irritable bowel Syndrome

1. IRRITABLE BOWEL SYNDROME
PRESENTER: DR.SIDDHARTH DHANDE

2. OUTLINE
• EPIDEMIOLOGY
• PATHOPHYSIOLOGY
• Genetic
• Visceral hypersensitivity
• Post infectious
• Bile acid
• Brain gut axis
• ROME IV CLASSIFICATION

3. INTRODUCTION
• In OP > 30% of patients havefunctional
gastrointestinal disorders.
• IBSisthe most common functional bowel disorder
• In 1966, DeLor coined the term to the irritable bowel
syndrome (IBS) - functionalenteropathy
• IBS was defined as “a functional bowel disorder in
which abdominal pain is associated with defecation
ora change in bowel habits”

4. EPIDEMIOLOGY
IBS is a common disorder allover the world.
Prevalence 3% to 20% in the U.S .
Younger people have a higher prevalence of IBS
Female predominance, M :F 2 : 1
USprevalence rates for other common diseases
• – Diabetes 3%
• – Asthma 4%
• – Heart disease 8%
• – Hypertension 11%

5. EPIDEMIOLOGY INDIA

7. DEMOGRAPHICS
Prevelance – gender
Prevalence of subtypes in different
age group.

11. PATHOPHYSIOLOGY OF IBS

12. Biopsychosocial Conceptual Model for FGID’s
Gastroenterology 2016;150:1262–1279

13. IBS – GENETIC DISORDER
• Higher concordance in monozygotic twins
than in dizygotic twins
• Susceptibility locus for IBS has not yet been
identified
• MC - 5-HTT LPR polymorphism in the
serotonin transporter gene (SLC6A4)
• Familial IBS – Twice More common

15. Familial clustering of IBS
• Shared disease susceptibility genes for IBS among family
member
• Shared disease susceptibility genes for another entity that
increases risk of IBS (e.g., lactose intolerance, depression or
anxiety, somatization, or an immune system that increases
risk of infection)
• Shared household exposures, shared lifestyle behaviors, or
shared household experiences; or
• A combination of the above.

16. Sodium channel mutation
• SCN5A encodes the a-subunit of the voltage-gated sodium
channel NaV1.5
• LOF – Brugada Syndrome
• GOF – Type III long-QT (LQT) syndrome
• Nav1.5 - intestinal interstitial cells of Cajal and smooth muscle
• Modulation - Smooth muscle membrane potential and slow
wave upstroke
• H558R polymorphism & G298S missense mutation - reduced
peak inward Na current density
• D/T slower time to peak and no change in inactivation

20. RESULTS – SCNA5 MUTATION
• SCN5A mutations result predominantly in IBS-
C - 31% vs 10 %.
• About 2% of patients with IBS carry mutations
in SCN5A. (1-5%)
• Most of these are loss-of-function mutations
that disrupt NaV1.5 channel function
• NaV1.5 blocker, ranolazine, is associated with
significant constipation

21. Association with TNFSF15 and TNFa
• TNFSF15, also known as TL1A, is a member of the
TNF super family that binds to the death receptor
3 (DR3, TNFSF25) which activates a range of
inflammatory pathways via NFkB.
• TNFSF15 mRNA is upregulated in Crohn’s disease
and augments interferon-g production in lamina
propria mononuclear cells from Crohn’s patients
• IL-17 when they are stimulated by IL-23

23. RESULTS
• Relationship between TNFSF15 polymorphisms and the
TNFSF15 gene expression as assessed by mRNA in rectal
biopsies
• IBS after C jejuni infection and the association with persistent
lymphocyte and enteroendocrine cell hyperplasia
• Increased TNFSF15 mRNA in the rectal mucosa of IBS-D
patients and an association between SNPs in TNFSF15 and risk
of IBS-D
• Consistent association of IBS-D with poly- morphisms in the
TNFSF15 gene with a reduced risk associated with the
presence of the minor allele; ORs between 0.6 and 0.68 (95%
CI 0.47 to 0.93)

24. SEROTONIN METABOLISM

25. SEROTONIN - ACTION
• Intestinal enterochromaffin cells, which function as sensory
transducers of intraluminal stimuli such as pressure - 90% of
the body’s total stores of serotonin. Systemic – taken up by
platelets
• Activate both intrinsic and extrinsic primary afferent neurons,
is integral to gastrointestinal motility, and GUT BRAIN AXIS
• Decreased SERT activity results in decreased 5-HT uptake and
therefore decreased 5-HIAA production
• Platelet poor plasma (PPP) levels of 5-HT and 5-HIAA are
considered to be surrogate markers of intestinal 5-HT
metabolism
• KEY MEDIATOR – VISCERAL HYPERSENSITIVY AND
HEIGHTENED BOWEL MOTILITY

28. RESULTS
• Patients with IBS-D or celiac disease had increased numbers
of IELs and mast cells compared with HVs (both P <.001)
• Levels of SERT mRNA were reduced in the mucosa of patients
with IBS-D or celiac disease and were inversely correlated
with numbers of IELs ( P <.0001)
• Uptake of 5-HT by platelets from patients with IBS-D or celiac
disease was reduced
• uniformly decreased postprandial levels of plasma 5-HT in C-
IBS patients
• Binding of paroxetine to membranes of platelets from
patients with IBS-D was significantly greater

29. ABNORMAL MOTILITY
• Colonic and SI transit has been shown to be
delayed in IBS with constipation and accelerated
in IBS with diarrhea, but not all studies concur.
• There is no consensus on the exact patterns of
motor derangement that actually induce
constipation or diarrhea.
• Not sufficient to explain symptoms of
abdominal pain

30. VISCERAL HYPERSENSITIVITY
Balloon distention in the rectum was shown to
induce pain at lower vol in pts with IBS
In IBS there is abnormal sensitization within the
dorsal horn of the spinal cord or CNS .
But Visceral Hypersenstivity is found only in
60% of patients .

31. Subjects
reporting
pain
(%)
Whitehead et al. Dig DisScii
Healthycontrols
20 60 100
Distendingvolume (mL)
140 180
IBS
RECTAL HYPERSENSITIVITY IN IBS
•

32. 50
40
30
20
10
0
IBS
(n=86)
Healthy
volunteers
(n=25)
Pressure
(mmHg)
Barostat rectal distension
Discomfort/Pain
Bouin et al. Gastroenterology2002
Rectal barostat at 40 mmHg, to identify
IBS patients from HV and non-IBS pts
sensitivity = 96%, specificity = 72%;
PPV = 85% , NPV = 90%.
RECTAL HYPERSENSITIVITY IN IBS
•

33. 100
80
60
40
20
0
IBS
(n=126)
Healthy
volunteers
(n=30)
Subjects
with
hypersensitivity
Barostat rectal distension
Discomfort/Pain
Ludidi et al. Neurogastro Motil2012
Optimal cutoff for visceral
hypersensitivity at pressure 26
mmHg with a VAS ≥20 mm
RECTAL HYPERSENSITIVITY IN IBS
•
64%
7%

34. LOW-GRADE MUCOSAL INFLAMMATION, IMMUNE ACTIVATION,
AND ALTERED INTESTINAL PERMEABILITY
• Higher prevalence of symptoms compatible with IBS - acute
enteric infection
• Increased concentrations of pro-inflammatory cytokines, and
also higher numbers of mast cells, which are in close
proximity to enteric nerve fibres
• Increased concentrations of cytokines in the colonic mucosa,
• Increase in release of pro-inflammatory cytokines in
peripheral blood
• Increased activation of B lymphocytes
• Biological markers of humoral activation appeared to be
positively associated with bowel movements, stool form, and
depression

35. LOW-GRADE MUCOSAL INFLAMMATION, IMMUNE
ACTIVATION, AND ALTERED INTESTINAL PERMEABILITY
• IBS-D supernatants showed increased amounts of the
cytokines interleukin 1β, interleukin 10, TNFα, and interleukin
6
• Concentration associated with the frequency and severity of
pain.
• Defect in the integrity of the gastrointestinal mucosal
epithelial barrier.
• Post-infectious IBS were shown to have increased intestinal
permeability, as measured by use of urinary excretion of
lactulose and mannitol
• Increased density of epithelial gaps has been shown by
confocal laser endomicroscopy in the terminal ileum

37. DISORDERED BILE ACID METABOLISM
Produced by liver –
95% reabsorbed in
terminal ileum
Nuclear
farnesoid
receptor X
Transcription
of FGF - 19
Negative feedback
on hepatocyte via
FGF- 4
Reduction on
production
of new bile
acids

38. DISORDERED BILE ACID METABOLISM
• 20% of patients who meet criteria for IBS-D - idiopathic bile
acid diarrhoea, shown by 23-seleno 25-homotaurocholic acid
retention scanning.
• whether bile acid diarrhoea is a cause or a consequence of IBS
• total faecal bile acid levels were higher in those with IBS with
diarrhoea, and lower in those with IBS with constipation
• an association with stool number and form
• markers of bile acid synthesis including FGF-19, C4 - elevated
• Increase in faecal bile acids was associated with a dysbiosis,
increases in Escherichia coli and reductions in Leptum and
Bifidobacteria species.

41. BRAIN GUT AXIS
• The brain-gut axisisasystemof integrated circuitsthat allowsgut
activityto influence the brain, and brain activityto influence the
gut.
The symptoms in IBSare hypothesized to arise from dysregulation
within the brain-gut axis.
Numerous brain-gut neurotransmitters (ie, enkephalins,
NO ,tachykinins, CGRP, CCK,5-HT)
It is now realized that the
1. Altered colonic motility
2. Visceralhypersensitivityin IBSare determined byreciprocal
interactions between gut and brain.

42. The Microbiome -colonization
• Early gut colonization has four phases
– Phase 1: Sterile gut
– Phase 2: Initial acquisition: vagina, feces, hospital
– Phase 3: Breast feeding or bottle-feeding (different)
• Breast fed more bifidobacteria (up to 90% of flora)
• Bottle fed more diverse; more Bacteroides , and
Clostridial species
– Phase 4: Start of solids; move to adult flora (Fermicutes
and bacteriotedes)
• Bifidobacteria remain key flora into adulthood
Ley, Peterson, Gordon. Cell 2006 ;124:837
Ley, et al. PNAS. 2005, 102: 11070
Edwards, et al. Br J Nutr. 2002

43. Major Bacteria Phyla and Genera Predominating in Human Gut Microbiota
Munoz-Garach A, Diaz-Perdigones C, Tinahones FJ.
Microbiota y diabetes mellitus tipo 2. Endocrinol Nutr
. 2016;63:560---568.
Phyla Representative genera
Firmicutes (60-80%) ‒ Ruminococcus
‒ Clostridium
‒ Lactobacillus
‒ Enterococcus
Bacteroidetes (20-30%) ‒ Bacteroides
‒ Prevotella
‒ Xylanibacter
Actinobacteria (< 10%) ‒ Bifidobacterium
Proteobacteria ((< 1%) ‒ Escherichia
‒ Enterobacteriaceae

44. What bacteria produce which
neurotransmitter?
1. Lactobacillus and Bifidobacterium species produce
GABA
2. Lactobacillus produces Acetylcholine
3. Escherichia, Bacillus, and Saccharomyces produce
norepinephrine
4. Candida, Streptococcus, Escherichia, and Enterococcus
produce serotonin
5. Bacillus and Serratia produce dopamine

45. • Several members of Bacteroidetes phylum were increased
12-fold in patients, while healthy controls had 35-fold
more uncultured Clostridia.
• Methanogens under-represented
• Archaea is associated with delayed transit
• Uncultured R. torques-like - increased pain sensation
• C. aerofaciens negatively correlated with PBMC-produced
proinflammatory cytokines
• Bacteroides and Prevotella - decreased expression of
amino acid metabolism pathways

47. ALTERATION IN BRAIN FUNCTION
• Reduced inhibitory feedback on the emotional arousal
network
• Central processing of sensory information – Abberant -
diffusion tensor imaging
• Heightened awareness of, or attention to, gastrointestinal
symptoms or stimuli
• Reductions in the activity of areas of the cortex involved in
inhibiting or downregulating the response to such stimuli.
• Activity of the dorsolateral prefrontal cortex was impaired
during behavioural selection tasks

50. ROLE OF DIET IN IBS

51. FODMAPs
Fermentable
Oligosaccharides – few simple sugars linked together (fructans,
galactans)
Disaccharides – double sugar (lactose)
Monosaccharides – single sugar (fructose)
And
Polyols – sugar alcohols (sorbitol, mannitol, isomalt, xylitol,
glycerol)

52.  Short chain carbohydrates
 Poorly absorbed in the small intestine & delivered to the colon
 Rapidly fermentable by gut bacteria resulting in gas and SCFA
 Small, osmotically active molecules increasing water load to
the colon
 Cumulative effect of FODMAPs produces symptoms in IBS
patients

53. Mechanisms of Individual FODMAPs
• Lactose: with reduced activity of brush border enzyme lactase
– Lactase splits lactose into glucose + galactose which can then
be absorbed
• Fructose: slow, low-capacity transport mechanism across
epithelium
– Glucose facilitates absorption across the transporter
– 1:1 ratio of fructose to glucose is considered FODMAP friendly
– >0.2g excess fructose compared to glucose per serving is high
FODMAP
• Fructans/Galactans: humans lack digestive enzyme
– Therefore not broken down and 100% of people malabsorb
• Polyols: too large for passive diffusion
– Has a laxative effect (i.e. prunes)

54. FODMAPs exert osmotic & fermentation related
effects which trigger symptoms in IBS
Murray et al. Am J Gastroeterol 2014;109:110
• Fructose but not inulin distends the small bowel with water.
• Adding glucose to fructose reduces the effect of fructose on SBWC
and breath hydrogen.
• Inulin distends the colon with gas more than fructose, but causes few
symptoms in healthy volunteers.

55.  Included: Six RCTs and 16 non-randomized interventions
 There was a significant decrease in IBS SSS scores for those individuals
on a low FODMAP diet in both the RCTs and non-randomized
interventions
 Significant improvement in the IBS-QOL score for RCTs and for non-
randomized interventions.
 Following a low FODMAP diet was found to significantly reduce
symptom severity for abdominal pain, bloating and overall symptoms
in the RCTs.

56. US RCT Comparing the Low FODMAP Diet vs
m-NICE Guidelines in IBS-D
• Compare the efficacy of the low-FODMAP diet to a diet based
upon modified guidance from the National Institute for Health
and Care Excellence (mNICE) in US adults with IBS-D
• Single center trial at UMHS
• Dietitian guided mNICE recommendations:
• Small frequent meals
• Caffeine and alcohol in moderation
• Avoidance of known trigger foods
• Avoidance polyols (sugar-free gum, etc)
Eswaran, Chey, et al. 2016

57. Endpoints
Primary endpoint:
Adequate relief of overall IBS symptoms during 50% or more of the
last 2 weeks of study period (weeks 3-4)
Secondary Endpoints
A decrease in mean daily Bristol Stool Form Scale value of ≥1
compared to baseline for 2/4 weeks
≥30% reduction in mean daily abdominal pain score for 2/4 weeks
≥30% reduction in mean daily bloating score for 2/4 weeks

58. Baseline Symptom Severity
Symptom Low
FODMAP
mNICE p-value
N = 50 N = 42
Abd Pain Score 5.10 ± 1.5 5.06 ± 1.34 p = .9051
Bloating Score 4.87 ± 1.83 5.01 ± 2.07 p = .7195
Urgency Score 4.98 ± 1.93 5.39 ± 2.1 p = .3347
Bristol Stool Form 5.21 ± .60 5.25 ± .70 p = .7710
Stool Frequency 3.45 ± 1.66 3.37 ± 1.76 p = .8204

59. Urgency
* = p ≤.05
◦ = p ≤.01
# = p ≤.001
§ = p ≤.0001
Weekly Abdominal Symptom Scores
P values refer to the change WITHIN group
comparing to baseline score
○
§
§
§
1
2
3
4
5
6
Baseline Week 1 Week 2 Week 3 Week 4
Average
Daily
Abdominal
Pain
Scores
(0-10)
m-NICE Low FODMAP
#
§
§
§
1
2
3
4
5
6
Baseline Week 1 Week 2 Week 3 Week 4
Average
Daily
Abdominal
Bloating
Score
(0-
10)
m-NICE Low FODMAP
Eswaran, Chey et al. DDW 2016

60. 54.3 53.4
59.4
69.3
0
10
20
30
40
50
60
70
80
m-NICE Low FODMAP
p<.0001
p=.03
p < .0015
Mean
Value
Baseline Week 4 Baseline Week 4
Overall IBS- QOL Scores
Overall IBS- QOL Scores

61. Study Conclusions
• Both dietitian-taught interventions improved IBS symptoms
• The low FODMAP diet led to significantly greater improvements in
abdominal symptoms
– Abdominal pain
– Bloating
• Modest improvements in stool consistency
• Benefits extend beyond GI symptoms
• This study supports a role for low FODMAP diet in the treatment of
IBS-D patients

62. DIAGNOSTIC CRITERIA
1950s: Increased gut motility
1980to 1999:Symptom-based criteria
– Manning criteria
– Rome criteria
1999:Rome II criteria
2006 :Rome III criteria
2016 : Rome IV criteria

63. MANNING CRITERIA
Abdominal pain that is relieved after a bowel
movement .
Looser stool at pain onset ,
More frequent stools at pain onset
Abdominal distention (visible)
Sensation of incomplete rectal evacuation
Passage of mucus

64. Demerits :Symptoms were specific, but not
sensitive, for identifying IBS
They were of greater diagnostic value in women.
Merit :The Manning criteria identify additional
patients with IBS-like symptoms who arguably also
should be classified as true IBS

65. ROME I CRITERIA
• ≥3 months of continuous or recurrent abdominal
pain or discomfort relieved with defecation
AND
Disturbed defecation (≥ 2 of the following):
1. Altered stool frequency
2. Altered stool form (hard or loose/watery)
3. Altered stool passage (straining or rgency, feeling of
incomplete evacuation)
4 . Passage of mucu

66. ROME II CRITERIA
Abdominal pain ≥12wk, which need not be
consecutive, in the preceding 12 mon asso. with
least 2 of the 3 following features:
• 1. Relieved with defecation
2. Onset associated with a change in stool
frequency
3. Onset associated with a change in stool formin
stool form

67. ROME III CRITERIA
• Recurrent abdominal pain or discomfort at least 3 days/month in the last 3
months associated with two or more of the following:
• Improvement with defecation
• Onset associated with a change in frequency of stool
• Onset associated with a change in form (appearance) of stool
• a Criterion fulfilled for the last 3 months with symptom onset at least 6
months prior to diagnosis
• B “Discomfort” means an uncomfortable sensation not described as pain
Drossman DA, Rome III:
Digestive Disease Week; May 20-25, 2006
86

68. Rome IV Classification and Criteria for FGIDs
Rome Foundation classification of FGIDs is based primarily on symptoms rather than physiological criteria
Gastroenterology 2016;150:1262–1279

69. Bowel Disorders
• Irritable Bowel Syndrome
 FODMAP sensitivity
 Frequent vs. sporadic
 IBD-IBS, ulcerative colitis in remission
 Lactose or other disaccharide intolerance
 Post-infection
 Stool pattern – IBS-D,-D,-M, or –U
 With bloating
 With fecal incontinence
 With pain predominance
 With postprandial symptoms
 With urgency

70. Gastroenterology 2016;150:1393–1407
Conceptual Framework- Functional
Bowel Disorders

71. ROME IV CRITERIA
• Recurrent abdominal pain, on average, at least 1 day/week in
the last 3 months, associated with two or more of the
following criteria:
• Related to defecation
• Associated with a change in frequency of stool
• Associated with a change in form (appearance) of stool
• Criteria fulfilled for the last 3 months with symptom onset at
least 6 months before diagnosis

72. C. BOWEL DISORDERS
C1. Irritable Bowel Syndrome: Diagnosis
https://irritablebowelsyndrome.net/clinical/new-rome-iv-diagnostic-criteria/ Last accessed on 02/01/2016
Rome III Criteria for Diagnosing IBS: a
Recurrent abdominal pain or discomfort at least 3
days/month in the last 3 months associated with two or
more of the following:
• Improvement with defecation
• Onset associated with a change in frequency of stool
• Onset associated with a change in form (appearance)
of stool
a Criterion fulfilled for the last 3 months with symptom
onset at least 6 months prior to diagnosis
B “Discomfort” means an uncomfortable sensation not
described as pain
Rome IV Criteria for Diagnosing IBS: c
Recurrent abdominal pain, on average, at least 1
day/week in the last 3 months, associated with two
or more of the following criteria:
• Related to defecation
• Associated with a change in frequency of stool
• Associated with a change in form (appearance)
of stool
c Criteria fulfilled for the last 3 months with
symptom onset at least 6 months before diagnosis

73. Gastroenterology 2016;150:1393–1407
• In contrast to the Rome III criteria, the term discomfort has been eliminated because it
is ambiguous to patients - One study of IBS patients found that patients exhibited wide
variations in their understanding of this term
• Current definition involves a change in the frequency of abdominal pain, stating that
patients should have symptoms of abdominal pain at least 1 day per week during the
past 3 months. This is in contrast to Rome III criteria, which defined IBS as the
presence of abdominal pain (and discomfort) at least 3 days per month
• Requirement for an increase in the frequency of abdominal pain is based on data from
the Report on Rome Normative GI symptom survey.
Rationale for Changes From Previous Criteria

74. IBS SUBTYPES
• Constipation predominant
• Diarrheapredominant
• Alternator (alternating bouts of
diarrhea and constipation)
This classification was suboptimal because it
was not evidence based .

75. IBS SUBTYPES – REVISED
CLASSIFICATION
The Rome III classification for IBS subtypes required that the
proportion of total stools using the Bristol Stool Form Scale be
used to classify
 IBS with predominant diarrhoea (>25% loose/watery, <25%
hard/lumpy)
 IBS with predominant constipation (>25% hard/ lumpy, <25%
loose/watery)
 Mixed-type IBS (>25% loose/watery, >25% hard/lumpy) and
 IBS unclassified (<25% loose/watery, <25% hard/ lumpy).

76. Gastroenterology 2016;150:1393–1407
Bristol Stool Form Scale
SUBTYPES

77. C2: Functional constipation
Diagnostic criteria a
1. Must include 2 or more of the following
a. Straining during more than 25% of defecation
b. hard stools (Bristol class 1-2) more than 25% of defecation
c. sensation of incomplete evacuation more than 25% of defecation
d. Sensation of anorectal obstruction more than 25% of defecation
e. Manual maneuvers to facilitate more than 25% of defecation
f. Fewer than 3 spontaneous bowel movements per week
2. Loose stools are rarely present without use of laxatives
3. Insufficient criteria for irritable bowel syndrome
a.Criterion fulfilled for the last 3 months with symptom onset at least 6 months prior to
diagnosis
Rx- osmotic laxatives (lactulose , PEG) , prokinetic , lubiprostone , linaclotide , CBT

78. C3. Functional Diarrhea
Diagnostic criteria
1. Loose (mushy) or watery stools(> 75 %) without
predominant abdominal pain or bothersome bloating ,
occurring more than 25% of defecation
2. Insufficient criteria for irritable bowel syndrome
a. Criteria fulfilled for the last 3 months with symptom onset
at least 6 months prior to diagnosis
Rx- Diet , probiotics , loperamide , bile acid binding resins ,
TCA , CBT

79. C4: Functional Abdominal Bloating/ distension
Diagnostic criteria a Must include both of the following
1. Recurrent bloating or distention at least 1 day/week ; Recurrent bloating
or distention predominates over other symptoms*
2. Insufficient criteria for a diagnosis of functional dyspepsia, IBS, or
other functional GI disorder
a. Criterion fulfilled for the last 3 months with symptom onset at least 6
months prior to diagnosis
*Mild pain related to bloating may be present as well as minor bowel
movement abnormalities
Rx- Diet ( low FODMAP, gluten free diet), Probiotics , Rifaximin ,
antispasmodic( Otilonium bromide plus simethicone for 6 month) , CBT ,

80. C5: Unspecified Functional bowel disorder
 Diagnostic criteria a
Bowel symptoms not attributable to an organic etiology and
do not fit criteria for a diagnosis of functional dyspepsia, IBS
or other functional GI disorder.
a. Criteria fulfilled for the last 3 months with symptom onset
at least 6 months prior to diagnosis

81. THANK YOU