Bench-to-bedside review: The gut as an endocrine organ in the critically ill

In health, hormones secreted from the gastrointestinal tract have an important role in regulating gastrointestinal motility, glucose metabolism and immune function. Recent studies in the critically ill have established that the secretion of a number of these hormones is abnormal, which probably contributes to disordered gastrointestinal and metabolic function. Furthermore, manipulation of endogenous secretion, physiological replacement and supra-physiological treatment (pharmacological dosing) of these hormones are likely to be novel therapeutic targets in this group. Fasting ghrelin concentrations are reduced in the early phase of critical illness, and exogenous ghrelin is a potential therapy that could be used to accelerate gastric emptying and/or stimulate appetite. Motilin agonists, such as erythromycin, are effective gastrokinetic drugs in the critically ill. Cholecystokinin and peptide YY concentrations are elevated in both the fasting and postprandial states, and are likely to contribute to slow gastric emptying. Accordingly, there is a rationale for the therapeutic use of their antagonists. So-called incretin therapies (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) warrant evaluation in the management of hyperglycaemia in the critically ill. Exogenous glucagon-like peptide-2 (or its analogues) may be a potential therapy because of its intestinotropic properties.


Introduction
In health, peptides released from the stomach and/or intestine modulate motility, secretion, absorption, mucosal growth and immune function of the gastrointestinal tract [1]. Th ese hormones also have eff ects outside the gastrointestinal tract, particularly in relation to the regulation of energy intake and glycaemia [1]. In critically ill patients, both the prevalence and magnitude of disordered gastrointestinal and metabolic function are substantial [2]. Moreover, many of these abnormalities are associated with poor outcomes [3]. It is now apparent that a number of gastrointestinal hormones mediate, or have the potential to mediate, some of the functional abnormalities that occur in the critically ill, either via increased or decreased secretion. Th e present review focuses on the abnormalities in gastrointestinal function and glucose metabolism that occur in the critically ill, focuses on current understanding of the eff ects of gastrointestinal hormones in health and critical illness, and focuses on implications of the above for management and priorities for future research.

Gastrointestinal motility in critical illness
Abnormalities in gastrointestinal motor function have recently been described, and quantifi ed, in the critically ill using a number of measurement techniques not previously utilised in this cohort. Published studies are likely to have underestimated the prevalence and magnitude of these motor abnormalities, however, as -in our experience -patients with the most marked motor abnor malities are often the most technically demanding to study.
In the critically ill, motility of the entire gastrointestinal tract may be aff ected. In an observational study at our centre, the tone of the lower oesophageal sphincter was markedly reduced in all 15 critically ill patients studied and is likely to increase the propensity for gastro-oesophageal refl ux [4]. In patients that are sedated and ventilated, refl ux is regarded as a major cause of aspiration, and consequent ventilator-associated pneumonia [4].
Feed intolerance occurs in up to 50% of critically ill patients, predominately due to delayed gastric emptying, and is considered a risk factor for adverse sequelae, such as inadequate nutrition [3,5]. Th e motor function of the both the proximal and/or distal stomach is disordered in ~50% of critically ill patients and underlies the delayed gastric emptying (which may also contribute to a higher frequency, and volume, of gastro-oesophageal refl ux events) [6]. In health, the proximal stomach acts as a reser voir for liquid feed. In critical illness, however, the

Abstract
In health, hormones secreted from the gastrointestinal tract have an important role in regulating gastrointestinal motility, glucose metabolism and immune function. Recent studies in the critically ill have established that the secretion of a number of these hormones is abnormal, which probably contributes to disordered gastrointestinal and metabolic function. Furthermore, manipulation of endogenous secretion, physiological replacement and supra-physiological treatment (pharmacological dosing) of these hormones are likely to be novel therapeutic targets in this group. Fasting ghrelin concentrations are reduced in the early phase of critical illness, and exogenous ghrelin is a potential therapy that could be used to accelerate gastric emptying and/or stimulate appetite. Motilin agonists, such as erythromycin, are eff ective gastrokinetic drugs in the critically ill. Cholecystokinin and peptide YY concentrations are elevated in both the fasting and postprandial states, and are likely to contribute to slow gastric emptying. Accordingly, there is a rationale for the therapeutic use of their antagonists. So-called incretin therapies (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) warrant evaluation in the management of hyperglycaemia in the critically ill. Exogenous glucagon-like peptide-2 (or its analogues) may be a potential therapy because of its intestinotropic properties. usual relaxation that occurs in response to the presence of nutrient is delayed and reduced [7]. Th e coordination, magnitude and frequency of contractions in the proximal and distal stomach are reduced, leading to decreased transpyloric fl ow of chyme [7,8]. Th e interaction of nutrient with small-intestinal receptors (mediated, at least in part, via enterogastric hormones) is pivotal to the regulation of gastric emptying in health and critical illness. However, in the critically ill inhibitory smallintestinal feed back on gastric emptying appears to be substantially enhanced (Figure 1) [6].
Th e eff ects of critical illness on small-intestinal motility are poorly defi ned, although disorganisation of duodenal pressure waves occurs frequently, with increased retrograde activity and diminished propagation of antegrade pressure waves [9]. It is likely that some patients have slow small-intestinal transit, due to prolonged periods of quiescent motor activity, and that a proportion of patients, as a result of disordered burst-like motor activity, hav e subsequent rapid transit. Th is concept is supported by a study from Rauch and colleagues in which non-nutrient small-intestinal transit times in 16 neurointensive care patients (admitted <4 days) were measured using video capsule technology. Th ey reported that median transit times were similar, albeit with greater inter-subject variability, to those in health [10]. Th e eff ect of critical illness on colonic motility is yet to be evaluated.

Gastrointestinal absorptive and immune function in the critically ill
Absorption of nutrient is substantially impaired in the critically ill ( Figure 2) [11,12]. Th e altered absorption may be a consequence of disordered transit of chyme and/or impaired mucosal function [12]. In addition, the epithelial barrier function is impaired, with a consequent increase in gastrointestinal permeability, and a potential predisposition to translocation of enteric organisms, systemic infection and, hence, adverse outcomes [11,13].

Glucose metabolism in the critically ill
Hyperglycaemia is common in acute illness, even in those patients without pre-existing diabetes [14]. Th e Leuven trial established that marked hyperglycaemia (blood glucose >12 mmol/l) is associated with poor outcomes in surgical intensive care unit patients [15]. Th is landmark study resulted in a paradigm shift in the management of glycaemia in the critically ill. Subsequent studies, however, reported that substantial hypoglycaemia (blood glucose <2.2 mmol/l) occurred frequently with intensive insulin therapy, and hypoglycaemia is also associated with adverse outcomes [16]. Hence, while the optimum blood glucose target in the critically ill remains uncertain [17], treatment of hyperglycaemia and avoidance of iatrogenic hypoglycaemia are priorities. Moreover, there is evidence that glycaemic variability, in addition to mean glucose, is deleterious [18]. Safer methods for the manage ment of hyperglycaemia in the critically ill are therefore desirable.

Methods
We performed a comprehensive search, restricted to manuscr ipts written in English, on MEDLINE/PubMed, from inception to 1 July 2009. We used both the following MeSH terms and combinations of these terms: gastrointestinal hormones, ghrelin, motilin, cholecystokinin, peptide YY, glucagon-like peptide-1, glucagon-like peptide-2, glucose-dependent insulinotropic polypeptide, incretins, critical illness, intensive care. In addition, we searched the bibliographies of retrieved articles manually.

Results and discussion
Th e gastrointestinal hormones most likely to be of clinical signifi cance are reviewed. For each hormone, a summary of where the peptide is stored, stimuli for secretion and the location of receptors is provided. Studies relating to the potential physiological eff ects focus on the use of the specifi c antagonists. In addition, physiological replacement and pharmacological dosing studies are presented when relevant.

Ghrelin
Ghrelin is a 28-amino-acid peptide secreted primarily from the stomach during fasting [19]. Secretion is suppressed by meal ingestion, chiefl y as a result of the interaction of nutrients with the small intestine [20]. Th e magnitude of this suppression appears to be dependent on the length of small intestine exposed to nutrient [21], but not the energy load [22]. Fasting plasma ghrelin concentrations are inversely related to body weight, with relatively lower concentrations in obesity and higher concentrations in anorectic patients [23]. Receptors to ghrelin are distributed widely, including the hypothalamus, pituitary and stomach [24].
Studies using exogenous ghrelin (infused to replicate physiological fasting concentrations) indicate that ghrelin is an important acute stimulant of appetite [19]. Furthermore, treatment with an oral ghrelin mimetic for 2 years has been reported to increase fat-free body mass in older humans [25]. Exogenous ghrelin at supra-physiological concentrations accelerates gastric emptying in humans  38.9 ± 11.4 mmol/l/min vs. healthy subjects, 66.6 ± 16.8 mmol/l/min; P <0.001 (mean ± standard deviation). Reproduced from [12]. ICU, intensive care unit. and in animal models of sepsis-induced gastroparesis [26][27][28]. Th e ghrelin agonist, TZP-101, accelerates emptying substantially in patients with gastroparesis [29]. TZP-101 has also been reported to reduce the postoperative i leus time in animals [30], and this may also be the case in humans (Dr G Kostuic, personal communication). Pharmacological doses of ghrelin also increase fasting blood glucose and suppress plasma insulin secretion [31].
Fasting plasma ghrelin concentrations are markedly reduced (>50%) in the early phase of critical illness, with suppression continuing up to day 28 post admission [32]. Th e reduction in ghrelin secretion may play a role in delayed gastric emptying, weight loss and decreased appetite that all occur frequently in the critically ill. Th e same investigators reported that there was an exaggerated suppression of plasma ghrelin in response to nutrient in patients post cardiac surgery (day 6), when compared with preoperative concentrations, or in healthy controls, and suggested this may contribute to early satiation in postoperative patients [33]. Th e suppression of ghrelin (that is, change from fasting concentration), however, was apparent because of elevated fasting levels. While the increase in fasting concentrations in postoperative patients appears inconsistent with the fi ndings in critical illness, it is likely that 6 days after elective surgery, albeit major surgery, is not representative of the more profound changes in physiology that occur during critical illness.
Ghrelin (either physiological replacement or pharmaco logical doses) has not been evaluated as a therapy in critically ill patients. Exogenous ghrelin has, however, been reported to improve outcomes in patients with chronic organ failure. In open-label studies by Nagaya and colleagues, ghrelin was given for 3 weeks to patients with chronic lung disease or cardiac failure -with a consequent modest increase in exercise tolerance apparent with the intervention in both studies [34,35]. Th e underlying mechanism(s) is likely to be via both growth hormone eff ects (skeletal muscle strength) and growth hormone-independent eff ects (appetite).

Motilin
Motilin is structurally related to ghrelin, and motilin receptors are located throughout the gastrointestinal tract [36]. Motilin secretion is stimulated during the interdigestive state, and the peak plasma motilin concentration coincides with the onset of frequent gastrointestinal antegrade contractions (that is, phase III of the migrating motor complex) [37]. Exogenous motilin induces antegrade contractions in the stomach and, consequently, accelerates gastric emptying in health and gastroparesis [38].
Because oral formulations allow easier administration in outpatients, nonpeptide motilin agonists (motilides) have been developed as prokinetic agents, rather than motilin itself. Erythromycin has the capacity to accelerate gastric emptying profoundly in both healthy individuals and ambulant patients with gastroparesis [39,40]. Th e eff ect is attenuated by hyperglycaemia [41], however, and the response may not be sustained as a result of tachyphylaxis [42]. Motlilides have also been reported to increase lower oesophageal sphincter pressure [43] and to aff ect small-intestinal motility, such that intravenous erythromycin at doses ~3 mg/kg has been reported to slow small-intestinal transit [44,45].
Th e eff ect of critical illness on plasma concentrations of motilin is not known. Despite this, the gastrokinetic eff ects of motilides make them a suitable drug to improve feed tolerance in the critically ill [6]. While acceleration of gastric emptying may not improve fasting, or mealrelated, symptoms in ambulatory patients with gastroparesis, acceleration of the gastric emptying rate and, thereby, improving enteral feed tolerance is the primary outcome of relevance in the sedated critically ill patient, rather than symptom relief [6]. Accordingly, erythromycin has been shown to be a potent gastrokinetic in the critically ill [46,47], although in ~60% of patients its eff ects are diminished within 7 days [46].

Cholecystokinin
Cholecystokinin (CCK) is stored in enteroendocrine cells in the duodenum and jejunum, and is secreted in response to the presence of fat, protein and, to a lesser degree, carbohydrate in the small intestine [48]. Th e use of specifi c antagonists, such as loxiglumide, has aff orded a greater understanding of the physiological actions of CCK on luminal motility, secretory function and appetite. Appetite and energy intake are increased during loxiglumide infusion [49]. In the postprandial phase, CCK may reduce the lower oesophageal sphincter basal pressure and increase the frequency of transient lower oesophageal sphincter relaxations, with a consequent increase in the number of gastro-oesophageal refl ux events [50]. Endogenous CCK also slows gastric emptying in humans and may accelerate small-intestinal transit [51,52]. CCK is the principle physiological regulator of gallbladder contraction and augments pancreatic protein enzyme secretion, with both eff ects suppressed by loxiglu mide [53].
In critically ill patients, fasting plasma CCK concentrations are approximately twice those of healthy controls, and nutrient-stimulated CCK concentrations are some 1.5-fold greater [54]. Furthermore, fasting plasma CCK concentrations are higher in critically ill patients with delayed gastric emptying, when compared with those with normal emptying (Figure 3) [55]. Th e reduction in appetite (and gastric emptying) that occurs in healthy ageing has been attributed, in part, to increased concentrations and/ or sensitivity to CCK [56]. Likewise, CCK may have the same satiety eff ect in the critically ill, and CCK may be a mediator of slow gastric emptying in this group. Studies involving administration of a CCK antagonist are required to evaluate this hypothesis.
Th e mechanism(s) underlying exaggerated CCK response is also unknown. Prolonged nutrient deprivation in patients with anorexia nervosa is associated with an increase in plasma CCK [57]. Accordingly, we anticipated that early, rather than delayed, enteral nutrition in the critically ill may attenuate CCK secretion and improve feed tolerance. A shorter (<1 day) period neither blunted an increase in CCK concentration or accelerated gastric emptying, however, when compared with a longer (4 day) period of nutrient deprivation in critically ill patients [58].

Peptide YY
Peptide YY (PYY) is secreted predominantly from the colon and rectum, and, to a lesser extent, from the pancreas, distal small intestine and stomach [59]. Fat is the most potent stimulant of PYY secretion [59,60]. Plasma PYY concentrations increase within 15 minutes of a meal [60], suggesting that an indirect neural or hormonal response is responsible for initial stimulation, with peak concentrations occurring at ~1 hour [60]. CCK may mediate the initial PYY secretion, with subsequent direct intraluminal stimulation causing sustained PYY secretion [60]. Pharmacological doses of PYY slow gastric emptying and small-intestinal transit [61], and endogenous PYY is likely to modulate gastric emptying in health. Exogenous PYY also inhibits appetite, and these ano rectic eff ects have encouraged the investigation of PYY as a weight-loss therapy [62].
In an observational study of seven critically ill patients, Nematy and colleagues reported that fasting PYY concen trations were increased approximately threefold in the acute phase of critical illness, when compared with health [32]. Moreover, we reported that fasting plasma PYY concentrations in 39 critically ill patients were increased substantially in those that had delayed gastric emptying ( Figure 3) [55]. Our group has also shown that the PYY response to small-intestinal nutrient infusion is exaggerated in the critically ill when compared with health [54]. Animal models of sepsis suggest that PYY concentrations increase rapidly following systemic infection [63]. Like CCK, endogenous PYY secretion is increased; and if receptor sensitivity remains unchanged, both hormones are candidate mediators to slow gastric emptying in the critically ill. PYY concentrations have been shown to progressively normalise as the clinical condition improves.

Glucagon-like peptide-1
Th e so-called incretin eff ect refers to the greater insulinotropic response to an oral glucose load, as compared with an isoglycaemic intravenous infusion [64]. Glucagon-like peptide (GLP)-1 is one of the two known incretin hormones, and is secreted from intestinal L cells (which are located primarily in the distal ileum and colon) in response to luminal fat, carbohydrate and protein [65]. Studies using the specifi c GLP-1 antagonist, exendin  amide, have established that endogenous GLP-1 lowers fasting glycaemia and attenuates postprandial glycaemic excursions [66,67]. Th e glucose-lowering refl ects slower gastric emptying, as well as increased insulin and decreased glucagon secretion [66][67][68].
Pharmacological doses of GLP-1 reduce both fasting and postprandial glycaemia [69,70]. Importantly, the eff ects of exogenous GLP-1 to stimulate insulin and suppress glucagon are glucose dependent, and thus the risk of hypoglycaemia is not increased substantially, even with pharmacological dosing [71]. Furthermore GLP-1 in pharmacological doses appears to slow gastric emptying, which contributes substantially to the glucose-lowering eff ect [72]. Animal and human studies suggest that exoge nous GLP-1 inhibits fasting je junal motility [73,74], which is anticipated to slow small-intestinal transit. Th ere are signifi cant extra-gastrointestinal and islet cell eff ects of exogenous GLP-1, with the potential cardioprotective eff ects of specifi c interest to the critically ill cohort [75,76].
In non-intensive care unit inpatients receiving total parenteral nutrition, Nauck and colleagues established that pharmacological doses of GLP-1 have the capacity to lower glycaemia [77]. Subsequently, Meier and colleagues reported that in type 2 diabetic patients after major surgery an acute infusion of GLP-1 reduces fasting glucose [78]. Recently, GLP-1 has also been reported to lower peri operative glycaemia in cardiac surgical patients [79,80]. Given its inherent safety profi le yet substantial eff ects on gastrointestinal motility, we studied the eff ects of exogenous GLP-1 (1.2 pmol/kg/min) in nondiabetic critically ill patients, and established that GLP-1 markedly attenuates the glycaemic response to smallintes tinal nutrition (Figure 4) [81]. In critically ill patients, however, enteral nutrient is delivered predominantly via the intragastric route and marked slowing of gastric emptying may be undesirable. Accordingly, we evaluated the eff ects of exogenous GLP-1 on gastric emptying of an intragastric meal [82]. While an acute infusion of GLP-1 (1.2 pmol/kg/min) slowed gastric emptying when the latter was relatively normal (and to thereby contribute to glucose lowering), no eff ect was evident when emptying was already delayed [82].

Glucose-dependent insulinotropic peptide
Th e other known in cretin hormone is glucose-dependent insulinotropic peptide (GIP) -which is secreted from duodenal K cells [83], primarily in response to luminal fat and carbohydrate [84]. GIP is markedly insulinotropic, but in contrast to GLP-1, it has no entero gastrone eff ect (that is, it has no eff ect on either gastric acid secretion or gastric emptying). In addition, GIP is glucagonotropic during euglycaemia, and has a substantially diminished insulinotropic eff ect in type 2 diabetic patients [85].
Small-intestinal nutrient is recognised to stimulate GIP secretion in the critically ill [86], but the magnitude of GIP response when compared to secretion in healthy subjects has not been evaluated. Likewise the pharma cological eff ects of GIP in the critically ill are unknown.

Glucagon-like peptide-2
GLP-2 is co-secreted (with GLP-1) from L cells in response to luminal nutrient [87]. GLP-2 receptors are morphologically similar to the other proglucagon products (GLP-1, GIP) and are present in the stomach, small bowel, colon, lung and brain [88].  Exogenous GLP-2 has no eff ect on gastric emptying [88]. Furthermore, in contrast to GLP-1, the peptide is glucagonotropic and has no eff ect on insulin secretion [89]. Despite the islet cell eff ects, postprandial glycaemia is unaff ected by exogenous GLP-2 [89]. Animal models have consistently demonstrated that GLP-2 in pharmacological doses potently stimulates intestinal growth, enhances absorptive function and improves mesenteric blood fl ow, thereby protecting the intestinal mucosa from injury [90,91]. Th ere have been preliminary reports of benefi cial eff ects using both GLP-2, and its analogue, teduglutide, in patients with short-bowel syndrome [92,93]. Th e physio logical concentrations and/or eff ects of pharma co logical infusions of GLP-2 remain to be studied in the critically ill.

Clinical implications and future research directions
Further studies of the physiological eff ects of these hormones in the critically ill are indicated. It would be desirable to determine the basal and nutrient-stimulated concentrations of motilin, as well as the proglucagon products (that is, GLP-1, GIP and GLP-2) in this group. In addition, an improved understanding of the mechanism(s) of increased or decreased hormone concentrations in this heterogeneous group would be of benefi t.
Given the association between the rate of gastric emptying with hormone (CCK and PYY) concentrations, the use of specifi c antagonists is appealing in certain circum stances; for example, the CCK antagonist, loxiglumide, is a novel therapy that may prove to be a useful prokinetic in the critically ill. A potential concern is that CCK antagonists may also modify pancreatic exocrine function and, thereby, nutrient absorption. Accord ingly, the absorption of nutrient should be assessed in studies of CCK antagonist use. A specifi c group of critically ill patients who warrant study using one of these agents is those with severe acute pancreatitis. CCK analogues have the capacity to induce acute pancreatitis in humans [94]. Furthermore, studies of treatment with CCK antagonists in animal models of pancreatitis as well as in patients with chronic pancreatitis have reported benefi ts [94,95].
Studies of the eff ects of physiological replacement, or pharmacological doses, of several of these hormones may also be worthwhile. Exogenous ghrelin, and/or its analogues, are potential therapies to accelerate gastric empty ing in patients with delayed gastric emptying and ileus, and/or to stimulate appetite after prolonged critical illness. Th e use of ghrelin also has the potential to cause adverse eff ects in the critically ill, however, because ghrelin is the ligand for the growth hormone secretagogue receptor. While critical illness is associated with suppressed growth hormone secretion, trials with supra-physiological growth hormone replacement have reported adverse outcomes [96]. Despite the adverse eff ects reported in studies of pharmacological growth hormone, careful evaluation of the eff ects of short-term (7 to 21 days) treatment with ghrelin, or an analogue, to establish the eff ects on gastric emptying and/or appetite in the critically ill is indicated. Th e motilin receptor also represents a target for therapy in the critically ill. Concerns of erythromycin-associated adverse events, including the potential to induce antibiotic resistance, have limited the general use of motilides for feed intolerance [97]. Accordingly, there is a need to assess the effi cacy of nonantibiotic motilides -which have shown some promise in accelerating gastric empty ing in healthy individuals and ambulant patients [6].
Incretin-based therapies are likely to fi nd a place in the management of hyperglycaemia in the intensive care unit, whether associated with type 2 diabetes or stressinduced diabetes. As discussed, a potential advantage is that pharmacological GLP-1 does not appear to increase the risk of hypoglycaemia substantially [71] and, as such, the peptide may be infused on a continuous basis without the necessity to titrate the dose [98]. In addition, aff ecting both insulin and glucagon may attenuate the variability in glycaemia when using GLP-1 compared with insulin therapy. To date we have evaluated the eff ects of the synthetic peptide to establish proof of concept. It should be recognised that the peptide is, currently, prohibitively expensive for routine clinical use. Th ere may well be a substantial reduction in cost of the peptide, however, should a market become available.
Alternatively, GLP-1 analogues (resistant to dipeptylpeptidase-4 degradation) that are currently available for management of glycaemia in ambulant patients with type 2 diabetes may prove useful. While more aff ordable, these agents (such as exenatide and lir ag lutide) have potential disadvantages, including unpredictable plasma concentrations in the critically ill, as well as antibody formation, which require evaluation [99]. Further to evalu ating the eff ects of the individual proglucagon products (that is, GLP-1, GLP-2 and GIP), the use of dipeptyl-peptidase-4 inhibit ion to increase endogenous concentrations of all three peptides also merits evaluation. As described, profound eff ects on gastric emptying and/or small-bowel transit are almost certainly undesirable, a nd the eff ects of exogenous GLP-1 on the gastrointestinal tract during prolonged administration in the critically ill should be examined. Th e potential for an increased risk of gastro esophageal refl ux, and consequent aspiration, and the eff ects on nutrient delivery and absorption represent priorities for future studies.
GIP is probably the dominant incretin in health, does not slow gastric emptying and has the potential to cause weight gain [85]. Accordingly, GIP may have a more desirable profi le than GLP-1. However, the insulinotropic eff ect of GIP is markedly attenuated in type 2 diabetics as well as ~50% of their fi rst-degree relatives [100]. Th e reduction in insulinotropic eff ect is due, at least in part, to the eff ects of hyperglycaemia. Whether a proportion of patients with stress-induced hyperglycaemia will likewise be nonresponsive to GIP pharmacotherapy, thereby limiting its use to specifi c patients, remains to be determined.
GLP-2 has potential as a therapy to stimulate intestinal growth and improve nutrient absorption in the critically ill. Furthermore, GLP-2 may reduce secondary infections in the critically ill, given that GLP-2 decreased translocation of bacteria in a rat model of acute necrotising pancreatitis [101]. While previous therapies targeting luminal immune modulation have been successful in animal studies but unsuccessful in human critical illness trials [102], GLP-2 warrants evaluation as a potential therapy in specifi c subgroups of patients.

Conclusions
Th e secretion of a number of gastrointestinal hormones is disordered in the critically ill, and may mediate abnormalities in luminal motility and, potentially, changes in absorption, metabolism and immunity in this group. Treating disordered hormone secretion (with manipulation of endogenous secretion, specifi c antagonists, exogenous infusion of hormones, or their analogues) represents a novel therapeutic approach that warrants evaluation, and has the potential to lead to improved outcomes in critically ill patients.