Neurogastroenterol Motil (2006) 18, 608618

doi: 10.1111/j.1365-2982.2006.00790.x

REVIEW ARTICLE

Dietary factors in functional dyspepsia

C. FEINLE-BISSET & M. HOROWITZ

Department of Medicine, Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia

Abstract Functional dyspepsia (FD) is characterized by upper gastrointestinal symptoms, which are frequently exacerbated by meal ingestion. W\hile subgroups of FD patients exhibit a range of disturbances in upper gastrointestinal motor function, including delayed gastric emptying and abnormal intragastric meal distribution, which may reect impaired proximal gastric relaxation and/or antral dysmotility, the association between symptoms and abnormalities in motor function appears to be relatively weak. More recently, the concept of visceral hypersensitivity to mechanical and chemical/nutrient stimuli has been promoted as important in the aetiology of dyspeptic symptoms. Somewhat surprisingly, the role of dietary factors, that is, those factors, related directly to food ingestion, including patterns of nutrient intake, potential intolerance to specic foods or macronutrients, as well as cognitive factors, have been largely ignored. Moreover, presently available treatments fail to take into account the fact that symptoms are frequently induced by eating. This review focuses on the relevance of dietary factors to FD. Keywords functional dyspepsia, eating behaviour, dietary fat, gastrointestinal motor function, gastrointestinal hormones, cognitive factors.

INTRODUCTION
Functional dyspepsia (FD) is characterized by persistent, or recurrent, upper gastrointestinal symptoms,

Address for correspondence Christine Feinle-Bisset, PhD, Department of Medicine, Eleanor Harrald Building, Level 6, Royal Adelaide Hospital, Adelaide, SA 5000, Australia. Tel: +61 8 8222 5247; fax: +61 8 8223 3870 e-mail: christine.feinle@adelaide.edu.au Received: 22 September 2005 Accepted for publication: 2 March 2006

predominantly pain or discomfort in the upper abdomen. The symptom spectrum is, however, diverse and includes the inability to nish a normal-sized meal, epigastric fullness, bloating, epigastric discomfort, pain, nausea, belching, and vomiting. Categories of dysmotility-like and ulcer-like FD, while of debatable practical value because of their substantial overlap, have been proposed in an attempt to characterize sub-groups of FD patients, particularly in research studies. In contrast, a category of meal-related FD is generally not accepted, despite the fact that anecdotally many patients report that their symptoms are induced, or exacerbated, by eating. Up to 15% of the adult population in Western countries have FD. In view of the temporal association between dyspeptic symptoms and food ingestion, it is prudent to attempt to identify underlying causes and mechanisms amongst factors that are related to eating. Meal ingestion is associated with diverse changes in gastrointestinal function (Fig. 1), and potential pathophysiological mechanisms include abnormally delayed, or accelerated, gastric emptying, disturbed intragastric meal distribution associated with impaired proximal gastric accommodation and increased antral lling, gastric or small intestinal hypersensitivity to mechanical and/or chemical/nutrient stimuli, gastric acid hypersecretion, and abnormalities in the secretion of, and/or sensitivity to, gastrointestinal peptides. Disturbances in upper gastrointestinal motor function in FD have received considerable attention (Table 1), and current treatments are, accordingly, primarily directed at these abnormalities, while therapies for visceral hypersensitivity remain to be established. It is, however, surprising that other factors, directly relating to food ingestion, which are known to have the capacity to modulate gastrointestinal motor function and sensitivity, including eating patterns (meal size and frequency, dietary macronutrient composition, overall energy intake), intolerances to specic foods, food
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Dietary factors in functional dyspepsia

Figure 1 Meal ingestion is associated with diverse changes in the environment of the gastrointestinal lumen and, as a result, in gastrointestinal function. These factors could either directly (solid arrows) or indirectly (dashed arrows) through exaggerated modulation of upper gut motility, induce dyspeptic symptoms.

Table 1 Reported disturbances in upper gastrointestinal motor function in FD Reported prevalence (%) 2060 41 3040 c. 40 c. 36 c. 30 4161 31

Motor abnormality Delayed GE Accelerated GE Abnormal intragastric meal distribution Impaired proximal gastric accommodation Wide fasting antrum Increased antral lling Antral hypomotility Small intestinal dysmotility

References
43,45,46 45 46

5,15,19

42 20 47,48 47

FD, functional dyspepsia; GE, gastric emptying.

groups or macronutrients (most notably fat), increased sensitivity to particular nutrients, abnormalities in the secretion of, and sensitivity to, gastric acid and gut hormones, as well as cognitive factors (e.g. aversions, anticipation of symptoms) have received little attention. It is also important to recognize that FD symptoms turn over in about 30% of patients; that is, many patients lose their symptoms, while others gain symptoms,1 implicating exogenous factors in the generation of symptoms and adding to the rationale for evaluating the role of diet. As FD is a heterogeneous disorder, diet could play a role in numerous ways in a given individual. This represents a major challenge in designing studies to identify relevant factors. Even in
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Figure 2 Energy intake at a cold, buffet-style meal in healthy subjects (n 13) consumed immediately after a 120 min duodenal infusion of either saline (control) or lipid (rate: 2.8 kcal min)1). Duodenal lipid signicantly reduced energy intake compared with saline (*P < 0.05). The data demonstrate the substantial interindividual variation in energy intake. The bars on the right are mean values SD for the respective study condition. Adapted from MacIntosh et al.60

healthy subjects there is a substantial intra- and interindividual variation in patterns of energy intake (Fig. 2), so that relatively large cohorts may be required to detect small, but signicant, differences, and it is likely that such variations will be greater in FD patients. Furthermore, it is important to recognize that larger-scale studies relating to dietary factors may well be associated with similar heterogeneity in their outcomes as recent studies of gastrointestinal motor

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and sensory functions. Thus, the lack of research in this area is, at least in part, testimony to the difculty in assessing eating patterns, as well as relationships between dietary factors and dyspeptic symptoms. Furthermore, FD patients are usually managed by gastroenterologists and general practitioners, and only rarely by specialized nutritional physiologists. The primary purpose of this review is to, on the one hand, redress the balance between the emphasis on disordered upper gastrointestinal motor function per se as a major aetiological factor in FD, and the relative neglect of the potential role of dietary factors, on the other, in the study of mechanisms underlying FD. Accordingly, the focus is on current knowledge relating to the role of those factors immediately related to food and nutrient ingestion, and priorities for future research. A comprehensive literature search (of Medline/PubMed databases with terms including functional dyspepsia or non-ulcer dyspepsia and nutrients or fat or carbohydrate or protein and energy intake or food intake and dyspeptic symptoms as keywords) was performed covering publications until submission of the revised manuscript in January 2006. Gastrointestinal motor function, while also related to meal ingestion and poten-

tially exacerbated by dietary factors, is only discussed briey, as this topic has been reviewed recently.2,3

EFFECTS OF PREVIOUS PATTERNS OF NUTRIENT INTAKE ON GUT FUNCTION AND ENERGY INTAKE
Studies in both animals and humans have established that previous patterns of nutrient intake have the capacity to modulate upper gastrointestinal motor and sensory function as well as food intake, that the magnitude of these effects can be substantial, and that these are associated with changes in small intestinal nutrient feedback (Table 2). For example, consumption of a high-fat diet for 2 weeks reduces pyloric pressures and the suppression of hunger in response to intraduodenal lipid.4 Moreover, many disorders, characterized by abnormal nutrient intake, are associated with changes in gastrointestinal function, including the anorexia of ageing, anorexia nervosa and delayed gastric emptying in the critically ill (Table 3). Accordingly, it is highly likely that patterns of nutrient intake will inuence gastrointestinal motor function and symptoms in FD.

Table 2 Effects of previous patterns of nutrient intake on upper gastrointestinal motor function and food intake in animals and humans Number of subjects Magnitude of effect (%)

Study design Rodents (rats) HF diet (54% energy) for 21 days

Outcomes

Reference

6 9 6 9 Humans Supplementation of diet with 200 g butter day)1 for 2 weeks Supplementation of diet with 70 g glucose day)1 for 7 days Fasting for 4 days 6 HS

Attenuates inhibitory effect of SI oleic acid on GE Energy intake Attenuates inhibitory effect of iv CCK on GE Energy intake Accelerates GE and Mouth-to-caecum transit of a HF meal Accelerates GE of Glucose Fructose Slows GE of glucose, but not saline, in Lean Obese Reduces tonic/phasic pyloric pressures Increases duodenal PWSs Attenuates suppression of hunger by SI lipid

2333 c. 18 1623 27

49 50

49 51

33 33 23 31

44

7 HS

52

12 HS 11 obese

High-energy (20 MJ), HF (c. 224 g, 42% energy) diet day)1 for 2 weeks

12 HS

12 17 35/36 43 14

53

HF, high-fat; SI, small intestinal; GE, gastric emptying; CCK, cholecystokinin; HS, healthy subjects; PWSs, pressure wave sequences. 2006 The Authors Journal compilation 2006 Blackwell Publishing Ltd

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Table 3 Changes in gastrointestinal function in some disorders associated with reduced energy intake Disorder Anorexia of ageing Changes in function Reduced hunger and energy intake Modest slowing of GE with relative redistribution of gastric content into antrum and impaired proximal gastric accommodation Increased fasting and postprandial CCK concentrations Increased sensitivity to the satiating actions of CCK-8 Slower GE Increased fasting and postprandial CCK concentrations (these abnormalities are apparently promptly reversible with normalization of nutrient intake before signicant weight gain) Slower GE Enhanced pyloric motor responses to ID nutrients Increased plasma CCK concentrations, fasting and in response to ID lipid References see
21,54

Anorexia nervosa

55 56

Critically ill patients

57 58 59

GE, gastric emptying; CCK, cholecystokinin; ID, intraduodenal.

ROLE OF DIETARY FACTORS IN THE GENERATION OF SYMPTOMS IN FUNCTIONAL DYSPEPSIA

The hypothesis that dietary factors play a role in the induction of dyspeptic symptoms has received little attention. Current evidence suggests that FD patients exhibit altered eating patterns and food intolerances (particularly to fatty foods), and that symptoms may also be affected by cognitive inuences.

Eating patterns
Functional dyspepsia patients frequently report that they are able to tolerate only small quantities of food, suggesting that their eating patterns differ from healthy subjects. This is supported by studies in tertiary referral patients, indicating that up to 55% of FD patients experience weight loss;5 such an association requires conrmation in FD patients recruited from the general population. Only two studies have hitherto evaluated eating patterns in FD, and in both of these the methodological limitations were substantial.6,7 In the rst study 7 of 40 patients with FD (14 men and 26 women), recruited from a gastroenterology outpatient clinic, females, in particular, reported lower energy intakes (by a mean of 23%), as assessed by a 7-day diet history, when compared with controls (patients treated predominantly for acute orthopaedic problems). However, this observation may represent an under-reporting of energy intake, which is a wellrecognized limitation of the use of food diaries. Furthermore, in this study 36% of FD males and 30% of females, compared with 21% of the male and 19% of the female controls, reported recent weight gain, which is difcult to reconcile with the reported energy
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intakes. There was also a higher prevalence (by about 14%) of snacking, and a lower prevalence (by about 24%) of eating large meals, in the FD patients, although these differences were not statistically signicant. The only other statistically signicant difference between FD patients and controls was that 55% of FD patients had three meals per day, compared with 80% of controls. However, as the denitions of meals and snacks were not provided, it is impossible to determine the signicance of this. The second study,6 which included 50 FD patients, recruited from a tertiary referral centre, and 50 healthy subjects, failed to nd any major differences in eating patterns between patients and controls. However, a major short-coming of this study was that food intake was only evaluated using food categories (rather than individual foods) and by a food frequency diary. Moreover, socioeconomic status differed markedly between the two groups, in that 88% of the controls, but only 54% of the patients, were employed. It is also uncertain whether patients experienced symptoms during the study. Hence, no meaningful conclusions can be drawn from either of these studies. When considering factors that are potentially involved in the regulation of food intake, including the relationship with dyspeptic symptoms, it is important to appreciate the difference between satiation and satiety (see Feinle-Bisset et al.2). Satiation refers to the process that controls meal size by terminating a period of eating, and is likely to be regulated by factors that arise immediately during, or soon after, eating, such as orosensory and cognitive inuences, gastric distension and the secretion of some gastrointestinal peptides. In contrast, satiety is the state of inhibition of hunger and further eating as a result of food consumption, measured as either the

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length of the inter-meal interval and/or the amount of food (or energy) consumed at a subsequent meal, and likely to be inuenced by intestinal and postabsorptive factors. The current use of these terms, particularly in the FD literature, is frequently incorrect.5 Whether patients with FD have either reduced, or abnormally enhanced, satiety remains to be determined. Future studies should ideally include prospective evaluations of eating patterns (energy intake and macronutrient composition), and their relationships with dyspeptic symptoms, utilizing detailed diaries in large cohorts of unselected patients.

Food intolerance
Anecdotally, specic food items and/or food groups, particularly fatty foods, have been linked to dyspepsia in that FD patients frequently report that rich and fatty foods exacerbate or induce symptoms.710 While only a handful of studies have evaluated the occurrence of food intolerances in FD (Table 4), it appears that FD patients exhibit more food intolerances than healthy subjects, although a recent study11 failed to nd any
Table 4 Summary of studies relating to food intolerance(s) in FD

difference in the consumption of frequently suspected culprit foods, as assessed using the Harvard Food Frequency Questionnaire, between persons with or without functional gastrointestinal symptoms. However, in this study, no distinction was made between patients with FD from those with irritable bowel syndrome (IBS). One study suggested that food intolerances may exist particularly in response to fatty foods fat intake, as assessed by food diaries, was signicantly (22%) less in females, but not in males, with FD than controls, indicative of a specic avoidance of fatty foods.7 In this context, it is important to recognize that fat is ingested in many different forms, depending on the type of food eaten (e.g. intracellular vs extracellular fat) and meal temperature, and in varying proportions with other macronutrients. Hence, the symptomatic response to fat may potentially vary, and the fat content of certain foods may not be appreciated, particularly as a high-fat is frequently associated with a high-carbohydrate content. The role of fat, as well as intake of the other macronutrients, and potential gender differences in the symptomatic responses warrant rigorous evaluation in prospective studies.

Reference
8

n 70 dyspeptic patients*

Techniques used to assess food intolerance(s) (1) Dietary history to identify offending food(s) (2) provocation test with offending food(s)

Most frequent food intolerance(s) [% patients] fried foods [52] pastry, cucumber [33] pickles, apples [30] spices, cooked cheese [27] oranges [26] sausages, suet puddings, curry [24] mayonnaise [80] nuts [70] sh [66] chocolate [62] fatty/fried foods [50] onions, peppers [45] citrus fruits [40] spices [35] alcohol [57] fried foods [55] spicy foods [54] fatty foods [49] onions, peppers [48] rich cakes, zzy drinks [35] No differences in intakes of wheat-, lactose- or fructose-containing foods/beverages, caffeinated drinks or alcoholic beverages

Concurrent assessment of symptoms No

50 FD patients 50 DU patients 50 HS 40 FD patients 40 OP controls

Dietetic interview (qnaire containing 39 foods)

No

10

Dietetic interview (open questions)

No

40 FD patients 40 PU patients 40 OP controls

Offending foods selected from a list provided

No

11

99 FGID patients 119 HS

Harvard Food Frequency Qnaire

No

*X-ray negative, no patients with peptic ulcer. FD, functional dyspepsia; DU, duodenal ulcer; HS, healthy subjects; qnaire, questionnaire; OP, outpatients (orthopaedic patients); FGID, functional gastrointestinal disorders. 2006 The Authors Journal compilation 2006 Blackwell Publishing Ltd

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Moreover, although FD patients are often advised to modify their dietary habits, e.g. to minimize intake of high-fat foods, the efcacy of such interventions has, hitherto, not been formally evaluated.

Upper gastrointestinal hypersensitivity

Food ingestion is initially associated with mechanical stimulation of receptors located in the gastric wall, the extent of which is dependent on the amount eaten, as well as the rate of eating. As the meal empties from the stomach and digestion processes are initiated in both the stomach and small intestine, the chemical composition of the meal becomes increasingly important in regulating gastric emptying, stimulating gastrointestinal hormones and suppressing hunger and subsequent food intake, as a result of exposure of receptors located in the small intestinal mucosa to nutrients. Hypersensitivity, that is the heightened perception of a physiological stimulus, to these factors appears to be important in the pathophysiology of FD. The majority of studies have focused on sensitivity to mechanical stimuli (e.g. gastric distension),12,13 while small intestinal chemosensitivity (to nutrients, acid and gastrointestinal hormones),1417 as well as interactions between mechanical and chemical stimuli,14,15,17 have received less attention. Hypersensitivity to mechanical stimulation In 1991, initial evidence that increased sensitivity of the proximal stomach to distension may account for symptoms in FD emerged.12 During proximal stomach distension with a balloon, or barostat, patients with FD reported sensations of rst perception, abdominal distension or pain at c. 50% lower distension pressures or volumes than healthy controls. This mechanical hypersensitivity is not evident in patients with organic causes of dyspepsia18 and may occur predominantly in patients with ulcer-like, as opposed to dysmotility-like, FD.17 More recently, it has been demonstrated that FD patients are also hypersensitive to antral distension,19 consistent with ultrasound studies reporting that in FD postprandial antral volume is increased.20 Recent studies also support a specic role for antral, as opposed to fundic or total stomach, distension in the regulation of energy intake.21 In healthy subjects, the perception of fullness following ingestion of a glucose drink was related to antral, but not fundic or total gastric, volume, and energy intake 60 min after ingestion of a yogurt preload was inversely related to antral volume. The relative importance of proximal, as opposed to distal, gastric hypersensitivity in the induction of dyspeptic symptoms is not known. It is,
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however, important to recognize that while the stomach can be divided into two different functional units, i.e. proximal and distal, it is overly simplistic to assume that the two act independently; rather, they are highly likely to interact.19 While (gastric) hypersensitivity to distension occurs in 3548% of FD patients,22,23 the clinical relevance remains uncertain because of the substantial variability in the outcome of different studies, associated with a lack of clear-cut relationships between symptoms and gastric hypersensitivity. For example, while one study found that symptoms of belching and postprandial pain were more common in those patients with hypersensitivity to gastric distension (74% and 81%, respectively), compared with patients who did not exhibit hypersensitivity, many of the patients without gastric hypersensitivity also experienced the same symptoms (belching: 51%, pain: 65%).22 Furthermore, a subsequent study failed to reveal any relationships.23 Hypersensitivity to nutrients The reports by FD patients that their symptoms are frequently induced, or exacerbated, by food, have stimulated the hypothesis that a meal has the capacity to induce symptoms indirectly, by inducing abnormal gastrointestinal motor responses (see below). There has, however, hitherto been relatively little interest in the possible, direct, role of gastrointestinal hypersensitivity to nutrients, particularly fat, as a pathophysiological mechanism. Fat is ingested predominantly in the form of triglycerides, and digestion to free fatty acids (predominantly in the small intestine) is required for the effects on gastrointestinal motility, hormone secretion, appetite suppression and gastrointestinal perception (see Feinle et al.24). For example, in healthy subjects the lipase inhibitor, orlistat, markedly attenuates perceptions of fullness and nausea induced by duodenal lipid and gastric distension. While a subsequent study25 failed to demonstrate an effect of orlistat on perception or gastric accommodation, this may potentially reect the design, in which orlistat was ingested as capsules immediately prior to ingestion of a mixed nutrient (49% carbohydrate, 35% lipid, 10% protein) meal. Since gastric emptying of liquid commences essentially immediately, ingested nutrients (i.e. carbohydrate, fat and protein) would have interacted with the small intestine in the absence of orlistat (which would have still resided in the stomach). Moreover, as orlistat specically inhibits gastrointestinal lipases, the presence of other nutrients may well have masked its effect, which would be most marked after a high-fat meal. Although the number of studies is small, it appears that 56100% of FD patients, particularly women,26

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are hypersensitive to oral and/or small intestinal fat.14,17,26 Initially, Houghton et al.26 reported that ingestion of a soup (300 ml volume) to which 30 g of fat had been added resulted in more symptoms (including epigastric pain, bloating, fullness and nausea) in FD patients than healthy controls, and when compared with the soup without fat, i.e. the presence of fat potentiated symptoms. These ndings were conrmed in a subsequent study from our laboratory,27 in which a group of FD patients consumed a palatable yogurt meal (300 g), which contained c. 24 g of fat on 1 day, and c. 1 g on the other; symptoms of fullness, bloating and nausea were 4050% greater following ingestion of the high-fat meal. In these studies symptom severity was unrelated to either gastric emptying26 or gastric volume, as measured by a barostat,27 suggesting that the responses were mediated by small intestinal receptors. In this context, it is, however, important to recognize that a decreased tolerance to water ingestion has been reported in FD,28 probably indicative of an increased perception of gastric distension, although the sensitivity to nutrient-containing is greater than to nonnutrient liquids.14 A number of recent studies of FD have employed a nutrient drink test5 and reported that FD patients consume less of the drink at the point of subjective fullness and report more symptoms, compared with healthy controls. While data derived from these studies are consistent with the concept of hypersensitivity to nutrients, the drinks used contained all three macronutrients (protein, carbohydrate and fat), so that the relative importance of individual nutrients in symptom induction cannot be assessed. Furthermore, the primary rationale for these studies was not the evaluation of the effects of nutrients, but the relationship between symptom induction and severity with disordered gastric motility. Finally, it cannot be discounted that the observations reect an expectation by the FD patients as to the amount that they may, or may not, be able to consume. With regards to the role of fat in FD symptom induction, a small number of laboratory-based studies have, indeed, shown that intraduodenal infusion of lipid, in the form of a long-chain triglyceride emulsion (Intralipid; Baxter Healthcare, Old Toongabbie, Australia), for c. 30 min, at a rate which approximates normal gastric emptying (12 kcal min)1), induces greater symptoms in FD patients than in healthy subjects and also exacerbates symptoms induced by concurrent gastric distension.14,15 Moreover, while the severity of dyspeptic symptoms is related to the small intestinal lipid load, this occurs in the absence of further gastric relaxation,15 suggesting a direct input from the small intestine. There is also limited evidence

that in FD patients nutrient hypersensitivity may be selective for fat, since intraduodenal infusion of isocaloric amounts of glucose (1 kcal min)1) does not induce symptoms.14 This may be due to the fact that intraduodenal fat may have more potent effects on pyloric stimulation and appetite suppression than isocaloric quantities of glucose. It should also be recognized that, following oral ingestion, the intragastric distribution and gastric emptying of fat may be dependent on posture, in that in the upright position, oil layers on top of higher density meal components, while in the left lateral decubitus position, oil is close to the pylorus.29 This has been shown in healthy subjects to affect appetite perceptions when oil is ingested with a low-nutrient liquid in the decubitus position, hunger is inversely related to the amount of oil emptied into the small intestine 29 and may also have implications in FD. The relative effects of fat, carbohydrate and protein, when ingested orally (as opposed to administered intraduodenally), different types of fat, as well as the possibility that delayed gastric emptying minimizes small intestinal hypersensitivity in FD warrant evaluation. Gastrointestinal hormones Food ingestion is associated with the stimulation of the secretion of a range of gastrointestinal hormones, including cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and suppression of ghrelin (see Little et al.30). CCK is secreted from the proximal small intestine predominantly in response to fat and protein, GLP-1 and PYY from the distal small intestine, GLP-1 particularly in response to carbohydrate and fat, and PYY particularly by fat, while ghrelin secretion occurs from the gastric mucosa, is maximal in the fasted state and suppressed by fat and carbohydrate, but not protein. There is persuasive evidence that all of these peptides are involved in the regulation of gastric emptying, as well as appetite and energy intake, and that interactions occurring between them and other gut stimuli (e.g. gastric distension) are important in mediating the latter effects. Furthermore, CCK and GLP-1 are known to have the capacity to induce nausea in healthy subjects when infused intravenously. Accordingly, it is conceivable that gut peptides play a role in the induction of dyspeptic symptoms. A few studies have evaluated the role of CCK in FD. We reported in a small cohort15 that the stimulation of CCK by duodenal lipid does not differ between FD patients and healthy controls, despite markedly different symptomatic responses, but this does not exclude the possibility of differences in the sensory responses to CCK. Indeed, a preliminary report,31 which evaluated
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the response to a supraphysiological dose of CCK, supports this hypothesis 27 of 30 patients with FD reported symptoms of fullness, nausea, bloating and pain in response to an intravenous infusion of CCK-8, compared with eight of 20 healthy subjects and one of 10 duodenal ulcer patients. The CCK1 receptor antagonist loxiglumide, when given orally for 8 weeks, relieved FD symptoms, as assessed by a cumulative symptom score, in 11 of 12 (92%) FD patients.32 However, in this study the response to placebo was marked [55% (6/11) of patients]. In a subsequent study, intravenous administration of the CCK1 antagonist, dexloxiglumide [the (D-)enantiomer of loxiglumide], was shown to reduce dyspeptic symptoms induced by duodenal lipid infusion, with or without concurrent gastric distension.15 In neither of these studies were symptoms totally abolished by CCK antagonism, suggesting that while CCK acting on CCK1 receptors plays a role in symptom induction in FD, it is not solely responsible, and that other factors, including other gastrointestinal peptides, are likely to be important, and questioning the usefulness of CCK1 antagonists as a sole treatment in FD. While both GLP-1 and PYY reduce energy intake, ghrelin is involved in the initiation of eating. Possibly, as suggested for CCK, FD patients may be hypersensitive to the actions of GLP-1 and PYY (as well as other peptides), and/or the effects of ghrelin on meal initiation may be diminished. A recent study33 reported a positive relationship between dyspeptic symptoms and plasma concentrations of acylated ghrelin, the biologically active form, however, plasma samples were taken only during fasting, and symptom assessment was not related temporally to the plasma ghrelin concentration. The role of these (and possibly other) gastrointestinal peptides, as well as their possible interactions, in the pathophysiology of FD warrants further evaluation. Gastric acid Although gastric acid secretion is normal in patients with FD, i.e. neither basal nor peak acid outputs differ from healthy controls, a subgroup of patients, namely those with ulcer-like FD, benet modestly from acid suppression by proton pump inhibitors.34 The gastric mucosa does not appear to be hypersensitive to acid infusion, however, it has recently been reported that in FD patients duodenal sensitivity to acid is increased.35 Impaired clearance of acid from the duodenal bulb and the proximal duodenum in the fasted, but not the postprandial, state, has also been reported,35 and probably reects impaired duodenal contractile activity.35 The relationship between the hypersensitivity to acid and that to nutri 2006 The Authors Journal compilation 2006 Blackwell Publishing Ltd

ents, particularly fat, and whether the inhibitory effect of fat on duodenal motility inuences acid clearance, warrant investigation.

Cognitive factors
While the contribution of cognitive factors to appetite regulation in healthy subjects has been recognized,36 their potential role in FD, particularly in relation to the initiation, or potentiation, of meal-related symptoms has essentially been ignored. For example, in healthy subjects, a nutrient-containing soup induces greater fullness when subjects are informed of the nature of the soup, compared with the control condition, in which they are not provided with any information.36 Both attention (due to anticipatory knowledge) and distraction (e.g. by asking the subject to perform a mental task) modulate the perception of duodenal distension in FD,37 in that attention enhances, and distraction attenuates, perception. Moreover, the substantial placebo effect in FD is well recognized. It would, therefore, not be surprising if patients with FD respond with symptoms to certain foods as a result of a previous negative learning experience, or information they have received. In early studies, attempts to provoke symptoms by offering the putative offending food(s), particularly fatty foods, in the laboratory setting were made with disappointing outcomes.8,38 Although 75100% 8,38 of patients reported that fried or fatty foods caused symptoms in their daily lives, these symptoms could not be reproduced during studies. However, this is perhaps not surprising as these studies were poorly controlled and patient selection was less than optimal, so that patients suffering from dyspepsia due to gastric and duodenal ulcers, gallstones and hiatus hernia were included. In a recent study, we evaluated the hypothesis that the information given to FD patients with regards to the fat content of a standardized, appetizing, yogurt meal would affect symptom severity.27 Patients received either a high-fat or a low-fat yogurt, each on two occasions. On one occasion, they were provided with the correct information (i.e. this is a high-fat yogurt or this is a low-fat yogurt), while on the other two occasions, they received incorrect information. The information provided had a pronounced effect on symptoms, particularly fullness and bloating, most notably in response to the low-fat yogurt, in that symptoms were much higher when subjects were informed incorrectly that they had received the highfat yogurt. Although an acute study, these observations support the concept that cognitive factors are relevant to FD symptoms.

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The mechanism(s) mediating the effects of cognitive factors on symptoms are unknown, although psychological stress has marked effects on gut motility,39 and it has been suggested that the secretion of some gastrointestinal hormones, including CCK and somatostatin, is enhanced following stress in FD patients, but not in healthy subjects.40 These preliminary observations have potentially important implications for the treatment of FD and warrant further evaluation in larger scale, chronic studies, particularly the role of cognitive inuences in every-day life.

established whether such relationships are evident in patients with less severe symptoms and whether specic symptoms are associated with particular motor abnormalities.

THERAPEUTIC IMPLICATIONS
Current treatments for FD are targeted predominantly at improving gastric motor function and emptying, and have ignored the potential role of diet, despite the fact that many patients report a worsening of symptoms after eating. While, as discussed, knowledge relating to the role of dietary factors in FD is scant, the available data have implications for potential therapeutic approaches. As FD is a heterogeneous disorder, the challenge of a dietary approach lies in the identication of patients who are likely to respond to the therapy. This may well require thorough evaluation using diaries that prospectively assess dyspeptic symptoms (occurrence and severity) in temporal association with eating patterns. The frequent (predominantly anecdotal) reports by patients that fatty foods exacerbate symptoms certainly suggest that a reduction in intake of fatty foods may prove useful, although this requires formal evaluation. There may also be a role for lipase inhibitors, to reduce the amount of free fatty acids in the small intestinal lumen, potentially leading to a reduction in the release of CCK and other gastrointestinal peptides, although the adverse effects associated with lipase inhibition would have to be considered. The effect of antagonists to gastrointestinal peptides other than CCK, alone and in combination, also warrants evaluation. The possibility that a number of patients experience symptoms for cognitive reasons requires further exploration before considering cognitive-behavioural therapies; if such therapies prove benecial, they are likely to be relatively inexpensive and associated with few, or no, adverse effects.

ROLE OF GASTROINTESTINAL MOTOR FUNCTION

Food ingestion is associated with well-characterized changes in upper gastrointestinal motor function, including relaxation of the proximal stomach, suppression of antral and duodenal pressure waves and stimulation of tonic and phasic pyloric pressures, serving to regulate gastric emptying for optimal small intestinal digestion and absorption. Not surprisingly, the provocation of symptoms by food in FD has hitherto led to a focus on disturbances in gastrointestinal motor function, which has been discussed extensively.2,3 And while food ingestion, as discussed above, may induce dyspeptic symptoms directly, it also needs to be recognized that dietary factors may potentially exacerbate a pre-existing underlying motility or sensory disorder. It is well established that disturbances in gastric emptying and gastrointestinal motor function occur in subgroups of FD patients (Table 1). The prevalence of reported disturbances has, however, varied markedly between studies, most likely due to variations in the subject/patient selection criteria and differences in methodologies and experimental protocols. The demonstration of motor abnormalities per se does not provide unequivocal evidence for a causal role in FD, thus, the challenge has been to establish associations between symptoms and these abnormalities. While some investigators have reported statistically signicant associations,5,4143 these have, in most cases, been relatively weak, and there are at least as many studies that failed to do so.23,26,27 It is also important to note that the magnitude of delay in gastric emptying (and other motor abnormalities) is, in most cases, modest, which is compatible with being diet-induced, given what is known about the effects of modications in patterns of nutrient intake.44 Furthermore, many studies that have reported relationships between symptoms and motor abnormalities have involved tertiary referral patients,5,41,43 who are more likely to have severe symptoms. It, therefore, remains to be

CONCLUSIONS
This review has summarized current (and limited) knowledge regarding the role of dietary factors in symptom induction in functional dyspepsia, including eating patterns, food intolerances, gastrointestinal hypersensitivity to nutrients, acid and gut peptides, as well as cognitive factors. While the majority of available studies have focused on the role of upper gastrointestinal motor disturbances in symptom induction and failed to establish clinically meaningful relationships between symptoms and such abnormalities, a few studies indicate that certain foods, particularly those rich in fat, may provoke dyspeptic
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symptoms. However, chronic studies formally demonstrating that symptoms in FD are exacerbated by food are yet to be performed. It is likely that patients adjust their dietary habits by excluding offending foods to avoid symptoms. Dietary modications represent a promising target for a therapy, e.g. a reduction in dietary fat may have benecial effects on symptoms by normalizing gastric emptying or proximal and/or distal gastric motility, or directly, by effects on gastrointestinal sensitivity. Large-scale studies are required to evaluate the impact of dietary habits on symptoms and the role of dietary intervention as a therapeutic strategy. Such data may provide the basis for the establishment of the category of meal-related FD. Furthermore, the clinical relevance of altered satiation and satiety, as well as the contribution of cognitive inuences, require clarication.

ACKNOWLEDGMENTS
C. Feinle-Bisset acknowledges support by a Career Development Award as well as a research grant (no. 242802) from the National Health and Medical Research Council (NHMRC) of Australia.

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