQ8)
Loss of tolerance
Potential celiac:
CD3+ T cell infiltrate +
Ttg AB+/no atrophy
Gluten-sensitive:
CD3+ T cell infiltrate +/Ttg AB-/no atrophy
Symptomatic response to GFD
Celiac disease (AB+, atrophy)
Refractory sprue
Enteropathy-associated lymphoma
Verdu et al., Am J Gastroenterol 2009;104:1587-94

52. Gluten-free diet in patients with IBS-D
Gluten-containing diet (GCD) associated with:
• higher small bowel permeability;
• significant decreases of expression of ZO-1, claudin-1 and occludin in the rectosigmoid mucosa
These effects were significantly greater in HLA-DQ2/8 positive patients
Gluten alters bowel barrier functions in patients with IBS-D (reversible mechanism for the disorder?)
Vazquez-Roque MI et al., Gastroenterology 2013;144:903-11

54. New pathophysiologic aspects in FGID
Stress (CRF)
anxiety, depression
Genetic polymorphisms
(IL-10, TGF-β, TNF-α, IL-6, SERT)
Gene expression
Increased mucosal
permeability (↓ ZO-1)
Mucosal
immune
activation
Altered enteroendocrine
metabolism
(serotonin)
Neuroplasticity
(SP, NGF)
Food hypersensitivity (gluten?)
BAM
Transient infection
Altered microbiota (dysbiosis?)
Barbara and Stanghellini Gut 2009;58:1571-5

55. Mucosal immune cells in the colon:
Comparison among different inflammatory disorders
80
*#
70
60
*#
50%
* P<0.001 vs HC
# P<0.001 vs IBS
*#
*
50
40
30
20
10
0
“physiologic
inflammation”
HC
IBS
Microscopic
colitis
Inactive
UC
Active
UC
Cremon et al., Am J Gastroenterol 2009;104392-400

56. Innate and adaptive immune activation in the colonic
mucosa of patients with IBS
*
HC
IBS
*
*
*
*
Cremon et al., Am J Gastroenterol 2009;104392-400

57. Activated mast cells in proximity to colonic nerves correlate
with abdominal pain in irritable bowel syndrome
Severity of abdominal pain (VAS)
Tryptase +ve MC
NSE +ve nerves
Mast cell
• More closely apposed to
nerves
3
2
1
0
0.0
Nerve
r = 0.75
p = 0.001
4
0.5
1.0
1.5
N° mast cells < 5 µm to nerves
2.0
• Activated when close to nerves
• Mucosal supernatants evoke increased activation of sensory nerve pathways in rodents
• MC-nerve vicinity correlated with severity of abdominal pain
Barbara et al., Gastroenterology 2004;126:693-702
Barbara et al., Gastroenterology 2007;132:26-37
Cenac et al., J Clin Invest 2007;117:636-47

58. Immune cell count in the colonic mucosa
Best cutoff range between IBS and HC: 20.2%-20.3%
HC
IBS
UC
1,0
0,9
0,8
Sensitivity
0,7
0,6
0,5
0,4
0,3
50 µm
50 µm
50 µm
0,2
0,1
*
P<0.001 vs HC
#
P< 0.001 vs IBS
0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0
Specificity
Best cutoff range between UC and IBS: 33.8%-34%
1,0
0,9
0,8
0,7
Sensitivity
*
#
0,0
*
0,6
0,5
0,4
0,3
0,2
0,1
0,0
0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0
Specificity
Cremon et al., DDW2013

59. Mast cell count in the colonic mucosa
HC
IBS
UC
Best cutoff range between IBS and HC: 4.3%-4.7%
1,0
0,9
0,8
50 µm
0,7
50 µm
*
*#
**
P<0.001 vs HC
#
P=0.098 vs UC
**
P=0.009 vs HC
Sensitivity
50 µm
0,6
0,5
0,4
0,3
0,2
0,1
0,0
0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0
Specificity
Cremon et al., DDW2013

60. Diagnostic accuracy of mucosal immune biomarkers
in IBS vs HC
Biomarkers
Best cutoff range
Immune cell count Mast cell count
TLR-4 mRNA
IFN-γ mRNA
20.2-20.3%
4.3-4.7%
1.063-1.149
0.001-0.257
Diagnostic accuracy
80.6%
87.3%
83.3%
86.7%
Sensitivity
77.1%
93.8%
80.0%
85.0%
Specificity
87.5%
73.5%
90.0%
90.0%
+ve predictive value
92.5%
88.2%
94.1%
94.4%
-ve predicitive value
65.6%
84.7%
69.2%
75.0%
Cremon et al., DDW2013

61. Diagnostic accuracy of mucosal immune biomarkers
in UC vs IBS
Biomarkers
Best cutoff range
Immune cell count Mast cell count
TLR-4 mRNA
IFN-γ mRNA
33.8-34.0%
---
1.536-1.653
6.764-8.674
Diagnostic accuracy
90.0%
---
88.9%
96.3%
Sensitivity
87.5%
---
85.7%
100.0%
Specificity
91.7%
---
90.0%
95.0%
+ve predictive value
87.5%
---
75.0%
87.5%
-ve predicitive value
91.7%
---
97.7%
100.0%
Cremon et al., DDW2013

64. New pathophysiologic aspects in IBS
• IBS is a multifactorial disease
• Application of novel thechniques discovers the
participation of cellular and molecular mechanisms
in IBS pathophysiology
• During the last years, the role of the intestinal
microbiota in IBS pathophysiology has received
great interest
• Microbiota committee evaluating the role of the
intestinal microbiota in functional gastrointestinal
disorders
• Evidence of microbiota changes (dysbiosis) in IBS?

65. The effect of a nonabsorbed oral antibiotic (rifaximin)
on the symptoms of the irritable bowel syndrome
Mean improvements after 10 weeks follow-up
• A double blind placebo-controlled study
• 10 days of treatment (400 mg t.i.d)
• Significant improvement in IBS symptoms
• Prolonged effect (2 ½ months)
Global improvement %
• 87 IBS patients (Rome I)
* p = 0.020
45
*
40
35
36.40%
(SD, 31.46%)
30
25
20
15
Placebo
5
0
21.00%
(SD, 22.08%)
Rifaximin
10
1
2
3
4
5
6
7
8
9
10
Time beyond treatment, wk
Pimentel M et al., Ann Intern Med 2006;145:557-563

66. Rifaximin for patients with IBS without constipation
% Responders
50
Primary End-point
*
*P<0.001
40
30
20
10
0
Placebo Rifaximin
• Two identically designed, phase 3, multicentre,
double blind, placebo-controlled studies
(TARGET 1 and TARGET 2) in 1260 patients
with IBS
Pimentel et al., N Engl J Med 2011;364:22-32

68. Subtyping IBS by predominant stool pattern
100
75
50
IBS-C
IBS-M
IBS-U
IBS-D
25
% Hard or Lumpy Stols (type 1, 2)
Bristol Stool Form Scale
0
25
50
75
100
% Loose or Watery Stools (type 6, 7)
Bowel pattern subtypes are highly unstable
- 75% of patients changes subtypes over 1 year
- 29% switch between IBS-C and IBS-D
Drossman DA et al., Gastroenterology 2005,128:580-9
Longstreth et al., Gastroenterology 2006;130:1480-91

70. Diagnosis and treatment of chronic constipation:
a European perspective
Tack J, Muller-Lissner S, Stanghellini V, et al., Neurogastroenterol Motil 2011;23:697–710

71. Prucalopride is effective in severe chronic constipation
• Prucalopride: highly selective 5-HT4 receptor agonist
• In October 2009, prucalopride (Resolor) received EU approval for the treatment of chronic constipation
in women in whom laxatives fail to provide adequate relief
Camilleri et al., N Engl J Med 2008;358:2344-54

72. Current Management of IBS
IBS Symptoms
Constipation
• Reassurance/diet
• Increase fiber (20 g)
• Osmotic laxative
Diarrhea
Gas/Bloating
First Line
• Reassurance/diet
• Loperamide
• Diphenoxylate
• Reassurance/diet • Reassurance/diet
• Treat the
• Treat constipation/diarrhea
• Antispasmodics
constipation
(e.g. PEG)
• Stool softener
• Bisacodyl
• Prokinetics
• Tegaserod*
• Prucalopride**
• Secretory stimulators
• Lubiprostone*
• Linaclotide*
Pain
(e.g. otilonium bromide,
trimebutine, peppermint oil)
Second Line
• Alosetron*
• Bile acid
sequestran
• Antibiotics
• Probiotics
*Not available in Europe
**Approved in Europe for the symptomatic treatment of chronic constipation
in women in whom laxatives fail to provide adequate relief
• Antibiotics
• Probiotics
• Antibiotics
• Probiotics
• Tricyclic antidepressants
• Selective serotonin
reuptake inhibitors
Adapted from Mayer EA. N Engl J Med 2008;358:1692-9

73. Linaclotide: mechanism of action
• Linaclotide, a novel peptide agonist of
guanylate cyclase-C receptors
• Binding to GC-C results in the conversion of
GTP to cGMP
• cGMP accumulation→ phosphorylation of
the cystic fibrosis transmembrane regulator
(CFTR) → chloride / bicarbonate secretion
• Inhibition
exchanger
of
the
sodium/hydrogen
• cGMP may act to inhibit colonic nociceptors
Brierley SM. Curr Opin Pharmacol 2012;12:632-40

74. FDA and EMA end-points in clinical trials of
linaclotide in patients with IBS-C
Rao S et al., Am J Gastroenterol 2012;107:1714-24 (trial 31)
Chey WD et al., Am J Gastroenterol 2012;107:1702-12 (trial 302)