IBS – The Physiologist’s Perspective
Dr Anthony R. Hobson PhD
Consultant Clinical Scientist, London
The Functional Gut Clinic
Reclaiming the ‘F’ word
• The f-word – ‘functional’ has become a by-word for ‘failure’ to
understand what is actually wrong with the patient.
• Understanding how the gut is functioning (and what is causing gut
dysfunction) is key to targeting treatment, we have the technology
and we need to re-claim the f-word as a credible diagnosis.
• The Functional Gut Clinic is the first GI Physiology Unit in the UK to
achieve the new IQIPS/UKAS accreditation process (equivalent to
JAG in endoscopy) as well as be CQC accredited.
• Provides diagnostic services using state of the art equipment,
advanced analysis techniques and acquisition protocols to maximise
the diagnostic yield of tests.
Symptoms
Physiology
Function
Behaviour
Accurate Diagnosis
Effective Treatment
CNS reactivity
The model
HPA-axis reactivity
ANS reactivity
Microbiota-mucosal interface
Caecal fermentation (pH)
Differential changes in
inflammatory profile,
pain sensitivity, motility
and secretion.
Brain Imaging
Psychological
profiling
Testing the model
Blood Assays
Real-time ANS recordings
pH profiling
Breath Tests
GI Motility and Neurophysiology
Biopsies
Stool samples
The pain hypothesis
• IBS patients have more gut symptoms and
pain than healthy people so are they more
sensitive to GI pain?
Does gut stimulation activate the cortex?
MEG
A
FMRI
B
Does brain activation correlate with stimulation
intensity and sensory perception?
Cohen et al
Does brain activation always correlate with
stimulation intensity and sensory perception?
Sidhu, H. et al. Am J Physiol Gastrointest Liver Physiol 2004
Is the brain’s response to pain specific to the
experimental stimulus?
Pain
Anticipation
Insula
DLPFC
Cingulate
Yaguez et al Gastroenterology. 2005
Extinction
MEG - Evoked field potential recorded following painful electrical
stimulation of the gut
~80ms
Somatosensory cortex
(Sensory discrimination)
Temporal sequence
of activation
~140ms
250ms
Cingulate cortex
(Affective)
Hobson et al Gastroenterology 2005
Ano-rectal sensory neurophysiology – Hypersensitivity in IBS
Arebi and Hobson et al NGM 2011
Hypersensitivity in IBS – lack of habituation
Arebi and Hobson et al NGM 2011
The pain hypothesis
• Subset of IBS patients have increased sensory
nerve sensitivity (ascending pathways).
• Subset of IBS patients have hypersensitivity
driven by lack of central inhibition of pain
(descending pathways).
• Subset of IBS have normal sensitivity
• Subset of IBS are hyposensitive
• ‘IBS’ patients span the entire sensory
spectrum
The psychological hypothesis
• IBS patients have more psychological comorbidity than healthy people so is it all in the
brain?
Psychological profiles
Arebi and Hobson et al NGM, 2011
Personality profiles
*
Arebi and Hobson et al NGM, 2011
No correlation between
psychological or personality
measures and objective or
subjective measures of pain
sensitivity
The neuro-immune hypothesis
• IBS patients have a more irritable gut than
healthy people so is their neuro-immune
system different?
Stress and immunity
•
•
•
•
Acute stressors – public speaking (supress TH-1)
Sustained stress – academic examinations (supress TH-2)
Chronic stress – bereavement (?)
The immune system cannot mount an optimal defence
against all possible threats so uses environmental
information to ‘weight’ the system in favour of most
probable risk.
• Confers evolutionary advantage
• In the absence of real threats leaves you with the
symptomatic ‘baggage’ without the survival benefit.
PBMC IL-8 release to LPS in IBS and Controls (pro-inflammatory)
18000
*
16000
14000
*
*
*
*p<0.0001
*
12000
10000
Cx study 1
8000
IBS Study 1
6000
4000
2000
0
LPS 0
LPS 0.1
LPS 0.3
LPS 1
LPS 3
LPS 10
PBMC IL-10 release to LPS in IBS and Controls (anti-inflammatory)
1800
*
1600
*
1400
*
1200
1000
*p<0.01
*
*
Cx Study 1
800
IBS Study 1
600
400
200
0
LPS 0
LPS 0.1
LPS 0.3
LPS 1
LPS 3
LPS 10
PBMC TNF-alpha release to LPS in IBS and Controls (pro-inflammatory)
10000
*
9000
8000
*
*
*
7000
*p<0.0001
6000
*
5000
Cx Study 1
IBS Study 1
4000
3000
2000
1000
0
LPS 0
LPS 0.1
LPS 0.3
LPS 1
LPS 3
LPS 10
PBMC IFN-gamma release to LPS in IBS and Controls – TH-1
3500
*
3000
*p<0.02
*
2500
*
*
2000
CX Study 1
IBS Study 1
1500
1000
500
0
LPS 0
LPS 0.1
LPS 0.3
LPS 1
LPS 3
LPS 10
PBMC IL-4 release to LPS in IBS and Controls – TH2
100
90
80
70
60
Cx
50
IBS
40
30
20
10
0
LPS 0
LPS 0.1
LPS 0.3
LPS 1
LPS 3
LPS 10
TH-17 profile?
Neuro-immune link - Correlation between IL-8 and VDVAS-I
25000
20000
IL-8
15000
IL8
Linear (IL8)
10000
5000
0
0
5
10
15
VDVAS-I
R = 0.61, p<0.0001
20
25
Is there a unifying hypothesis?
• Stress effects all of the above systems is this
the unifying factor?
Co-incubation with stress hormone CRF inhibits IFN-G in controls
3500
3000
2500
2000
Cx Means CRF 0
Cx Means CRF 1
IBS Means CRF 0
1500
IBS Means CRF 1
1000
500
0
LPS 0
LPS 0.1
LPS 0.3
LPS 1
LPS 3
LPS 10
Experimental design for evaluating stress in IBS
Murray et al Gastroenterology 2004
Development of an IBS stress model
Rectal Mucosal Blood Flow
Physical Stress
Psychological Stress
Acute autonomic response to stress is similar in IBS and Controls, but
recovery is slightly prolonged in IBS.
Murray et al Gastroenterology 2004
Development of an IBS stress model
Rectal Perception Thresholds
Physical Stress
Psychological Stress
Stress induces rectal hypersensitivity in IBS but not controls.
Psychological stressors relatively easy to define
What if it’s something in the gut causing the
patients to be stressed and driving these
processes?
Digestion and Fermentation
Digestion and Fermentation
Around 15% of our
calorific intake is due to
secondary fermentation
and absorption in the
caecum / colon
Small Intestinal
Bacterial
Overgrowth
(SIBO)
Caecal malfermentation
Small intestinal bacterial overgrowth, caecal
fermentation and carbohydrate mal-absorption
• Recent (and not so recent research) has shown that
highly fermentable foods can exacerbate symptoms
in IBS (fibre, FODMAPS etc).
• Interaction between microbiota (location and
composition) and poorly digested carbohydrates
(predominantly) has become an area of focus.
• Can we carry out objective evaluation of these
processes to better understand these processes?
Hydrogen and Methane breath testing
Hydrogen and methane Breath testing - SIBO
70
10
9
60
8
VAS Score
GAS (PPM)
50
7
6
40
H+ ppm
CH4+
5
30
4
3
20
2
10
1
0
0
0min
15min
30min
45min
60min
16g of lactulose given in 200ml of water
75min
90min
105min
120min
Bloating
Nausea
Pain
VISUAL ANALOGUE SCALES
0
1
2
3
4
5
6
7
8
9
10
6
7
8
9
10
6
7
8
9
10
NAUSEA
0
1
2
3
4
5
BLOATING
0
1
2
3
4
5
PAIN / CRAMPING
Other factors
• Bowel movements
• Other GI symptoms (belching, borborygmi etc)
• Extra GI symptoms (headache, tiredness,
dizziness, emotional)
• Abdominal girth (pre and post study
distension)
The Wireless Motility Capsule (SmartPill)
Ingestible telemetric (‘wireless’) capsule-based technique
•
•
•
•
relatively non-invasive
no radiation
continuous monitoring (>5 days)
patients in own environment
Measures compartmental (gastric, small bowel and colonic) and
whole gut transit as well as quantifying contractility.
SmartPill – data outputs
ingestion
pH
rise
GRT
SBTT
pH
drop
excretion
CTT
temperature
pH
pressure
Pressure
Temperature
pH
SmartPill – Stomach
ingestion
Gastric acid buffered by test meal
Strong
contractions
pH
Rise in small bowel
temperature
pH
pressure
Pressure
Temperature
pH
SmartPill – small bowel
Small Bowel transit
temperature
pH
pressure
Pressure
Temperature
pH
pH
drop
Enters the colon
SmartPill – colon
Slow rise in pH
Colonic transit time
temperature
pH
Low caecal pH due to
fermentation and production of
Short Chain Fatty Acids
(SCFA)
pressure
Pressure
Temperature
pH
SmartPill – confirm expulsion
Slow rise in pH
temperature
Waiting pH
for at least 60-seconds
after flushing allows temperature
drop to confirm expulsion
pressure
Pressure
Temperature
pH
IBS versus Controls
• 16 female patients with IBS-A v 16 female
controls
• Abdominal Pain
• Bloating
• Visible distension
• Tend towards constipation but alternate to
periods of frequent loose stools
Farmer and Hobson 2014 WJG
Regional Transit Times Controls v IBS-A
P=0.01
Patients
Controls
(min)
(Mean ± SD)
(Mean ± SD)
AAUC (mmHg*s)
Transit Time
P-value
P<0.05
290  76
306  55.9
0.86
SBTT
305  14.5
270  25.9
0.24
CTT
1443  192.8
1861  263.7
0.21
2039  202
2437  279.4
0.26
GET
WGTT
GET: Gastric emptying time; SBTT: Small bowel transit time; CTT: Colonic transit time; WGTT: Whole gut transit time.
Farmer and Hobson 2014 WJG
Regional Contractility Controls v IBS-A
P=0.01
Controls
Patients
(AUC)
(Mean ± SD)
(Mean ± SD)
Antral
3590  708.3
4710  850.1
0.32
Duodenal
3909  919
6000  1310
0.20
Ileal
13414  2203
12679  2131
0.81
Cecal
4071  531.2
5176  878
0.29
Recto-sigmoid
20504  4583
11894  215
0.09
AAUC (mmHg*s)
Motility
AUC: Areas under the curve.
Farmer and Hobson 2014 WJG
P-value
P<0.05
Caecal pH
* P<0.05
* P<0.05
Farmer and Hobson 2014 WJG In Press
Caecal Contractility versus pH
(r = 0.54, P = 0.002)
Farmer and Hobson 2014 WJG In Press
Conclusions
• No overt differences between regional transit times
and motility between healthy controls and IBS.
• Only difference is lower caecal pH in IBS
• Caecal pH is a surrogate marker of SCFA production
due to bacterial fermentation
• SCFA inhibit colonic contractility
• Caecal pH is an objective biomarker of aberrant
fermentation in IBS and can be used to select
patients that may benefit from treatment of this
process.
New concepts
•
•
•
•
Mirrors gastroparesis in upper gut
SCFA mediated ‘caecoparesis’
More akin to ‘anal vomiting’ than diarrhoea
IBS – V ?
You heard it here first!
So what are the next steps
• A study to validate caecal pH as a biomarker of
caecal mal-fermentation in IBS
• Validate the caecal pH as a marker of
therapeutic efficacy in IBS
• Prove the concept of a ‘therapeutic window’
for caecal pH
• Role of stress, diet, pharmaceuticals, colonic
irrigation etc to test the model
Caecal pH - Therapeutic Window?
7.5
7
Constipation
6.5
6
Normal
5.5
5
Loose stools
4.5
4
Severe
Moderate
Mild
Constipation Constipation Constipation
Normal
Normal
Normal
Normal
Mild Loose
Moderate Severe Loose
Bowels
Loose Bowels
Bowels
Planned trial starting 1Q 2015
Study Plan
•
•
•
•
•
48-IBS patients will be recruited (self referred)
Online screening via questionnaire
Consultation with gastroenterologist
Diagnostics – SmartPill and HMBT
Randomised to 3-arms Low FODMAP, Control
Diet, Linaclotide for 28-days
• Repeat Diagnostics
• Treatment plan for GP and patient going forward
based on objective data
• WE NEED YOUR HELP RECRUITING PATIENTS
[email protected]