Gastrointestinal Nutrient Transit and Enteroendocrine Function After Upper Gastrointestinal Surgery (EndoGut)

The incidence of oesophagogastric cancer has increased by 400% since the 1970s in Ireland and the United Kingdom. In addition, refinement of perioperative management and the now widespread use of multimodal protocols for patients with locally advanced disease have significantly improved outcomes for patients with oesophagogastric cancer treatable with curative intent. Despite significant advances in chemoradiotherapy, surgical resection remains the primary curative option.

Unintentional weight loss and nutritional complications represent serious concerns for patients after radical resection, even among those who remain free from recurrent disease in the long-term. A study from the Swedish Esophageal and Cardia Cancer Registry reported a mean three year weight loss of 10.8% among disease-free patients, with 33.8% of this cohort demonstrating malnutrition at three years post-oesophagectomy.

Mechanisms contributing to weight loss for disease-free patients after upper gastrointestinal surgery are poorly understood, however an association between increasing magnitude of weight loss and the presence of increased satiety is described. Our recent studies at SJH have demonstrated four fold elevated postprandial satiety gut hormone concentrations after oesophagectomy, compared with baseline preoperative values. Postprandial gut hormone levels correlate significantly with postprandial symptoms and altered appetite at 3 months postoperatively, and with body weight loss at 2 years postoperatively. However, the mechanism leading to exaggerated postprandial gut hormone production after upper gastrointestinal surgery is poorly understood, limiting targeted therapeutic options.

In this study, we aim to characterise the role of altered nutrient transit and enteroendocrine cell function in the pathophysiology of excessive post-prandial gut hormone responses after upper gastrointestinal surgery. To do this, we will measure the gut hormone response to a standardised 400 kcal meal, as per previous studies, while concurrently assessing gastrointestinal transit time, and enteroendocrine cell morphology and function. In this way, we will determine whether the magnitude of the postprandial gut hormone response correlates with the rate of nutrient transit into the enteroendocrine L-cell rich small intestine, and whether enteroendocrine cell adaptation occurs after oesophagectomy.

Furthermore, we have previously observed that gut hormone suppression using octreotide is associated with increased ad libitum among subjects after upper gastrointestinal cancer surgery (Elliott JA et al, Annals of Surgery, 2015). The mechanism of action of octreotide may relate to SSTR-5-mediated negative feedback to the enteroendocrine L-cell, but this medication may additionally reduce enteroendocrine L-cell responses through its inhibitory effect on gastrointestinal motility - reducing the rapidity with which nutrients are delivered to the small intestine - and small intestinal nutrient sensing via inhibition of the Na+-dependent glucose transporter SGLT-18-10. Through conduction of this double-blind, randomised, placebo-controlled crossover study, we aim to establish the mechanism of action of octreotide-mediated increased food intake in patients after gastrointestinal surgery. This may inform the design of future targeted interventions for this patient group.

Study Overview

• Status: Completed
• Conditions: Nutrition Disorders; Esophageal Cancer; Surgery; Delayed Gastric Emptying; Appetite Disorders; Dumping Syndrome
• Intervention / Treatment: Drug: Octreotide Acetate; Drug: Saline Solution; Drug: Paracetamol; Drug: Sulfasalazine; Diagnostic test: Duodenal biopsy

• Study Type: Observational
• Enrollment (Actual): 40

Contacts and Locations

Study Locations

• Ireland
  • Dublin, Ireland, D4
    • Department of Surgery, St. James's Hospital
  • Dublin, Ireland, D8
    • Wellcome Trust-Health Research Board Clinical Research Facility, St. James's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients at least 9 months post upper gastrointestinal surgery and age-, weight- and sex-matched control subjects with gastroesophageal reflux disease or non-dysplastic Barrett's oeosophagus.

Description

Inclusion Criteria:

Patient group:

1. History of upper gastrointestinal surgery at least 9 months previously

Control group:

1. Patients with suspected or confirmed non-dysplastic Barrett's oesophagus or reflux who are age, weight and gender matched to the patient cohort

Exclusion Criteria:

1. Pregnancy, breastfeeding
2. Recurrent disease after surgery
3. Other active malignancy
4. Significant psychiatric disorder or cognitive decline or communication impairment limiting capacity to provide informed consent
5. Other disease or medication which may impact gut hormone physiology
6. Previous upper gastrointestinal resection
7. Certain allergies or dietary intolerances
8. Anticoagulants

Patients with contraindications to the study medications (as per www.medicines.ie) will not be automatically excluded, but will be invited to participate in an attenuated protocol where that agent is not given. It is not anticipated that this will be a frequent occurrence, however this strategy will minimise unnecessary participant exclusion.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Upper Gastrointestinal Surgery - Transit	Drug: Octreotide Acetate; 50mcg octreotide acetate by subcutaneous injection 10 minutes prior to a 400kcal mixed meal challenge; Drug: Saline Solution; Equivalent volume of 0.9% saline by subcutaneous injection 10 minutes prior to a 400kcal mixed meal challenge; Drug: Paracetamol; Paracetamol 1g by mouth consumed with a 400kcal mixed meal challenge; Drug: Sulfasalazine; 1g sulfasalazine by mouth consumed with a 400kcal mixed meal challenge
Control - Transit	Drug: Octreotide Acetate; 50mcg octreotide acetate by subcutaneous injection 10 minutes prior to a 400kcal mixed meal challenge; Drug: Saline Solution; Equivalent volume of 0.9% saline by subcutaneous injection 10 minutes prior to a 400kcal mixed meal challenge; Drug: Paracetamol; Paracetamol 1g by mouth consumed with a 400kcal mixed meal challenge; Drug: Sulfasalazine; 1g sulfasalazine by mouth consumed with a 400kcal mixed meal challenge
Upper Gastrointestinal Surgery - Gut Function	Diagnostic test: Duodenal biopsy; Biopsy from the second part of the duodenum taken at routine endoscopic surveillance, undertaken for another clinical indication.
Control - Gut Function	Diagnostic test: Duodenal biopsy; Biopsy from the second part of the duodenum taken at routine endoscopic surveillance, undertaken for another clinical indication.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area under the curve for paracetamol at 30 minutes after a 400kcal mixed meal stimulus	30 minutes post meal

Secondary Outcome Measures

Outcome Measure	Time Frame
Peak paracetamol level	Within 300 minutes post meal
GLP-1 area under the curve over 300 minutes after a 400kcal mixed meal stimulus	Within 300 minutes post meal
Glucose area under the curve over 300 minutes after a 400kcal mixed meal stimulus	Within 300 minutes post meal
Insulin area under the curve over 300 minutes after a 400kcal mixed meal stimulus	Within 300 minutes post meal
Visual analogue scales	Within 300 minutes post meal
EORTC health related quality of life	At one year post surgery, on the day of assessment

Other Outcome Measures

Outcome Measure	Time Frame
Duodenal enteroendocrine cell density	At one year post surgery, on the day of assessment
Duodenal enteroendocrine L-cell density	At one year post surgery, on the day of assessment
Duodenal enteroendocrine cell mRNA expression profile	At one year post surgery, on the day of assessment

Collaborators and Investigators

• Sponsor: St. James's Hospital, Ireland
• Investigators: Principal Investigator: Carel W le Roux, FRCP FRCPath PhD, Conway Institute of Biomolecular and Biomedical Research

Publications and helpful links

General Publications

• Elliott JA, Docherty NG, Eckhardt HG, Doyle SL, Guinan EM, Ravi N, Reynolds JV, Roux CWL. Weight Loss, Satiety, and the Postprandial Gut Hormone Response After Esophagectomy: A Prospective Study. Ann Surg. 2017 Jul;266(1):82-90. doi: 10.1097/SLA.0000000000001918.
• Elliott JA, Jackson S, King S, McHugh R, Docherty NG, Reynolds JV, le Roux CW. Gut Hormone Suppression Increases Food Intake After Esophagectomy With Gastric Conduit Reconstruction. Ann Surg. 2015 Nov;262(5):824-29; discussion 829-30. doi: 10.1097/SLA.0000000000001465.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): July 1, 2021
• Study Completion (Actual): July 1, 2021

Study Registration Dates

• First Submitted: November 6, 2018
• First Submitted That Met QC Criteria: November 6, 2018
• First Posted (Actual): November 8, 2018

Study Record Updates

• Last Update Posted (Actual): August 16, 2021
• Last Update Submitted That Met QC Criteria: August 12, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Insulin; GLP-1; Octreotide; Esophagectomy; Somatostatin; Gut hormones; Enteroendocrine L-cell; Early satiety; Dumping syndrome; Gastrointestinal transit
• Additional Relevant MeSH Terms: Mental Disorders; Digestive System Diseases; Pathologic Processes; Postoperative Complications; Neurologic Manifestations; Gastrointestinal Diseases; Stomach Diseases; Paralysis; Postgastrectomy Syndromes; Disease; Feeding and Eating Disorders; Nutrition Disorders; Gastroparesis; Dumping Syndrome; Physiological Effects of Drugs; Anti-Infective Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antipyretics; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Acetaminophen; Octreotide; Sulfasalazine
• Other Study ID Numbers: CRFSJ075 and 0095; 2016-02-CA(9) (Other Identifier: SJH/AMNCH Research Ethics Committee); 2016-03-11(1) (Other Identifier: SJH/AMNCH Research Ethics Committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No