Aetiopathogenesis of Functional Dyspepsia

NZ 2019 Aetiopathogenesis of functional dyspepsia

Genetic DUODENAL LUMEN

predisposition GUT EPITHELIUM

BRAIN ↑ Epithelial permeability Pathogens or allergens Anxiety or stress response APC

Eotaxin release

LAMINA PROPRIA Eosinophil activation

Disordered motility and visceral hypersensitivity Immune cells Th2-cell Interleukin-4 response Interleukin-13 Interleukin-5 Early satiety

Eosinophil degranulation B-cell response ↑ Inflammatory cytokines TNFα, Eosinophil interleukin-10, and Epigastric recruitment interleukin-1β Release of Nerve proallergic IgE pain, infringement DUODENUM Delayed gastric emptying burning Nerve firing

Muscle contractions Fullness post and pain Talley & Ford.MUSCL NE FIBER EnglS J Med 2015:373:1853-63 meal Nicholas J. Talley AC, MD, PhD University of Newcastle, Australia Disclosures

Grant / Research Support Committees Commonwealth Diagnostics (International) (IBS) Australian Medical Council (AMC) Council Member (ceased 2017) MBS Review Taskforce NHMRC Principal Committee, Research Committee HVN National Science Challenge NZ (no financial Asia Pacific Association of Medical Journal Editors (APAME) support) Patents Consultancies Biomarkers of irritable bowel syndrome (#12735358.9 - Takeda (gastroparesis) 1405/2710383 and (#12735358.9 -1405/2710384) Adelphi values (functional dyspepsia working group to develop a symptom based PRO instrument) Licensing Questionnaires (Mayo Clinic) Talley Bowel Disease Questionnaire, Mayo Dysphagia Questionnaire Allergens PLC GI therapies (non-invasive device company, consultant and Nestec European Patent Application No. 12735358.9 options) Singapore ‘Provisional’ Patent NTU Ref: TD/129/17 IM Health Sciences, USA “Microbiota Modulation of BDNF Tissue Repair Napo Pharmaceutical Pathway” Outpost Medicine Editorial Samsung Bioepis Synergy Medical Journal of Australia (Editor-in-Chief) Theravance Up to Date (Section Editor) Avant Foundation (judging of research grants) Precision and Future Medicine, Sungkyunkwan University School of Medicine, South Korea Community and patient advocacy groups Boards GESA Board Member. Gastroenterology Society of Advisory Board, IFFGD (International Foundation for Functional Australia GI Disorders) Rome IV Functional Dyspepsia

Epigastric pain Postprandial distress syndrome (EPS) syndrome (PDS)

Early Postprandial Epigastric Epigastric satiation, heaviness or pain burning may lose fullness weight

Bothersome, at least 1 day a week Bothersome, at least 3 days a week D3 Epidemiology by endoscopy

Of 1000 Swedish subjects: • 202 (20%) uninvestigated dyspepsia • 157 (16%) functional dyspepsia (FD) • 52 epigastric pain syndrome (EPS): 33% of FD • 122 postprandial distress syndrome (PDS): 78% • 17 EPS and PDS overlap: 11%

Functional dyspepsia common, postprandial distress most prevalent subtype

Aro, Talley et al. Gastroenterology. 2009;137:94-100 Epidemiology of FD

Italy Scandinavia USA Loiano & Monghidoro study Kalixanda study Olmsted County

No FD No FD No FD

FD FD FD

EPS alone Overlapping EPS EPS alone EPS alone Overlapping EPS and PDS and PDS

Overlapping EPS and PDS

PDS alone PDS alone PDS alone

Tack J & Talley NJ, Nat Rev Gastroenterol Hepatol 2013; 10:134 10-year FD follow-up FD IBS post upper GERD endoscopy: Change of FD, reflux (GERD), and IBS from GERD base-line to follow-up FD leads to symptomatic GERD or IBS IBS (same spectrum)

Aro P, Talley NJ, et al. Gastroenterology 2015;148:928-37 Functional dyspepsia may be increasing

• Östhammar community, Sweden • All inhabitants above 18 years born day 3, 12, 24 every month • 4 repeated validated ASQ postal surveys • 1988, 1989, 1995 and 2011 → 23 year follow up • Total 1884 participants participated on 4509 occasions • On average 2.4 occasions each

• 444 participated in all 4 surveys

Effect of time (mixed effects logistic regression adjusting age, sex): FD OR=2.24 (1.71-2.94) PDS OR=3.51 (2.57-4.81) EPS OR=1.5 (1.09-2.05)

Andreason, Talley et al. Odds of dyspepsia doubled - corresponding to an absolute increase in prevalence of 8 % (10 % PDS and 3 % EPS) Traditional pathophysiology of functional dyspepsia

Gastric acid Gastric acid NOT increased

Gastritis NOT associated H. pylori with symptoms

Impaired fundic Functional dyspepsia with accommodation early satiety

Delayed gastric Correlates very poorly with emptying symptoms

Hypersensitivity Functional dyspepsia with to distention pain

Talley and Ford. N Engl J Med 2015373:1853-63 Empirical evidence: what works?

Functional dyspepsia patient H. pylori positive H. pylori negative

H. pylori PPI Eradication No response No response Response

Response TCA Response Success No response Response Prokinetic Response No response

Consider psychotherapy

ACG Guideline Moayyedi PM, Lacy BE et al. Am J Gastroenterol 2017;112:998-1013 Forest plot of randomized controlled trials comparing PPIs with placebo in FD

• 15 RCTs, 5853 FD patients • RR = 0.87 (95% CI 0.82 -0.94) • NNT = 10 (95% CI 7- 20)

Moayyedi et al. Am J Gastroenterol 2017;112:998-1013 Is there a subgroup that responds better to PPI? Rome III definitions: Postprandial distress not EPS – WHY?

Pinto-Sanchez MI et al. Cochrane Library 2017 H. pylori and gastritis: a Nobel story

Functional dyspepsia: • Rome IV • Kyoto consensus

Gut. 2015;64(9):1353-67 H. pylori and functional dyspepsia

Figure 10. Forest plot of randomized controlled trials comparing H. pylori eradication with placebo antibiotics in H. pylori-infected patients with functional dyspepsia. EPS may be most responsive

NNT = 17

Moayyedi et al. Am J Gastroenterol 2017;112:998-1013 H. pylori gastritis is NOT associated with dyspepsia symptoms – so why does eradication therapy work?

• Longitudinal population-based study Osthammar, Sweden • A randomly sampled adult population completed a validated GI symptom questionnaire in 2011 (N = 1175) • Participants <80 years of age and who were eligible were invited to undergo upper endoscopy (OGD) (N = 947); 402 accepted and 368 successfully underwent OGD with antral and body biopsies. H. pylori serology was also performed • Participants: 368 community individuals (average 54.1 years, range 20-79 years; 47.8% male) • Main outcome measures: Prevalence of histological gastritis and its subtypes, association between symptoms and findings on endoscopy Results: Gastritis was found in 40.2%. • Gastritis and gastritis subtypes were not associated with GI symptoms versus those with a normal gastric biopsy • Postprandial distress syndrome (PDS) negatively associated with gastritis, specifically H. pylori gastritis – WHY?

UEGW 2019. Zuzek, Walker, Talley et al. Gastritis in a Community Population – Prevalence of Histological Types and Association with Symptoms Prokinetics, fundic relaxors and visceral analgesics Examples of localization and nature of target receptors

Camilleri et al. Gastroenterology 2016;150:1319-31. Functional Dyspepsia: fundic relaxation as a target

Normal fundic Meal accommodation or receptive relaxation

Relax the fundus: Impaired fundic accommodation ➢ Serotonin 5HT4 agonists: cisapride with a redistribution of food to antrum 40% ➢ Serotonin 1 agonists: sumatriptan (5HT1p), buspirone (5HT1a)

➢ Acotiamide

➢ STW 5 (Iberogast) Tack et al. Gastroenterology 1998; 115:1346-52 Acotiamide in functional dyspepsia Japanese phase 3 study

➢ Enhances acetylcholine release via • FD 100 mg acotiamide or placebo TID 4 M1/M2 antagonism wks ➢ Inhibits acetylcholinesterase activity • Elimination rate all 3 meal-related ➢ Accelerates gastric emptying and symptoms 15% acotiamide vs. 9% placebo (p=0.004): NNT 16 enhances gastric accommodation

Matsueda et al., Gut 2012 Forest plot of randomized controlled trials comparing motility modifying drugs with placebo in functional dyspepsia patients

Moayyedi, PM et al. AJG 2017

✓ Cisapride ✓ Tegaserod ✓ Acotiamide ? Others Functional dyspepsia treatment trial (NIH): Antidepressants

Talley NJ et al. Gastroenterology. 2015;149(2):340-9 Other antidepressants in FD

Mirtazepine 15 mg daily n=29 F with weight Venlafaxine XR: 8 wks (2 wks 75 mg once loss: tetracyclic antidepressant, anti-emetic, daily, 4 wks 150 mg once daily, and 2 wks 75 mg once daily) appetite stimulant

Early satiety Diaries

40 Mirtazapine Placebo 30

20 Mean severity score (VAS) score severity Mean 10

0 Week - Week Week Week Week Week Week Week Week 1 1 2 3 4 5 6 7 8 Clin Gastroenterol Hepatol. 2016;14:385-392 Clin Gastroenterol Hepatol. 2008;6:746-52 Accommodation (ml) Symptom score 100 150 200 250 300 50 10 15 20 25 30 35 40 0 Buspirone 5 0 Fullness Run * † - in Accommodation Bloating * † Placebo (5HT 1A dyspepsia in functional agonist) Belching * Nausea Buspirone Tack et al. * * Pain Clin Epigastric burning Intragastric volume (ml) 100 200 300 400 500 600 700 Gastroenterol 0 Postprandialvolumethreshold Run Buspirone Placebo Run - in - in Hepatol Placebo ➢ ➢ weeks) 3 timesfor 4 daily Buspirone years) meanage, 38.5 n=17 ( crossoverstudy placebo Double . 2012;10:1239 13 women; Buspirone - - blind controlled, * (10 mg, , - 45 Functional dyspepsia management

By definition: NO cause known

➢Why do PPIs work if gastric acid not increased? And why possibly better in PDS than pain? ➢Why might H. pylori eradication work in a subset if gastritis is not the cause of symptoms? ➢Prokinetics and antidepressants can reduce symptoms but do not modify the natural history of the disease ➢Are alternative treatment options emerging? Clin Gastroenterol Hepatol. 2007 5:1175-83

MBP – degranulation in FD may be key…

S100 nerve fibresS100

Clusters of eosinophils in D1 observed in 26 FD Carbol (51%) vs. 10 controls (21%) (p=0.003) ChromotropeEosinophil degranulation PDS not EPS linked to duodenal eosinophils Pediatric study: duodenal eosinophilia – FD

Wauters, Walker, Talley et al. APT 2017; 45: 1358-64

• Duodenal eosinophilia in pediatric FD in the absence of macroscopic (endoscopy) or routine histology findings • Duodenal eosinophilia should be considered as a therapeutic target in pediatric FD • Consistent with US observations Singh et al. Pathol Res Pract 2018 214:1173-1178 Independent verification Leuven: altered permeability, neuronal structure and function FD ±IBS MBP HuCD

Controls MBP HuCD

Duodenal eosinophils in FD (n= 15 cases vs. 15 controls) Cirillo et al. Am J Gastroenterol 2015;110:1205-15 FD & Duodenal Eosinophilia Postprandial distress syndrome (PDS)

•Talley NJ et al. Clin Gastroenterol Hepatol. 2007. Sweden • Bafutto M et al DDW 2009, 2012. Brazil • Walker MM et al. Aliment Pharmacol Ther. 2010 London • Futagami S et al. Am J Gastroenterol. 2010. Japan • Pignataro SB et al DDW 2011. Argentina • Walker MM et al J Gastroenterol Hepatol 2014. Australia • Wang X et al Ann Diagn Pathol 2015. China • Vanheel, Tack et al Gut 2015/ Cirillo C et al Am J Gastro 2015. Belgium • Graham et al DDW 2017 Houston; Chaudhari et al. 2017 India; Halland et al. Mayo Clinic 2018; Wauters 2019 Leuven; Lee et al. Korea 2019, Taki et al. Japan 2019, Sakar et al. Myamar Duodenal eosinophilia and GERD

Change of PDS to OR 95% CI

GERD PDS to incident GERD Eosinophilia in D1, 1.6 0.50-4.84 symptoms over 10 years: OR 8.8, 95% CI 3.4-22.9 crude*

Eosinophilia in D1, 1.8 0.52-6.06 EPS OR 2.3, 0.56-9.24

adjusted Ronkainen J, Talley NJ et al. Aliment Pharmacol Eosinophilia in D2, 4.1 1.19-14.0 Ther. 2019 May 20.

crude* Age dichotomized at 60 years, H. pylori positive by histology or culture. Eosinophilia in D2, 6.3 1.50-26.37 *Adjusting for age and sex only **Variables in the final model: age, gender, use of proton pump inhibitors adjusted** (PPIs), smoking (yes/no), H. pylori infection and anxiety.

Duodenal eosinophilia (D2) was associated with a 6-fold increased risk of NEW ONSET symptomatic GERD at 10 year follow-up in PDS (but not EPS) Duodenal eosinophilia and anxiety

Ronkainen, Talley et al. DDW 2019

Crude incident ANXIETY (%) at 10 years follow-up Kalixanda study N=213 (FD n=89) 10 year follow-up % 16 P<0.001 Incident anxiety 6% 14 % 14 Incident depression 1% 12 12 10 10 D1 8 8 P=0.01 6 6 4 4 2 2 0 0 PDS Control EPS Control Duod eos No eos

Duodenal eosinophilia (D2) associated with a 5-fold increased risk of new onset anxiety at 10 year follow-up in PDS (but not EPS) Smoking and functional dyspepsia

• Cohort study Walkerton, Ontario, Canada 2002-2003 – follow -up 2008 • Of 2597 subjects eligible, 1088 (42%) provided data for analysis: 706 (65%) acute gastroenteritis • Risk for dyspepsia at 8 years in exposed by Rome II 2.30 (95% CI 1.63-3.26) Ford et al. Gastroenterology 2010;138:1727-36 • Prevalence of dyspepsia higher in females; smokers; premorbid IBS; anxiety or depression; >7 days diarrhea or cramps during acute illness

Italian population-based endoscopy study: Loiano and Monghidoro Independent risk factors for FD: unemployment (OR, 5.80; 95% CI, 1.56–21.60), divorce (OR, 2.76; 95% CI, 1.10–6.91), cigarette smoking (OR, 1.74; 95% CI, 1.11–2.70), IBS (OR, 3.38; 95% CI, 1.85–6.19) Zagari et al. Gastroenterology 2010; 138: 1302–1311 Smoking associated with higher eosinophil counts in FD

Smoking linked to post -infectious FD (Walkerton study)

Walker, Talley et al. J Gastroenterol Hepatol. 2014;29:474-9 Increased cytolethal distending toxin B antibodies in FD?

• Anti CdtB- IBS: P=0.06 Anti-CdtB and Cytolethal anti-vinculin: distending toxin B (CdtB) is produced Australian by bacteria that cause random acute gastroenteritis population- • Post-infectious based animal model sample demonstrates that (vinculin no host antibodies to differences; clinic CdtB cross-react with sample no vinculin in the gut, FD: P=0.005 producing an IBS-like significant phenotype differences) (autoimmune) Talley et al. CTG 2019 in press Rumination syndrome and functional dyspepsia

Regurgitation is effortless

Not preceded by retching/nausea

50% FD symptom overlap

Clinically do NOT confuse with vomiting – cannot retain in the mouth Rumination and duodenal eosinophilia Halland, M., Talley, N.J., Jones, M. et al. Dig Dis Sci 2019; 64(3):832-837

• 22 patients with rumination syndrome mean age of 39.2, 77% female • 10 controls (iron deficiency/volunteers) mean age 34.3, 80% female Homing small intestinal 400 *

350 T cells and FD 300 • Cytokine release and 250 CD4+α4β7+CCR9+ lymphocytes

(pg/ml) 200 correlated with symptom intensity



150 pain, cramps, nausea, vomiting

TNF-

100

50 14

0 12 HC FD 10

 Delayed gastric emptying 8

7+CCR9+ (%) 7+CCR9+

correlated (r=0.78, p=0.02)  4 6 with CD4+α4β7+CCR9+ 

CD4+ 4 lymphocytes, and IL-1β, TNF- α and IL-10 secretion 2 0 Tobias, Talley, Holtmann et al. Am J Gastro 50 100 150 200 250 300 2011;106:1089-98 GET (T1/2) Montelukast in FD and eosinophilia (pediatrics)

• Competitive antagonist of the cys LT 1 receptor (asthma) • n=24; 83% a positive clinical response to montelukast • 50% a complete or nearly complete clinical response • Unrelated to systemic drug exposure or to mucosal drug concentration • No significant changes in eosinophil density, eosinophil activation, or serum cytokines

Friesen et al. BMC Gastroenterology 2009, 9:32. Duodenal eosinophils suppressed on PPI – not just acid!

Duodenal Eosinophil Count

• IL-13 increases Eotaxin-3 in immortalised EoE epithelial cells

• Omeprazole (PPI) blocks IL-13 induced Eotaxin-3 release

• PPI can decrease inflammation e.g. IL-8, VCAM

Cheng et al. Gut 2013; 62: 824-32 Potter, Walker, Talley et al. Gut 2018 H1/H2 blocker in FD: duodenal eosinophils may predict response (mast cell-eosinophil axis?)

• Retrospective study n=15 • Dual histamine blockade (ranitidine 150-300mg twice daily, loratadine 10-20mg daily) 6 months • Median age of 42.9 years (range 17-81 years) and 80% (12/15) were female. • EPS 40%, PDS 13%, EPD/PDS overlap 47% • 14/15 PPI failures • Symptom improvement 10/15 (67%) • Mean eosinophil count for responders 23/mm2, vs. 7/mm2 in non-responders (n=9, p=0.04, Student T test)

Potter, Walker, Talley et al. Gut 2019 Apr 30. pii: gutjnl-2019-318412. Brisbane Aseptic Biopsy Device

Membrane

Aseptic Aseptic Standard (Tissue Biopsy) (Surface) (Tissue Biopsy) Biopsy forceps advanced Most abundant Bacterial community genera are: profiles, grouped by biopsy device. Each coloured bar 1. Streptococcus • The Brisbane Aseptic Biopsy Device allows 2. Prevotella represents a bacterial genus 3. Lactobacillus for contamination free sampling of the MAM as assessed by 16S rRNA 4. Veillonella gene sequencing followed by 5. Neisseria • This device has enabled detailed taxonomic assignment. 6. Porphyromonas characterisation of the duodenal MAM, Holtmann, Morrison, Talley et al. which is dominated by Streptococcus Aliment Pharmacol Ther. 2016;43:1186-96. Membran e

Biopsy forceps advanced More Bacteria = Increased Symptoms More Bacteria = Lower quality of life Brisbane Aseptic Device Holtmann, Morrison, Talley et al. Aliment Pharmacol Ther. 2016;43:1186-96 Duodenal microbiome abnormal in FD

• FD patients (n = 9) and controls (n = 10) • Duodenal biopsies - quantitative PCR and next generation sequencing 16s rRNA gene • FD: bacterial load associated with significantly augmented symptom responses during nutrient challenge test and lower disease-specific QoL • Duodenal microbiota dominated by Firmicutes at the phylum level and by Streptococcus, Prevotella and Veillonella at the genus level • Actinomyces significantly decreased in FD patients compared to controls

FD a distinct duodenal microbial Shanahan, Morrison, Talley, Holtmann. signature vs. controls Gut 2016;66(6):1168-1169. Gastric emptying in functional dyspepsia negatively correlated with relative abundance of genus Veillonella in duodenum

A Univariate: R= -0.72; p < 0.0005; FDR q < Univariate: R= -0.7; p < 0.0005; FDR q < C 0.001 Slow stomach 0.005 Multivariate: p < 0.05; FDR q < 0.05 Multivariate: p < 0.05; FDR q < 0.05 emptying 5

4 identified in 3 20-40% with

2 Relative Abundance Relative

Relative Abundance Relative dyspepsia

(square root transformed) root (square (square root transformed) root (square

Gastric Emptying t-lag (minutes) Veillonella Gastric Emptying t-lag (minutes) A small Veillonella

B D Univariate: R= -0.55; p < 0.005; FDR q < intestinal Univariate: R= -0.53; p < 0.01; FDR q = 0.19 0.05 Multivariate: p < 0.05; FDR q = 0.12 Multivariate: p < 0.05 ; FDR q = 0.13 (duodenal) 5

4 bacteria may

3 Relative modulate

2 stomach

Relative Abundance Relative Abundance 1

Veillonella emptying

(square root transformed) root (square (square root transformed) root (square Gastric Emptying t-half (minutes) Veillonella Gastric Emptying t-half (minutes)

Shanahan, Morrison, Talley, Holtmann et al. DDW 2018 Smoking linked to functional dyspepsia & duodenal eosinophils Smoking associated with alterations of duodenal microbiome A B Current Never smoker smoked ■ Current ■ Previous ■ Never

Prevotella spp. (2222) Neisseria spp. (1060621) Colour Neisseria spp. (1092944) ■ Current Neisseria cinerea (1070334) ■ Previous Leptotrichia spp. (4338263) ■ Never Prevotella spp. (895629) Neisseria spp. (1056389) Prevotella nanceiensis (1012376) Oribacterium spp. (527630) Symbol Prevotella spp. (398192) ● CD Class TM7-3 (799024) ■ FD Prevotella melaninogenica  ID (4307391) Streptococcus spp. (1098340) Streptococcus spp. (1088134) Rothia mucilaginosa (368097) Streptococcus spp. (4399761) Prevotella intermedia (72112)

4 3 2 1 0 Relative abundance Linear discriminant analysis score (log10)

Duodenal microbiome and smoking Shanahan ER, Talley NJ, Morrison M, Holtmann GJ et al.. Microbiome. 2018;6:150. An altered duodenal microbiota in FD

• Functional dyspepsia by Rome III randomised to rifaximin 400 mg tid or placebo 2 weeks n =86 • At week 8, there were significantly more subjects in the rifaximin than in the placebo group who experienced adequate relief of global dyspepsia symptoms (78% vs. 52%, P = 0.02) • Rifaximin superior to placebo in providing adequate relief of • No strong human data on site or mechanism belching and post-prandial of action fullness/bloating (PPF) at week 4, • ? Microbiome (animal data suggests upper and higher response in females small intestine site of action)

Tan VP et al. Aliment Pharmacol Ther. 2017; 45: 767-76 Diet and FD: Systematic Review

• 16 of 6451 studies in a database search of six databases • Wheat-containing foods implicated in FD symptom induction in 6 studies, 2 that were gluten-specific • A gluten-free diet demonstrated a reduction in symptoms ? FODMAPs • Dietary fat was associated with FD in all 3 specific studies • Specific foods reported as inducing symptoms were high in either natural food chemicals, high in fermentable carbohydrates or high in wheat/gluten • Randomised trials investigating the roles of gluten, FODMAPs, high fat ingestion and naturally occurring food chemicals in the generation of functional dyspepsia symptoms are warranted

Duncanson, Talley et al. J Hum Nutr Diet 2017 Sept15. doi: 10.1111/jhn.12506 Duodenal eosinophils a biomarker for wheat sensitivity?

➢ Duodenal eosinophilia (circled) in NCWS ➢ Increased rectal eosinophils also observed

Carroccio et al Am J Gastroenterol 2012; 107:1898–1906 Carroccio et al. Clin Gastroenterol Hep 2018 in press

• ? Innate immune system involvement – Increased intestinal permeability – Interferon gamma expression – Epithelial cell damage – Duodenal (and rectal) Diagnosis by double-blind wheat challenge eosinophilia ]

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] Aetiopathogenesis of functional dyspepsia

• Female gender • Immune activation • Psychological distress • Cytokines e.g. TNF alpha, • Somatisation (non-GI symptoms) microbiome signalling • Sleep dysfunction • Increased small intestinal • Smoking eosinophils • Herbivore pet (parasites) • Altered microbiome • Post-gastroentertitis • Antibiotics • Food antigen driven • Wheat, FODMAPs inflammation • Atopic diseases • Autoimmune • Autoimmune diseases • Genetic predisposition • Familial, genes – GNβ3

Kim et al. JNM 2018 Jun 23. doi: 10.5056/jnm18068 Talley & Ford. N Engl J Med 2015;373: 1853-63 Esmaillzadeh et al. 2014;89(4):282-90 Paula et al. NGM 2015; 27: 1580-6 Koloski et al. NGM 2015; 27; 1317-25 Gathayia et al. NGM 2009; 21: 922 Li et al. BMC Psychiatry 2018;18(1):133 Disease model for functional dyspepsia, IBS & GERD

Anxiety Systemic symptoms

Brain-Gut

Small bowel Brain-Gut homing T cells, Cytokines cytokines, Increases Fundic disaccommodation microbial Reflux TLESRs and food redistribution signals with antral distention Acid Duodenal eosinophil Gut- Brain & mast cells

Smoking Microbiome duodenum altered Food antigen(s) Distal GI involvement - IBS Post infection Parasites Microbiome Talley NJ. Am J Gastroenterol. 2017; 112:141-144 Take home points - functional dyspepsia

A firm diagnosis allows treatment to be optimized (often misdiagnosed as GERD or gastroparesis) • In the setting of endoscopy negative dyspepsia, consider H. pylori infection, celiac disease • Reassure, educate, stress reduction •Therapeutic options for functional dyspepsia: ➢ Stop smoking, exercise? ➢ Diet: consider gluten, low FODMAP? ➢ Test for and eradicate H. pylori ➢ Acid suppression (PPI, H2 blocker) ➢ Prokinetic – domperidone, tegaserod ➢ Centrally acting agent e.g. TCA, mirtazapine • New approaches – identify duodenal eosinophilia and treat, rifaximin? 49 Thank you! Australian Gastrointestinal Research Alliance

 Professor Marjorie Walker Thank you Professor Mike Jones  A/ Professor Simon Keely • Hunter Community Study – Professor Nicholas Talley – Professor John Attia Professor Gerald Holtmann – Professor Marjorie Walker – A/Professor Mark McEvoy  Professor Mark –MorrisonProfessor Mike Jones – Stephen Hancock  Dr. Michael Potter– A/ Professor Simon Keely – Dr. Elizabeth Holliday  Dr Natasha Koloski– Dr. Greg Brogan  Gillian Harris – Gillian Harris  Bernadette Rickards– Bernadette Rickards  Raquel Cameron– Raquel Cameron • Australian Gastrointestinal Research Alliance – Leanne Tarrant Title AGIRA 2019 AUSTRALIA INTERNATIONAL COLLABORATIONS • Neurogastroenterology: Nick Talley (UON), Gerald Holtmann (UQ), Anatomical Pathology: Marjorie Walker (UON), Mucosal Immunology: Simon Keely (UON), • Belgium: Leuven TARGID group Jan Tack, Lucas Wauters, Microbiology: Mark Morrison (UQ), Biostatistics and Psychology: Mike Jones • Brazil: Mauro Baffutto (Macquarie University), • PhDs: Magnus Halland (Mayo USA ) – Rumination, Michael Potter – NCWS and • Chile/UK (Leeds): Content Study, Paul Harris Diez, Jean Crabtree coeliac disease, Gayatri Das – Dietary surveys, Georgia Carroll – Surgery • Finland University of Oulu: Jukka Ronkainen colorectal cancer, Bridie Goggins – IBD Cell biology, Amena Aktar - IBD Immunology, Grace Burns - FD Project immunology, Jessica Bruce - FD Project • P.R. China Sir Run Run Shaw Hospital, Zhejiang University, Ning cell biology, Sharmila Prasad – Pharmacy IBD Dai • Immunology: Kyra Minahan (UON), Andrea Mathe (UON) Anh Do (UQ) • Sweden, Karolinska Institutet: Anna Andreasson, Linn Inganäs , • Research Nurses, Digestive Health: Bernadette Rickards, Gillian Harris (UON), Lars Engstrand, Henry Nyhlin, Lars Kjellstrom, Åke Ost, Lars Nursing: Sally Chan (UON,Teressa Hanssen (UQ) Agréus, Lars Engstrand, Peter T. Schmidt, Pertti Aro • Epidemiology: Mark McEvoy, John Attia, Carlos Riveros, Zak McPherson (UON). Neurogastroenterology Science: Deborah Hodgson, Christopher Dayas, • Switzerland: Basel,Mark Fox, Lucianno Carneiro Bob Callister (UON), Microbiology: Ian Grainge (UON), Erin Shanahan (UQ), • United Kingdom, London: Mucosal Immunology Group King’s Organ Crosstalk /VIVA: Phil Hansbro (UON) College, London: Nick Powell • Pharmacy and Experimental Pharmacology: Susan Hua (UON), Dietetics: Tracy Burrows, Kerith Duncanson (UON), Heidi Staudacher (UQ), Psychology/ • United Kingdom, Hull/York: Martin Veysey Research Admin: Natasha Koloski (UQ joint with UoN):MRI and brain gut • United Kingdom, Leeds: Alex Ford interactions: Marcus Gray (UQ), Surgery (UON): Peter Pockney, Life Sciences (UON): Bob Callister, Chris Dayas, NIER (UON): Balaji Seshadri Shiv Bolan, • USA: Mayo Clinic Yuri Saito, Magnus Halland • AGIRA & JHH CLINICAL/ GASTROENTEROLOGY PROJECTS: • USA: Mucosal inflammation Program, University of Colorado Gastroenterology Staff Specialists: Steven Bollipo, Stephen Philcox, Robert Denver, with Simon Keely Gibson, Robert Foster, Alkesh Zala, Lay Theng Gan, Kate Napthali, Sean Ferencz, Sivathasan Sellathurai, Registrars/ Trainees: Thomas M. Goodsall, • USA: Texas: Ellionore Jarbrink Patrick Flynn, Dane Cook, John Chetwood, Georgia Edwards , Greg Brogan, • USA: Harvard University, Tony Lembo Angie Harris,: Nicola Wood, Emergency Medicine: Sebastian Chang , Registrar: Ahmed Ruslan (UON), Microbiology/ Infectious Diseases: John Ferguson, Rob • USA: University of Florida,Baha Moshiree Miller School of Pickles, Paediatrics: Joerg Mattes, Scott Nightingale, Adam Collison, Anna Medicine | University of Miami LeFevre, • USA: University of Utah, Ashok Tuteja • Macquarie University, Psychology: Alissa Beath, Anastasia Ejova, University of Sydney, Gastroenterology: Martin Weltman, Andrew Keegan, Jim Kalanter, University of New South Wales, Gastroenterology: Shan Rajendra, Bin Wang, Guy Eslick, University of Sydney SEALS: Arvi Lemberg, St George & Sutherland Clinical School, University of New South Wales: Emad El- Omar, Gastroneterology, Adelaide, Michael Horowitz