Activation of the ileal brake by carbohydrates and plant extracts – A pilot study in ileostomy patients to develop sample collection and analytical methods

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The gastrointestinal (GI) tract and specifically the most distal part of the small intestine, the ileum, has become a renewed focus of interest for mechanisms targeting appetite suppression. The ‘ileal brake’ is stimulated when energy-containing nutrients are delivered beyond the duodenum and jejunum and into the ileum, and is named for the feedback loop which slows or ‘brakes’ gastric emptying and duodenojejunal motility. More recently it has been hypothesised that the ileal brake also promotes secretion of satiety-enhancing GI peptides and suppresses hunger, and hence in turn places a ’brake’ on food intake. Postprandial delivery of macronutrients to the ileum, other than unavailable carbohydrates (CHO) which bypass absorption in the small intestine en route to fermentation in the large bowel, is an uncommon event and hence this brake mechanism is rarely activated following a meal. Evidence linking the ileal brake to enhanced satiety can be found from a number of studies that have delivered nutrients to the ileum enterally. Early nasoileal (NI) tube feeding studies where lipid emulsions were infused directly into the ileum significantly decreased appetite and food intake (Welch et al., 1985; Welch et al., 1988b; Welch et al., 1988c)(Maljaars et al., 2008, 20009, 2010, 2011, 2012; see review by Shin et al., 2013). There is some preliminary evidence that commercial lipid formulations designed to resist digestion and absorption in the proximal small intestine are transported to the ileum and suppress food intake (Burns et al., 2000, 2001, 2002; Diepvens et al., 2007), although findings from these feeding studies remain mixed (Smit et al., 2011; Chan et al., 2012). Our research group has recently shown that hunger and food intake can be altered acutely by infusion of glucose in to the ileum using an NI tube (Shin et al., unpublished data) suggesting that carbohydrates can also activate the ileal brake mechanism. However, no corresponding evidence exists for ileal brake activation following the ingestion of carbohydrate containing foods. This is likely to be due to the very efficient digestion and absorption of carbohydrates by the proximal SI resulting in minimal glucose availability in the ileum. In order to ensure arrival of CHOs into the distal small intestine (ileum) it is necessary to induce a degree of carbohydrate malabsorption in the proximal small intestine (duodenum and jejunum). This approach has previously been demonstrated using a carbohydrate meal and pharmacological interventions such as the a-glucosidase inhibitor migitol (Lee et al., 2002; Kaku et al., 2012) or a novel glucose transport inhibitor LX4211 (Zambrowicz et al., 2013) where enhanced ratings of satiety and postprandial GLP-1 and PYY concentrations beyond 2 h have been demonstrated, indicating ileal brake activation. A number of natural occurring plant phytochemicals have been demonstrated to posses similar carbohydrate malabsorption potential (Lakshimi et al., 2012), although their ability to trigger ileal brake activation has not as yet been demonstrated in vivo. We have recently identified in vitro, a commercially available grape seed extract (Oxifend, Registerd Trademark, grape seed extract, New Zealand Extracts Ltd) and quercetin possessing the ability to inhibit the activity of starch digestive enzymes and the absorption of glucose by the gut mucosa, respectively. By combining these extracts with a starch based meal we hope to induce enough glucose malabsorption in the proximal SI to activate the ileal brake. However, efficacy of these blockers singularly or in combination has not yet been assessed in a human study population.

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