IBS The Physiologist s Perspective

Transcription

1 IBS The Physiologist s Perspective Dr Anthony R. Hobson PhD Consultant Clinical Scientist, London

2 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.

3 Symptoms Physiology Function Behaviour Accurate Diagnosis Effective Treatment

4 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.

5 Brain Imaging Testing the model Psychological profiling Blood Assays Real-time ANS recordings ph profiling Breath Tests Biopsies GI Motility and Neurophysiology Stool samples

6 The pain hypothesis IBS patients have more gut symptoms and pain than healthy people so are they more sensitive to GI pain?

7 Does gut stimulation activate the cortex? MEG A FMRI B

8 Cohen et al Does brain activation correlate with stimulation intensity and sensory perception?

9 Does brain activation always correlate with stimulation intensity and sensory perception? Sidhu, H. et al. Am J Physiol Gastrointest Liver Physiol 2004

10 Is the brain s response to pain specific to the experimental stimulus? Pain Anticipation Extinction Insula DLPFC Cingulate Yaguez et al Gastroenterology. 2005

11 Hobson et al Gastroenterology 2005 MEG - Evoked field potential recorded following painful electrical stimulation of the gut ~80ms Somatosensory cortex (Sensory discrimination) ~140ms Temporal sequence of activation Cingulate cortex (Affective) 250ms

12 Ano-rectal sensory neurophysiology Hypersensitivity in IBS Arebi and Hobson et al NGM 2011

13 Hypersensitivity in IBS lack of habituation Arebi and Hobson et al NGM 2011

14 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

15 The psychological hypothesis IBS patients have more psychological comorbidity than healthy people so is it all in the brain?

16 Arebi and Hobson et al NGM, 2011 Psychological profiles

17 Personality profiles * Arebi and Hobson et al NGM, 2011

18 No correlation between psychological or personality measures and objective or subjective measures of pain sensitivity

19 The neuro-immune hypothesis IBS patients have a more irritable gut than healthy people so is their neuro-immune system different?

20 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.

21 PBMC IL-8 release to LPS in IBS and Controls (pro-inflammatory) * * * * * *p< Cx study 1 IBS Study LPS 0 LPS 0.1 LPS 0.3 LPS 1 LPS 3 LPS 10

22 PBMC IL-10 release to LPS in IBS and Controls (anti-inflammatory) * * *p< * * * Cx Study 1 IBS Study LPS 0 LPS 0.1 LPS 0.3 LPS 1 LPS 3 LPS 10

23 PBMC TNF-alpha release to LPS in IBS and Controls (pro-inflammatory) * * * * *p< * LPS 0 LPS 0.1 LPS 0.3 LPS 1 LPS 3 LPS 10 Cx Study 1 IBS Study 1

24 PBMC IFN-gamma release to LPS in IBS and Controls TH * * * * *p<0.02 CX Study IBS Study LPS 0 LPS 0.1 LPS 0.3 LPS 1 LPS 3 LPS 10

25 PBMC IL-4 release to LPS in IBS and Controls TH Cx IBS LPS 0 LPS 0.1 LPS 0.3 LPS 1 LPS 3 LPS 10

26 TH-17 profile?

27 IL-8 Neuro-immune link - Correlation between IL-8 and VDVAS-I IL8 Linear (IL8) VDVAS-I R = 0.61, p<0.0001

28 Is there a unifying hypothesis? Stress effects all of the above systems is this the unifying factor?

29 Co-incubation with stress hormone CRF inhibits IFN-G in controls Cx Means CRF 0 Cx Means CRF 1 IBS Means CRF 0 IBS Means CRF LPS 0 LPS 0.1 LPS 0.3 LPS 1 LPS 3 LPS 10

30 Murray et al Gastroenterology 2004 Experimental design for evaluating stress in IBS

31 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

32 Development of an IBS stress model Physical Stress Rectal Perception Thresholds Psychological Stress Stress induces rectal hypersensitivity in IBS but not controls.

33 Psychological stressors relatively easy to define

34 What if it s something in the gut causing the patients to be stressed and driving these processes?

35 Digestion and Fermentation

36 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

37 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?

38 Hydrogen and Methane breath testing

39 GAS (PPM) Hydrogen and methane Breath testing - SIBO VAS Score H+ ppm CH4+ Bloating 30 4 Nausea Pain min 15min 30min 45min 60min 75min 90min 105min 120min 0 16g of lactulose given in 200ml of water

40 VISUAL ANALOGUE SCALES NAUSEA BLOATING PAIN / CRAMPING

41 Other factors Bowel movements Other GI symptoms (belching, borborygmi etc) Extra GI symptoms (headache, tiredness, dizziness, emotional) Abdominal girth (pre and post study distension)

42 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.

43 SmartPill data outputs ph ph ingestion rise drop GRT SBTT CTT excretion temperature ph pressure Pressure Temperature ph

44 SmartPill Stomach ingestion Gastric acid buffered by test meal Strong contractions temperature ph Rise in small bowel ph pressure Pressure Temperature ph

45 SmartPill small bowel Small Bowel transit ph drop Enters the colon temperature ph pressure Pressure Temperature ph

46 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

47 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

48 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

49 AAUC (mmhg*s) Regional Transit Times Controls v IBS-A Transit Time (min) Patients (Mean ± SD) P=0.01 Controls (Mean ± SD) P-value P<0.05 GET SBTT CTT WGTT GET: Gastric emptying time; SBTT: Small bowel transit time; CTT: Colonic transit time; WGTT: Whole gut transit time. Farmer and Hobson 2014 WJG

50 AAUC (mmhg*s) Regional Contractility Controls v IBS-A Motility (AUC) Patients (Mean ± SD) P=0.01 Controls (Mean ± SD) P-value Antral P<0.05 Duodenal Ileal Cecal Recto-sigmoid AUC: Areas under the curve. Farmer and Hobson 2014 WJG

51 Caecal ph * P<0.05 * P<0.05 Farmer and Hobson 2014 WJG In Press

52 Caecal Contractility versus ph (r = 0.54, P = 0.002) Farmer and Hobson 2014 WJG In Press

53 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.

54 New concepts Mirrors gastroparesis in upper gut SCFA mediated caecoparesis More akin to anal vomiting than diarrhoea IBS V? You heard it here first!

55 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

56 Caecal ph - Therapeutic Window? Constipation Normal Loose stools 4 Severe Constipation Moderate Constipation Mild Constipation Normal Normal Normal Normal Mild Loose Bowels Moderate Severe Loose Loose Bowels Bowels

57 Planned trial starting 1Q 2015

58 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

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