How the gut talks to the brain:

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1 How the gut talks to the brain: Implications for obesity and malnutrition Dr Jessie A Elliott HRB Surgical Research Fellow Wellcome Trust-HRB CRF & Department of Surgery, St. James s Hospital, Dublin

2 Regulatory support Logistics Proximity of laboratory facilities Clinical Research Infrastructure WT-HRB CRF IMP management Dedicated hub for participants and researchers Ethos Support staff Clinical Context National Oesophageal Centre SJH Research Training Fellowship Training Transferable skills Funding High volume centre Dissemination

3 Regulation of nutrient intake Leptin deficiency Intrinsic factors Leptin replacement Extrinsic factors Heterozygote Psychosocial Education etc Eating behaviour Hypothalamus Integration of visceral signals Homozygote Intrinsic factors Nutritional status: Post-prandial vs fasting (gut) Obesity vs low BW (adipose, gut)

4 Long-term body weight reduction after bariatric surgery vs standard medical therapy Swedish Obese Subjects SOS study (n = 4047) Medical Rx Band VBG Bariatric surgery RYGB Sjöström et al., JAMA, 2007

5 RYGB Gastric band Lean Obese 400 kcal le Roux et al. Annals of Surgery, 2006

6 The SCALE RCT 3.0 mg Liraglutide (GLP-1 analogue) versus Placebo 3731 patients, 2:1 allocation ratio, 56-week treatment period Obese/overweight, non-diabetic Placebo-adjusted BWL = 5.6% Pi-Sunyer et al. NEJM, 2015 NCT

7 Enteroendocrine regulation of nutrient intake

8 Weight loss and malnutrition among oesophageal cancer patients 89.7% had at least micronutrient deficiency Elliott et al. Ann Surg, 2015

9 Hypothesis Gut hormones are pathophysiologic mediators of altered appetite and weight loss after GI cancer surgery

10 Study Aims Among post-oesophagectomy patients: Aim 1: Prospectively characterise the post-prandial gut hormone profile after surgery Aim 2: Determine effect of gut hormone blockade on ad libitum food intake

11 Methods: Aim 1 Prospective Study Patients remaining eligible Pre-surgery POD 10 6 weeks 3 months Inclusion criteria 1. Planned for oesophagectomy with curative intent Gastric conduit reconstruction Pyloroplasty Exclusion criteria 1. Unable to eat 2. Previous GI surgery 3. Medications affecting gut hormones 4. Poorly controlled T2DM ClinicalTrials.gov NCT

12 Methods: Aim 1 Prospective Study Time (mins) Plasma sample 400 kcal meal stimulation Visual analogue scale Sigstad score (dumping syndrome) Quality of life (QLQ C30, OES18, OG25) Body weight, anthropometry ClinicalTrials.gov NCT

13 Methods: Aim 2 Crossover study Study cohort Oesophagectomy (n = 10) Control (n = 8) Randomisation Oesophagectomy 1. Oesophagectomy 5cm gastric conduit Pyloroplasty 2. Disease-free 1 year post-op 3. No clinically significant dysphagia 4. No previous GI surgery Visit 1 Octreotide Placebo Control 1. Barrett s oesophagus 2. No previous GI surgery Visit 2 Placebo Octreotide 3. Age, weight and gender matched to esophagectomy group ClinicalTrials.gov NCT

14 Methods: Aim 2 Crossover study

15 Total T o ta ta GLP-1 l G L P -1 (p (p M (pm) ) T o ta l G L P -1 A U C The gut hormone response is exaggerated after oesophageal cancer surgery m o n th s 6 w e e k s d a y s B a s e lin e P = ** ** * B a s e lin e 1 0 d a y s 6 w e e k s 3 m o n th s kcal M in u te s Elliott et al. Ann Surg, 2016

16 Is the exaggerated gut hormone response linked to altered gastrointestinal QoL after oesophagectomy? Eating Symptoms Score Lack of Appetite Score P = R 2 = 0.54 P = R 2 = 0.57 Total GLP-1 AUC [3 months] Total GLP-1 AUC [3 months] Elliott et al. Ann Surg, 2016

17 Is the exaggerated gut hormone response linked to altered gastrointestinal QoL after oesophagectomy? Early Satiety Score Trouble Enjoying Meals Score P = R 2 = 0.74 P = R 2 = 0.73 Total GLP-1 AUC [3 months] Total GLP-1 AUC [3 months] Elliott et al. Ann Surg, 2016

18 Post-prandial P o s n d Total ia l G L P GLP-1-1 (p M ) (pm) Does the gut hormone response predict long-term nutritional outcome? P = R 2 = 0.66 P = R 2 = 6 6 % % W e h t lo s s %body weight loss

19 F o o d In ta k e (k c a l) F o o d In ta k e (k c a l) A P = B P = S a lin e C o n tro l O c tre o tid e 0 S a lin e O c tre o tid e O e s o p h a g e c to m y Elliott et al. Ann Surg, 2015

20 Summary After upper GI cancer surgery 1. Patients experience significant body weight loss, early satiety and post-ingestive symptoms 2. Associated with an exaggerated post-prandial satiety gut hormone response 3. Pharmacologic modulation of the satiety gut hormone response increases food intake

21 Conclusion Body weight QoL Satiety Food intake Arcuate Nucleus GLP-1 Rapid nutrient transit Enteroendocrine L-cell

22 Next steps? 5 min post-prandial Mechanisms RCT Control VSG RYGB Octreotide LAR or placebo Washout

23 Acknowledgements Clinical Research Facility, St. James s Hospital, Dublin, Ireland Professor Michael Gill Derval Reidy Anna Burdzanowska Ruth McHugh, Helena Desmond Fergal Seeballuk Conway Institute, University College Dublin, Dublin, Ireland Prof. Carel W le Roux, Dr. Neil Docherty, Hans Eckhardt Department of Surgery, St. James s Hospital, Dublin, Ireland Prof. John V Reynolds Mr. Narayanasamy Ravi Dr. Jacintha O Sullivan Sinead King Jenny Moore Dr. Suzanne Doyle, Michelle Fanning, Dr. Emer Guinan Dr. Conor Murphy

24 How the gut talks to the brain: Implications for obesity and malnutrition Dr Jessie A Elliott HRB Surgical Research Fellow Wellcome Trust-HRB CRF & Department of Surgery, St. James s Hospital, Dublin

25 Reserve slides

26 Results: Aim 1 Patient characteristics (n = 13) Sex N (%female) 4 (31%) Age (years) Median (range) 63 (46 79) Pre-illness weight (kg) Median (range) 88 (63 124) Pre-illness BMI (kg/m 2 ) Median (range) 30.3 ( ) Histologic type Adenocarcinoma Squamous cell carcinoma Type of operation 2 Stage 3 Stage Transhiatal 8 (62%) 5 (38%) 9 (69.2%) 3 (23.1%) 1 (7.7%) Neoadjuvant therapy 10 (77%) Pathologic Stage T1 T2 T3 N0 N1 N2 5 (38.5%) 1 (7.7%) 7 (53.8%) 6 (46.2%) 4 (30.8%) 3 (23.1%) 3 month %BWL = 14.3% ( %)

27 Reduced prevalence of diabetes after bariatric surgery vs standard medical therapy Swedish Obese Subjects (SOS) study Sjöström et al., JAMA, 2014

28 Early weight loss independent effects of RYGB and VSG on glucose metabolism at 1 week post-operatively Preop 1 wk 3 mo 1 yr Days -2.7 ± ± ± ± 25 Weight 129 ± ± ± ± 20 %BWL 0% 2 ± 2% 13 ± 4% 22 ± 9% NB Jørgensen, JJ Holst et al. Am J Physiol Endocrinol Metab, 2012

29 32% reduction in ad libitum calorie intake Gutzwiller et al. Gut, 1999

30 1/3 disease-free patients developed malnutrition after surgery Martin et al. Br J Surg. 2007, 2009

31 Results: Aim 1 Significant body weight loss after oesophagectomy % P re -illn e s s b o d y w e ig h t * * 9 0 * * * * * * * 8 0 P < B a s e lin e D ia g n o s is P re o p e ra tiv e 6 w e e k s 3 m o n th s P o s t-o p e ra tiv e ly Weight, kg Median (range) 88 (63 124) 79 (63-102) 81 (65-96) 76 (60-91) 72 (60-92) 3 month %BWL = 14.3% ( %)

32 F u lln e s s V A S (c m ) D e s ire T o E a t V A S (c m ) H u n g e r V A S (c m ) Results: Aim 1 Self-reported desire to eat, hunger, fullness m o n th s 6 w e e k s m o n th s 6 w e e k s 1 0 d a y s B a s e lin e d a y s B a s e lin e P < M in u te s 3 m o n th s 6 w e e k s 1 0 d a y s B a s e lin e P < kcal M in u te s 0 P < M in u te s

33 T o ta l G L P -1 (p M ) T o ta l G L P -1 A U C Results: Aim 1 Post-prandial GLP-1 response after oesophagectomy m o n th s 6 w e e k s d a y s B a s e lin e ** P = ** * B a s e lin e 1 0 d a y s 6 w e e k s 3 m o n th s kcal M in u te s

34 Results: Aim 1 Post-ingestive symptoms and GLP-1 peak S ig s ta d S c o re 2 0 * * * * * S ig s ta d S c o re P = B a s e lin e 6 w e e k s 3 m o n th s P = R 2 = T im e s in c e s u rg e ry T o ta l G L P m in (p M )

35 Summary: Aim 1 The post-prandial satiety gut hormone response is significantly exaggerated early after oesophagectomy, in association with body weight loss and increasing post-ingestive symptoms Aim 2: Determine effect of gut hormone blockade on ad libitum food intake

36 Methods: Aim 2 Crossover study Study cohort Oesophagectomy (n = 10) Control (n = 8) Randomisation Oesophagectomy 1. Oesophagectomy 5cm gastric conduit Pyloroplasty 2. Disease-free 1 year post-op 3. No clinically significant dysphagia 4. No previous GI surgery Visit 1 Octreotide Placebo Control 1. Barrett s oesophagus 2. No previous GI surgery Visit 2 Placebo Octreotide 3. Age, weight and gender matched to esophagectomy group ClinicalTrials.gov NCT

37 Methods: Aim 2 Crossover study

38 Results: Aim 2 Baseline characteristics of study population Control (n = 8) Oesophagectomy (n = 10) P-value Gender (%female) 3/10 (30%) 2/8 (25%) 0.61 Age 58.5 ± ± Body mass index 28.9 ± 0.9 Post-op: 25.5 ± 0.9 Pre-op: 28.8 ± Mean ± standard error

39 Results: Aim 2 Clinicopathologic characteristics of oesophagectomy group Years since surgery, median (range) 2.17 ( ) Histologic type Adenocarcinoma 10 (100%) 4.0% Pathologic Stage T0 T1 T2 T3 2 (20%) 6 (60%) 0 (0%) 2 (20%) N0 N1 9 (90%) 1 (10%) Neoadjuvant CRT 4 (40%) Type of operation Ivor-Lewis Transhiatal 6 (60%) 4 (40%) 1 year %BWL (mean±se) 10.3 ± 4.0%

40 Aim 2: Results Oesophagectomy is associated with an exaggerated post-prandial satiety gut hormone response T o ta l G L P -1 (p M ) T o ta l P Y Y (p g /m l) * * * * * * * * * * * * * * * * C o n tr o l O e s o p h a g e c to m y C o n tr o l O e s o p h a g e c to m y Saline day fasting [ ] and post-prandial [ ] plasma GLP-1 and PYY concentrations

41 P o s t-p ra n d ia l G L P -1 (p M ) Aim 2: Results Post-prandial GLP-1 levels significantly correlated with %weight loss post-oesophagectomy P = R 2 = 6 6 % % W e ig h t lo s s

42 Aim 2: Results Octreotide attenuates the post-prandial satiety gut hormone (GLP-1 and PYY) response T o ta l G L P -1 (p M ) T o ta l P Y Y (p g /m l) * * * C o n tr o l O e s o p h a g e c to m y C o n tr o l O e s o p h a g e c to m y Octreotide day fasting [ ] and post-prandial [ ] plasma GLP-1 and PYY concentrations

43 Aim 2: Results Single dose octreotide is associated with increased ad libitum calorie intake among post-oesophagectomy subjects, but not controls F o o d In ta k e (k c a l) F o o d In ta k e (k c a l) A P = B P = S a lin e O c tre o tid e 0 S a lin e O c tre o tid e C o n tro l Oesophagectomy E s o p h a g e c to m y Trend towards lower calorie intake in OES group on saline day (P = 0.085) No difference in calorie intake between groups on octreotide day (P = 0.51))

44 Summary After oesophagectomy with gastric conduit reconstruction: 1. Patients experience significant and sustained body weight loss 2. Weight loss and post-ingestive symptoms are associated with an exaggerated post-prandial satiety gut hormone response 3. Pharmacologic blockade of the gut hormone response increases ad libitum food intake

45 Conclusion Body weight GI QoL Satiety Food intake Arcuate Nucleus Post-ingestive symptoms GLP-1 PYY OXM Rapid nutrient transit Enteroendocrine L-cell

46 Anorexia, early satiety and weight loss after upper gastrointestinal surgery: What can we learn from bariatrics? XXV Waterford October Surgical Meeting Jessie Elliott HRB Surgical Research Fellow NG Docherty 1, HG Eckhardt 1, N Ravi 2, CW le Roux 1, JV Reynolds 2 1. Conway Institute of Biomolecular and Biomedical Research, University College Dublin 2. Department of Surgery, St. James s Hospital, Dublin, Ireland

47 Mechanisms of increased gut nutrient sensing post-bariatric surgery parallels after esophagectomy?

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49 Appetite, post-ingestive symptoms and quality of life after oesophagectomy Key Themes Weight loss and physical change Eating as a social activity Stigma Embarrassment Sub Themes Persistent illness identity Bodily disruption Appetite loss Nausea, diarrhoea Altered taste and smell of food Dysphagia Adapted from Wainwright, Blazeby et al. Qualitative Health Research, 2007

50 Conclusion Exaggerated post-prandial gut hormone responses mediate appetite changes post-oesophagectomy, offering a novel target for appetite modulation in this cohort Appetite Reduced intake Weight loss

51 G lu c o s e (m m o l/l ) G lu c o s e A U C Post-prandial blood glucose after oesophagectomy m o n th s 8 6 w e e k s 1 0 d a y s B a s e lin e ** P = ** B a s e lin e 1 0 d a y s 6 w e e k s 3 m o n th s M in u te s

52 F a s tin g T o ta l G h re lin (p g /m l) % B W L Aim 1: Results No difference in fasting ghrelin between unoperated control and esophagectomy subjects P = P = P = 0.17 R 2 = P = 0. 0 O e s C o n tr o l R 2 = 0 T o ta l F a s tin g G h re lin (p g /m L )

53 Aim 1: Results Post-prandial GLP-1 levels significantly correlated with %weight loss post-oesophagectomy P o s t-p ra n d ia l G L P -1 (p M ) P = R 2 = 6 6 % % W e ig h t lo s s

54 Temporal recovery of early reduced ghrelin production post-esophagectomy Authors Year N Time-point %control Doki et al (3-67) months Koizumi et al months 12 months 107.4% 99.7% 125.0% Miyazaki et al (6-24) months 53 (39-80) months 56.0% 111.6% From Doki et al. Surgery, 2006

55 Ghrelin and body weight loss after oesophagectomy Author Year N Surgery DF Time-points Outcome Doki , 26 2SE WS (28), GCC (7) Digital pyloric bougie Koizumi SE/3SE GCC Digital pyloric bougie Miyazaki SE/3SE GCC Yamamoto SE GCC Yes 3 and 7 days (n=9) 25 (3-67) months (n=26) No Pre-operative 1, 3, 6, 12 months post No Pre-operative 7 days 6-24 months >36 months Yes Pre-operative Day 0, 1, 3, % and 49.8% of baseline at days 3 and % of baseline at 25 (5-67) months Ghrelin levels negatively correlated with ΔBMI at <36 months Ghrelin levels positively correlated with time since surgery No difference between WS or GCC reconstruction Ghrelin reduction at 1 month (63.9%) recovered to 75.8%, 99.7% at 3, 6 months post Appropriate rebound at 12 months (125.0%) but continued BWL Appetite score increases over time from surgery Correlation between appetite score and ghrelin 38.7% of baseline at day 7 (P < 0.01) 56.0% of baseline at 22.1 (6-24) months (P < 0.05) 111.6% of baseline at 53.4 (39 80) months %ΔGhrelin correlated with %BWL at 6-24 months, but not at >36 months 33% (15-90%) baseline at day 1 50% baseline at day 3-10 DF, disease-free; 2SE, 2-stage oesophagectomy; 3SE, 3-stage oesophagectomy; WS, whole stomach; GCC, greater curvature conduit; BMI, body mass index; BWL, body weight loss

56 Miyazaki et al Weight loss at 6-24 months post-oesophagectomy correlates with % ghrelin But weight loss continues despite recovery of ghrelin levels to baseline by approximately 36 months post-operatively

57 Doki et al Temporal recovery of early reduced ghrelin production post-esophagectomy with either whole stomach or gastric conduit reconstruction

58 Rapid nutrient transit after VSG Chambers et al, Am J Physiol Endocrinol Metab Feb 15

59 Mechanisms contributing to post-operative exaggerated L-cell responses A: Lack of anticholinergic responsiveness indicates loss of neural regulation of gastric emptying post-vsg B: Lack of Exenatide (Exn-4, a GLP-1 analogue) responsiveness indicates loss of paracrine regulation on gastric emptying ( ileal brake ) Isocaloric duodenal nutrient infusion However, even when nutrients are infused directly into the intestine at an identical rate, GLP-1 secretion is greater post-vsg relative to sham Chambers et al, Am J Physiol Endocrinol Metab Feb 15

60 le Roux et al. Annals of Surgery, 2007

61 From the first day after RYGB or SG the post-prandial GLP-1 response is exaggerated, resulting in increased glucose disposal S Madsbad, and JJ Holst, Diabetes, 2014