Functionele Maagdarmklachten als Stoornissen van Gut-Brain Interacties Leiden alle wegen naar Rome IV?

Functionele Maagdarmklachten als Stoornissen van Gut-Brain Interacties Leiden alle wegen naar Rome IV? Lukas Van Oudenhove, MD, PhD Assistant Professor (KU Leuven Special Research Fund) Laboratory for Brain-Gut Axis Studies (LaBGAS) Translational Research Center for Gastrointestinal Disorders (TARGID) Department of Clinical & Experimental Medicine University of Leuven, Belgium Leuvense Dagen Kindergeneeskune, 18 mei 2017

Overview introduction functional gastrointestinal disorders brain-gut axis psychobiological mechanisms of gastrointestinal symptom perception microbiota-gut-brain axis

Functional Gastrointestinal Disorders what s in a name? definition purely symptom-based diagnostic criteria based on (evidence-based) expert consensus ( Rome committees ) no evidence for organic process/disease explaining symptoms implications status of the disorders syndrome group of symptoms frequently occurring together disease entity patho(physio)logy explains symptoms & determines treatment heterogeneity!

Functional Dyspepsia Rome IV definition one or more of the following (bothersome) no evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms duration minimum 3 months, onset minimum 6 months subdivided in epigastric pain syndrome postprandial distress syndrome Stanghellini et al, Gastroenterology 2016

Pediatric Functional GI Disorders Rome IV classification Rome III: exclusion diagnosis no evidence of an inflammatory, anatomic, metabolic, or neoplastic process that explain the subject s symptoms Rome IV: positive symptom-based diagnosis after appropriate medical evaluation, the symptoms cannot be attributed to another medical condition. Benninga et al, Gastroenterology 2016 Hyams et al, Gastroenterology 2016

Functional Gastrointestinal Disorders pathophysiology? complex interaction biological, psychological & social factors 1 (groups of) etiopathogenetic factors in FGID gastric sensorimotor dysfunction 2 hypersensitivity dysmotility gut microbiota gut permeability low-grade inflammation 3 psychosocial factors/psychiatric co-morbidity 1 history of sexual/physical abuse personality traits (neuroticism,...) symptom-specific psychological processes (GI-specific anxiety,...) psychiatric disorders (depression, anxiety disorders, ) somatization /(functional) somatic co-morbidity 1 (psychological) tendency to experience and report multiple somatic symptoms that cannot be adequately explained by organic findings functional somatic syndromes (fibromyalgia, chronic fatigue syndrome,...) interaction poorly understood! 1. Van Oudenhove et al, Gastroenterology 2016 2. Boeckxstaens et al, Gastroenterology 2016 3. Barbara et al, Gastroenterology 2016

Functional Gastrointestinal Disorders biopsychosocial model Drossman et al, Gastroenterology 2016

Brain-Gut Axis overview HUMORAL GUT-BRAIN GI hormones BRAIN-GUT Hypothalamo-Pituitary- Adrenal Axis NEURAL Autonomic Nervous System

Functional Gastrointestinal Disorders systemic disorders of gut-brain interactions symptom reporting visceral perception affective cognitive networks sensorimotor network Brain modulatory pathways Brain modulatory pathways (health related) cognitions behavior coping personality spinal (orthosympathic) dorsal horn descending modulatory pathways autonomic network CRF (GI specific) anxiety attention vigilance afferent nerves mechanoreceptors GI immune & barrier function gut microbiota CRF (interoceptive) conditioning stressful life events mechanical GI stimulation GI motor (dys)function CRF HPA-axis ANS arousal adapted from Van Oudenhove et al, Biopsychosocial Aspects of Functional Gastrointestinal Disorders (Rome IV), Gastroenterology 2016 adapted from Van Oudenhove & Aziz, Nature Rev Gastro Hepatol 2013 and Naliboff & Rhudy in Mayer & Bushnell, IASP Press 2009

Descending pain modulatory pathways Törnblom & Drossman, Neurogastroenterol Motil 2015

Overview introduction psychobiological mechanisms of gastrointestinal symptom perception microbiota-gut-brain axis

Psychological impact on GI symptoms overview symptom reporting visceral perception affective cognitive networks sensorimotor network Brain modulatory pathways Brain modulatory pathways (health related) cognitions behavior coping personality spinal (orthosympathic) dorsal horn descending modulatory pathways autonomic network CRF (GI specific) anxiety attention vigilance afferent nerves mechanoreceptors GI immune & barrier function gut microbiota CRF (interoceptive) conditioning stressful life events mechanical GI stimulation GI motor (dys)function CRF HPA-axis ANS arousal adapted from Van Oudenhove et al, Biopsychosocial Aspects of Functional Gastrointestinal Disorders (Rome IV), Gastroenterology 2016 adapted from Van Oudenhove & Aziz, Nature Rev Gastro Hepatol 2013 and Naliboff & Rhudy in Mayer & Bushnell, IASP Press 2009

Gastric accommodation normal physiology

Gastric accommodation measurement in healthy subjects

Gastric accommodation (ml) Functional Dyspepsia patients have impaired gastric accommodation 300 FD patients (n=259) 200 Controls (n=48) 100 0 0 5 10 15 20 25 30 35 40 45 50 55 60 Time after meal (min) Weltens*, Ly*, Tack & Van Oudenhove, Clin Gastroenterol Hepatol 2015

Gastric accommodation is inhibited by anxiety in healthy subjects

Gastric accommodation is inhibited by anxiety in Functional Dyspepsia Gastric accommodation (ml) Gastric accommodation (ml) 250 Average STAI 200 STAI upper limit 150 100 50 0 0 5 10 15 20 25 30 35 40 45 50 55 60 Time (min) 200 150 100 Co-morbid GAD (n=30) No co-morbid GAD (n=213) 50 0-50 5 10 15 20 25 30 35 40 45 50 55 60 Time (min) -100 Weltens*, Ly*, Tack & Van Oudenhove, Clin Gastroenterol Hepatol 2015

Brain activity IBS patients have an increased ACTH response to CRH injection 6 Control IBS 4 2 0-2 -4-6 -8-10 -12 0 3000 6000 9000 12000 15000 18000 21000 ACTH_AUC Kano,, Van Oudenhove,, Fukudo, submitted

Male IBS patients have an increased colonic motility response to CRH injection # phasic volume events 16 14 12 10 8 6 4 2 * Control_men (17) Control_wemen (14) IBS_men (14) IBS_wemen (14) 0-20_0 0_20 20_40 40_60 60_80 80_100 100_120 min Kano,, Van Oudenhove,, Fukudo, submitted

STAI score Psychosocial stress increases small intestinal permeability in healthy subjects LMR Salivary Cortisol (ng/ml) 0.06 lactulose-mannitol ratio ** 0.04 cortisol stressor p=0.22 p=0.01 LMR 0.02 60 anxiety *** # *** 0.00 Basal Speech Shock salivary cortisol 20 *** 40 15 10 20 0 Basal Speech Shock mixed models + Bonferroni: ** P<0.01 vs. basal *** P<0.001 vs. basal # P<0.05 vs. speech Vanuytsel et al, Gut 2013 5 0 Basal Speech Shock

Emotional modulation of visceral pain paradigm Emotion induction period Emotional pain modulation period time 0 time 1 time 2 ES ES ES ES ES ES ES ES ES ES SAM VAS SAM start emotion induction stop emotion induction Emotion induction Validated classical music Velten mood induction statements IAPS pictures Weltens, Schaub, Aziz, Tack, Van Oudenhove* & Coen*, in preparation

Pain intensity (0-100) Pain intensity (0-100) Visceral pain perception is modulated by emotional state in healthy subjects *** 80 *** *** 60 40 20 0 Negative Neutral Positive 70 65 Negative β=-0.064; p=1 60 Neutral β=-0.48; p=0.0026 55 50 Positive β=-0.72; p=0.0001 45 40 0 1 2 3 4 5 6 7 8 9 10 Stimulus number Weltens, Schaub, Aziz, Tack, Van Oudenhove* & Coen*, in preparation

Learned fear of innocuous GI sensations in health INNOCUOUS ESOPHAGEAL DISTENSION PAINFUL ESOPHAGEAL DISTENSION BASELINE ACQUISITION EXTINCTION Ceunen, Zaman,..., Vlaeyen, Van Oudenhove* & Van Diest*, Clin Gastroenterol Hepatol 2016

Learned fear of innocuous GI sensations in health Ceunen, Zaman,..., Vlaeyen, Van Oudenhove* & Van Diest*, Clin Gastroenterol Hepatol 2016

Learned fear of innocuous GI sensations generalization & effect on visceral perception Zaman, Weltens, Ly,..., Van Oudenhove* & Van Diest*, Psychosom Med 2016

Clinical relevance of fear learning Exposure-based cognitive-behavioural therapy for IBS CBT (exposure-based) internet-based large effect sizes up to 18 months exposure crucial GI-specific anxiety IBS symptoms Ljotsson et al, Am J Gastroenterol 2011 Ljotsson et al, J Consult Clin Psychol 2013 Ljotsson et al, Behav Res Ther 2014

DEPRESSION SOMATIZATION meal meal

Brain responses to painful rectal distension IBS: role of acute fear + correlation: dorsal pons - correlation: dorsal pons - pacc Berman et al, J Neurosci 2008

Brain responses to painful rectal distension FD: role of acute fear - correlation: pacc R + correlation: dorsal pons L Van Oudenhove et al, American Journal of Gastroenterology 2010

Anticipation of painful rectal distension IBS versus healthy controls IBS PATIENTS (n=17) HEALTHY CONTROLS (n=15) Berman et al, J Neurosci 2008

Anticipation of painful gastric distension FD versus healthy controls R L R DEACTIVATIONS: sham > baseline L Van Oudenhove et al, American Journal of Gastroenterology 2010

Anticipation of painful rectal distension IBS versus healthy controls: effects of uncertainty Figure 1 a: fmri protocol (one trial) Visual Cue?! 0 or or + VAS (anxiety, discomfort) 3 s 6 15 s 18 s 19 s Rest 3 s b: contrasts for context modulation anticipation distention Kano,, Van Oudenhove, Fukudo, Psychosom Med, in press

Anticipation of painful Visual rectal Cue distension IBS versus healthy controls: oreffects of uncertainty?! 0 or + VAS (anxiety, discomfort) 3 s 6 15 s 18 s 19 s Rest 3 s b: contrasts for context modulation anticipation distention Certain vs. Uncertain? certain! uncertain 0 safe Distention certain vs. Distention uncertain No Distention uncertain vs. No Distention safe Kano,, Van Oudenhove, Fukudo, Psychosom Med, in press

Anticipation of painful rectal distension IBS versus healthy controls: effects of uncertainty I protocol (one trial) + VAS (anxiety, discomfort) 15 s 18 s 19 s Rest 3 s trasts for context modulation anticipation distention? certain Distention certain vs. Distention uncertain! uncertain 0 safe No Distention uncertain vs. No Distention safe Kano,, Van Oudenhove, Fukudo, Psychosom Med, in press

Brain responses to ancitipation of visceral pain differential fear learning in IBS versus healthy controls ACQUISITION Icenhour,, Elsenbruch, Neurogastroenterol Motil 2015

Brain responses to anticipation of visceral pain role of CRF system in IBS versus healthy controls Hubbard et al, J Neurosci 2011

Functional dyspepsia CB1-receptor availability Ly, Ceccarini, Weltens, Bormans, Van Laere, Tack & Van Oudenhove, Psychother Psychosom 2015

ANXIETY OR 1.21 1.23 [1.13-1.31]*** [1.15-1.32]*** path a a IBS OR 1.09 [1.04-1.15]** path b INFECTIOUS GASTROENTERITIS OR 2.59 [1.43-4.71]** path c Wouters et al, Gut 2016

Functional Gastrointestinal Disorders biopsychosocial model Drossman et al, Gastroenterology 2016

Overview introduction psychobiological mechanisms of gastrointestinal symptom perception microbiota-gut-brain axis

Microbiota-gut-brain axis Mayer et al, J Neurosci 2015

stress-induced hyperthermia elevated plus maze forced swim test response to forced swim test Bravo, Forsythe et al, Proceedings of the National Academy of Sciences USA 2011

Gut Microbiota & Stress Sensitivity Central GABA receptors cingulate gyrus prelimbic cortex infralimbic cortex basolateral amygdala central amygdala locus coeruleus hippocampus: dentate hippocampus: CA3 hippocampus: CA1 Bravo, Forsythe et al, Proceedings of the National Academy of Sciences USA 2011

Probiotic & Brain Function in Healthy Humans Resting State & Emotional Responses Tillisch,..., Mayer, Gastroenterology 2013

Probiotic treatment decreases depressive symptoms & emotional brain responses in IBS Pinto Sanchez et al, Gastroenterology, in press

Take home messages Functional GI disorders results from a complex interaction between biological, psychological & social processes Psychobiological mechanisms of gastrointestinal symptom perception & generation psychological modulation of visceral afferent input efferent output of emotional/autonomic circuits modulates GI function dysfunctional in FGID Gut-brain signals & psychological processes nutrient & microbiota signaling may influence our psychobiology