Gastrointestinal Nutrient Transit and Enteroendocrine Function After Upper Gastrointestinal Surgery

Appetite Disorders, Delayed Gastric Emptying, Dumping Syndrome, Esophageal Cancer, Nutrition Disorders, Surgery

Gut hormones, GLP-1, Enteroendocrine L-cell, Early satiety, Dumping syndrome, Gastrointestinal transit, Insulin, Octreotide, Somatostatin, Esophagectomy

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.

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