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This thesis presents studies relating to effects of different macronutrients, predominantly fat and carbohydrate, on gastrointestinal motility, hormone release/suppression, appetite and energy intake in healthy subjects, and on symptom generation in patients with functional dyspepsia. The three broad areas that have been investigated in these studies are: (i) the effect of load, and duration, of small intestinal nutrient exposure on gastric motility, gastrointestinal hormone release/suppression, appetite and energy intake in healthy subjects, (ii) the dietary factors that may contribute to symptom generation in patients with functional dyspepsia, through analysis of diet diaries and acute nutrient challenges, and (iii) the effects of the herbal medication, Iberogast®, on gastric motility in healthy subjects. The ingestion of nutrients, triggers a number of gastrointestinal responses, including the modulation of antropyloroduodenal motility, gastrointestinal hormone release/suppression, and the suppression of appetite and energy intake, resulting in a slowing of gastric emptying to an average rate of 1 - 3 kcal/min, which is required for efficient nutrient digestion and absorption. Additionally, the rate at which glucose enters the small intestine influences postprandial glycaemia and incretin responses. These responses have been demonstrated in animals to be dependent on the length, and region, of the small intestine exposed to fat and glucose, however, this has not been directly investigated in humans. Functional dyspepsia is a clinical condition, characterised by chronic upper abdominal symptoms, such as nausea, bloating and early fullness, without a known cause, which affects approximately 11 - 29 % of the population. Many studies have reported that disturbed gastric motor activity may be the cause of these symptoms, but patients frequently experience symptoms following ingestion of food, and some patients report to eat smaller meals more frequently and avoid fatty and spicy foods. In addition, laboratory-based studies have indicated that functional dyspepsia patients may be hypersensitive to fat, but not carbohydrate. To date, the treatments used to reduce symptoms are frequently directed at the normalisation of gastroduodenal motility, using prokinetics. However, the beneficial effect of these drugs is relatively small and variable, and their adverse effects can be substantial. Herbal drug preparations have recently received considerable interest as an alternative treatment option in functional dyspepsia. A commercially available herbal preparation, Iberogast® which contains nine plant extracts, has been reported to improve upper abdominal symptoms in functional dyspepsia and to decrease fundic tone, increase antral contractility and decrease afferent nerve sensitivity in experimental animals. The effects of Iberogast® in the human gastrointestinal tract have not been investigated. The first three studies presented in this thesis have focused on the effects of delivering fat and glucose into the small intestine at different loads (Chapter 5, 6 and 7), lower, comparable to, and higher than gastric emptying normally occurs, and at different durations of infusion (but still at similar caloric loads - Chapter 5, fat only), on gastrointestinal motility, plasma hormone release/suppression, glycaemia, and energy intake in healthy male subjects. The study in Chapter 5 demonstrated that antral pressure waves and pressure wave sequences were suppressed, and basal pyloric pressure, isolated pyloric pressure waves, and plasma cholecystokinin and peptide YY stimulated, during both the low (1.33 kcal/min for 50 min: 67 kcal/min), and high (4 kcal/min for 50 min: 200 kcal), loads of lipid. The effect of the 4 kcal/min load was sustained so that the suppression of antral pressure waves and pressure wave sequences and increase in peptide YY remained evident after cessation of the infusion. The prolonged lipid infusion (1.33 kcal/min for 150 min: 200 kcal) suppressed antral pressure waves, stimulated cholecystokinin and peptide YY and basal pyloric pressure and tended to stimulate isolated pyloric pressure waves when compared with saline throughout the entire infusion period. These results indicate that both the load, and duration, of small intestinal lipid have an influence on antropyloroduodenal motility and patterns of cholecystokinin and peptide YY release. Chapter 6 demonstrated that lipid loads lower than gastric emptying normally occurs (0.25 kcal/min for 50 min: 12.5 kcal) transiently stimulated isolated pyloric pressure waves and cholecystokinin release and suppressed pressure wave sequences and hunger scores. Loads comparable to (1.5 kcal/min for 50 min: 75 kcal) and higher (4 kcal/min for 50 min: 200 kcal), than the normal rate of gastric emptying, were required to stimulate basal pyloric tone and peptide YY release and suppress antral and duodenal pressure waves. Only the 4 kcal/min load suppressed energy intake. The effects of lipid on all parameters, with the exception of hunger, were load-dependent. In addition, there were relationships between antropyloroduodenal motility and cholecystokinin and peptide YY concentrations with energy/food intake. The study in Chapter 7 demonstrated that loads of glucose lower than (1 kcal/min for 120 min: 120 kcal), comparable to (2 kcal/min for 120 min: 240 kcal) and higher than (4 kcal/min for 120 min: 480 kcal) the rate gastric emptying normally occurs, stimulated blood glucose, plasma insulin, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide and cholecystokinin concentrations and suppressed the number of antral pressure waves, 2 and 4 kcal/min loads were required for the suppression of duodenal pressure waves and pressure wave sequences and the stimulation of basal pyloric pressure and suppression of energy intake only after the 4 kcal/min loads. There were also relationships between glucagon-like peptide-1 and glucose-dependent insulinotropic peptide with basal pyloric tone, and food/energy intake with pyloric pressures. The studies presented in the subsequent three chapters investigated the contribution of dietary factors on the generation of symptoms in patients with functional dyspepsia when compared with healthy subjects (Chapter 8 and 9) and the effect of Iberogast® on motility in the healthy gastrointestinal tract (Chapter 10). The effects of equi-caloric high-carbohydrate vs. high-fat yoghurt preloads on symptom generation, plasma hormone concentrations, antral area and energy intake were compared between functional dyspepsia patients and healthy subjects (Chapter 8). Nausea and pain were greater in patients after the high-fat, when compared with high-carbohydrate and control, preloads and with healthy subjects. Discomfort was greater after all preloads in patients when compared with healthy subjects. Fasting cholecystokinin and stimulation of cholecystokinin by the high-fat preload were greater in patients, while fasting and postprandial peptide YY were lower in patients than in healthy subjects, with no differences in fasting, or postprandial, plasma ghrelin between patients and healthy subjects. Fasting antral area was greater in patients, with no differences postprandially between patients and healthy subjects. There were no differences in energy intake between the two groups. The relationship between the effect of dietary intake and eating behaviour over a 7-day period on the occurrence and severity of abdominal symptoms was compared between patients and healthy subjects (Chapter 9). The symptoms experienced by the patients included nausea, fullness discomfort, bloating and upper abdominal, and epigastric, pain, of a modest severity, which occurred within 30 min of eating. The number of “meals” ingested was significantly less in functional dyspepsia patients and there was a trend for total energy and fat intake to be less. The occurrence of these symptoms was also statistically related to the ingestion of fat and energy intake. The results of these studies indicate that diet, particularly the ingestion of fat, influences the development of symptoms in a subgroup of patients with functional dyspepsia. The study in Chapter 10 evaluated the effect of the herbal drug Iberogast® on gastric motility in the gastrointestinal tract. Iberogast® increased proximal gastric volume, increased antral pressure waves without affecting pyloric or duodenal pressures, and slightly increased the retention of liquid in the total stomach, but had no effect on gastric emptying of solids or intragastric distribution. These results demonstrate that Iberogast® affects gastric motility in humans, and the stimulation of gastric relaxation and antral motility may contribute to the reported therapeutic efficacy of Iberogast® in functional dyspepsia. The studies reported in this thesis provide new information about the regulation of gastric motility, hormone release/suppression, appetite and energy intake, by varying the loads of lipid and glucose infused into the small intestine in healthy subjects, which may have implications in patients with altered gastric motor functions, such as obese, type-2 diabetes and functional dyspepsia patients. In addition, studies in functional dyspepsia patients revealed that diet, in particular the ingestion of fat, contribute to the cause of their symptoms, and these findings may have important implications for the development of diet-based therapies for the treatment of functional dyspepsia. Furthermore, functional dyspepsia patients with impaired gastric relaxation and antral dysmotility may benefit from the effects of Iberogast® as demonstrated in the healthy gastrointestinal tract. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1331606 / Thesis (Ph.D.) - University of Adelaide, School of Medicine, 2008

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Helicobacter pylori (H. pylori) is a Gram-negative bacterium that infects and resides in the gastric mucosa of humans. Without treatment, H. pylori infection may cause chronic inflammation of the gastric mucosa. This inflammation creates progressive damage to the lining of the stomach and can lead to multiple diseases located in the upper gastrointestinal region. Worldwide prevalence of H. pylori infection is estimated to be close to 50%. H. pylori has been identified as the primary cause of peptic ulcer disease, gastric cancer, and mucosa-associated lymphoid tissue lymphoma. The purpose of this study was to identify the prevalence and risk factors associated with H. pylori infection among students, faculty, and staff at the University of Central Florida. A cross-sectional design with a convenience sample was implemented to acquire a study population of 60 participants. The sample was analyzed through the use of a twenty question survey and a rapid blood antibody test kit. The infection rate of the sample was 1.75%. Statistically significant results were found for the relationship between age and upper gastrointestinal symptoms. Trends were also noticed between alcohol consumption, stress levels, and upper gastrointestinal symptoms.

Gastrointestinal symptoms have a prevalence of 20-40% in the general adult population in the Western world. These symptoms are generally considered to be poor predictors of organic findings [e.g. peptic ulcer disease (PUD) or malignancy]. Approximately 50% of patients seeking care for such symptoms have no organic explanation for these upon investigation. When other organic or other functional conditions are excluded [e.g. PUD, gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS)] the remaining patients are labelled as having functional dyspepsia (persistent or recurrent pain and/or discomfort centred in the upper abdomen). Management of functional dyspepsia remains a challenge, reflecting the heterogeneity of the patients and the uncertain role of drug treatment. Also, prognostic factors for treatment success are largely unknown. I have therefore performed a series of studies to shed light on these issues: The first study (Paper I) was performed in a randomly selected adult population (n=1,001) assessing upper and lower gastrointestinal symptoms at two occasions with 1 to 6 month intervals. The results show that gastrointestinal symptoms are common (57%) and fluctuate to some extent in the shorter term. Troublesome dyspeptic symptoms remain in two out of three individuals. This proportion was similar whether or not organic findings were present. In the second study (Paper II) 799 patients with dyspeptic symptoms were evaluated with regard to whether gastrointestinal symptoms, identified by self-administered questionnaires, correlate with endoscopic diagnoses and discriminate organic from non-organic (functional) dyspepsia. The impact of dyspeptic symptoms on health-related well-being was also evaluated. Approximately 50% of these dyspeptic patients were found to have functional dyspepsia at upper endoscopy. A difference was discovered in the symptom profile between patients with organic and functional dyspepsia. Predicting factors for functional dyspepsia were found. This study shows that use of self-administered symptom questionnaires may aid in clinical decision making for patient management, e.g. by reducing the number of endoscopies, although probabilities of risks for organic dyspepsia are difficult to transfer to management of the individual patient. The results also indicate that the health-related well-being in patients with functional and organic dyspepsia is impaired to the same extent, illustrating the need for effective treatment of patients with functional dyspepsia, a group not well served by currently available treatment modalities. The aim of the third study (Paper III) was to develop and evaluate a selfadministered questionnaire focusing on upper abdominal and reflux complaints to allow for identification of patients with heartburn and factors that might predict symptom relief with omeprazole both in GERD and functional dyspepsia patients. The diagnostic validity of the questionnaire was tested against endoscopy and 24-hour pH monitoring. The questionnaire had a sensitivity of 92%, but a low specificity of 19%. Symptom relief by omeprazole was best predicted by the presence of predominant heartburn described as ‘a burning feeling rising from the stomach or lower chest up towards the neck’ and ‘relief from antacids’. These results indicate that this questionnaire which used descriptive language, appeared to be useful in identifying heartburn and predicting responses to omeprazole in patients with upper gastrointestinal symptoms. The fourth study (Paper IV) was a pilot study investigating the symptom response to omeprazole 20 mg twice daily or placebo for a duration of 14 days in 197 patients with functional dyspepsia. We concluded that a subset of patients with functional dyspepsia, with or without heartburn, would respond to therapy with omeprazole. In the final study (Paper V) the aim was to identify prognostic factors for the treatment success to a 4-week course of omeprazole 10 or 20 mg once daily in 826 patients with functional dyspepsia. The most highly discriminating predictor of treatment success was the number of days without dyspeptic symptoms during the first week of treatment. Fewer days with symptoms during the first week indicated higher response rates at four weeks. In addition, positive predictors of treatment response to omeprazole were identified as age >40 years, bothersome heartburn, low scores of bloating and diarrhoea, history of symptoms for <3 months and low impairment of vitality at baseline. The results indicate that early response during the first week to treatment with a proton pump inhibitor seems to predict treatment success after four weeks in patients with functional dyspepsia. Conclusion: These studies have shown that a large proportion of adult individuals in society, both those who seek and those who do not seek medical care, suffer from symptoms located in the upper part of the abdomen regardless of whether an organic cause is present. A subset of patients without organic findings and other functional conditions, i.e. functional dyspepsia, respond to therapy with omeprazole irrespective of the presence or absence of heartburn . An excellent way to predict the response to a full course of omeprazole in functional dyspepsia is to assess the early response (first week) to treatment. These findings allow for better and faster targeting of acid inhibitory therapy in functional dyspepsia, which potentially can result in more effective clinical management of these patients and savings of health care resources.

Objective The main objective of this thesis was to explore the effects of diet on gastrointestinal symptoms in prostate cancer patients treated with local curative radiotherapy, by evaluating dietary intake prior to treatment (Study I), the psychometric properties of a new questionnaire on patient-reported gastrointestinal side effects (Study II), and the effect of a dietary intervention on acute and long-term gastrointestinal symptoms up to 2 years after radiotherapy completion (Study III-IV). Methods A total of 130 men with localized prostate cancer referred to dose-escalated radiotherapy (ED2 87-102 Gy, α/β=3 Gy) were recruited to a dietary intervention trial. Patients were randomized to receive either standard care plus the dietary intervention of a fibre- and lactose-restricted diet (intervention group, IG; n=64) or standard care alone (standard care group, SCG; n=66). Data on gastrointestinal symptoms and dietary intake were collected pre-treatment and at seven time points during a follow-up period of 26 months. Results Prior to treatment, grain products and milk products were major sources of energy. Unbalanced fatty acid intake and low intake of selenium were observed (Study I). Validation of the Gastrointestinal Side Effects Questionnaire (GISEQ) revealed satisfactory internal consistency, moderate concurrent validity and adequate responsiveness (Study II). There were no significant effects of the intervention on acute or long-term gastrointestinal symptoms, but a tendency towards lower prevalence and severity of bloating and diarrhoea in the IG compared to the SCG during radiotherapy. Gastrointestinal symptoms were predominantly mild, and the frequency of clinically relevant symptoms was merely a few percent. Dietary adherence in the IG was initially good, but tended to decline beyond 12 months post-radiotherapy (Study III-IV). Conclusions A fibre- and lactose-restricted diet was not superior to the habitual diet in reducing gastrointestinal symptoms in patients undergoing high-dose, small-volume radiotherapy for localized prostate cancer. The GISEQ enables assessment of patient-perceived change in symptoms, but further work is needed to strengthen its psychometric qualities. It is suggested that continued research in this area target patient categories referred to irradiation of larger pelvic volumes with a higher risk of gastrointestinal symptoms, and that dietary interventions incorporate established strategies to enhance adherence and effectiveness.

Made available in DSpace on 2016-03-15T19:39:59Z (GMT). No. of bitstreams: 1 Patricia Fukuda de Siqueira Baptista.pdf: 1719530 bytes, checksum: 6206faad33c0cdff7d8d996720499582 (MD5) Previous issue date: 2013-02-07 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Autism Spectrum Disorder (ASD) are a heterogeneous group of syndromes characterized by impairment in social interaction, impairment in communication and a pattern of repetitive or stereotyped behaviors. Gastrointestinal disorders and associated symptoms are commonly reported in individuals with ASDs, but key issues such as the prevalence and best treatment of these conditions are not fully understood. The main objective of this study was to investigate gastrointestinal symptoms (GS) in individuals with Autism Spectrum Disorder, check its frequency and possible relation to serum levels of serotonin, eating habits and medication use. The sample consisted of 100 children / adolescents diagnosed with ASD aged 3 to 21 years old. For determination of gastrointestinal symptoms was used a questionnaire that assesses the presence and frequency of gastrointestinal disorders. The dosage of serotonin serum was determined by high performance liquid chromatography, dietary was assessed by food frequency questionnaire. The results showed that 42% of the participants had some type GS, being constipation the most often (31% of cases). It was found a correlation between severity of ASD and GS. In the analysis of serotonin hyperserotonemia was verified in 19% of patients and did not show correlations between dietary, use of medications and GS. / Transtornos do Espectro do Autismo (TEA) são um conjunto heterogêneo de síndromes caracterizadas por prejuízos nas interações sociais, deficiência na comunicação e um padrão de comportamentos repetitivos ou estereotipados. Doenças gastrointestinais e sintomas associados são comumente relatados em indivíduos com TEA, mas questões centrais como prevalência e melhor tratamento destas condições não são totalmente compreendidas. O objetivo principal deste estudo foi investigar os sintomas gastrointestinais (SGI) em indivíduos com Transtornos do Espectro do Autismo, verificar a sua frequência e possível relação com os níveis séricos de serotonina, hábitos alimentares e uso de medicamentos. A casuística foi composta por 100 crianças/adolescentes diagnosticados com TEA com idade entre 3 e 21 anos. Para determinação dos sintomas gastrointestinais foi utilizado um questionário que avaliou a presença e a frequência dos distúrbios gastrointestinais. A dosagem de serotonina sérica foi determinada pelo método de cromatografia líquida de alta eficiência e a dieta alimentar foi avaliada pelo questionário de frequência alimentar. Os resultados mostraram que 42% dos participantes apresentaram algum tipo de SGI, sendo a constipação o mais frequente (31% dos casos). Foi evidenciada uma correlação entre gravidade do TEA e sintomas gastrointestinais. Na análise de serotonina foi verificada a hiperserotonemia em 19% dos pacientes e não foram evidenciadas correlações entre dieta alimentar, uso de medicamentos e SGI.

Adolescents with type 1 diabetes (T1DM) are given nutritional education, but the knowledge about their adherence to the food recommendations and associations between dietary intake and metabolic control is poor. Gastrointestinal symptoms are more prevalent in adults with T1DM than in healthy controls, which may be due to disturbed gastrointestinal motility. The meal content affects the gastric emptying rate and the postprandial glycaemia in healthy adults and adults with type 2 diabetes. Meal ingestion also elicits several postprandial hormonal changes of importance for gastrointestinal motility and glycaemia. Eating disorders are more prevalent in young females with T1DM than in healthy females, and are associated with poor metabolic control. The prevalence of eating disorders in adolescent boys with T1DM is not known.  This thesis focuses on eating and gastrointestinal function in adolescents with T1DM. Three population-based, cross-sectional studies demonstrated that adolescents with T1DM consume healthy foods more often and have a more regular meal pattern than age- and sex-matched controls. Yet both boys and girls are heavier than controls. The intake of saturated fat is higher and the intake of fibre is lower than recommended in adolescents with T1DM. Patients with poor metabolic control consume more fat and less carbohydrates than patients with better metabolic control. Gastrointestinal symptoms are common in adolescents with T1DM, but the prevalence is not increased compared with controls. Gastrointestinal symptoms in patients are associated with female gender, daily cigarette smoking, long duration of diabetes, poor metabolic control during the past year, and an irregular meal pattern. Adolescent boys with T1DM are heavier and have higher drive for thinness than healthy boys, but do not differ from them in scales measuring psychopathology associated with eating disorders.   In a randomized, cross-over study, we found that a meal with a high fat and energy content reduces the initial (0–2 hours) postprandial glycaemic response and delays gastric emptying in adolescents with T1DM given a fixed prandial insulin dose compared with a low-fat meal. The glycaemic response is significantly associated with the gastric emptying rate. Both a high- and a low-fat meal increase the postprandial concentrations of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) and suppress the postprandial ghrelin levels in adolescents with T1DM. The postprandial changes of these hormones are more pronounced after the high-fat meal. Insulin-like growth factor binding-protein (IGFBP) –1 concentrations decrease after insulin administration irrespective of meal ingestion. The GLP-1 response is negatively associated with the gastric emptying rate. The fasting ghrelin levels are negatively associated with the postprandial glycaemic response, and the fasting IGFBP-1 levels are positively associated with the fasting glucose levels.  We conclude that nutritional education to adolescents with T1DM should focus more on energy intake and expenditure to prevent and treat weight gain. It should also focus on fat quality and fibre intake to reduce the risk of macrovascular complications and improve glycaemia. Gastrointestinal symptoms in adolescents with T1DM should be investigated and treated as in other people irrespective of having diabetes. However, adolescents with long duration of diabetes, poor metabolic control, and symptoms from the upper gut should have their gastric emptying rate examined during euglycaemia. There may be an increased risk for development of eating disorders in adolescent males with T1DM since they are heavier than healthy boys and have higher drive for thinness. This should be investigated in future, larger studies.  For the first time, we showed that a fat-rich meal delays gastric emptying and reduces the initial glycaemic response in patients with T1DM. The action profile of the prandial insulin dose to a fat-rich meal may need to be postponed and prolonged compared with the profile to a low-fat meal to reach postprandial normoglycaemia. Circulating insulin levels affect postprandial GIP, GLP-1, and ghrelin, but not IGFBP-1, responses less than the meal content. The pronounced GIP-response to a fat- and energy-rich meal may promote adiposity, since GIP stimulates lipogenesis. Such an effect would be disadvantageous for adolescents with T1DM since they already have increased body fat mass and higher weights compared with healthy adolescents. Adolescents with T1DM may have subnormal postprandial ghrelin suppression, which may be due to their increased insulin resistance or elevated growth hormone levels. This needs to be investigated in future, controlled studies.

<p>Studies concerning social consequences, gastrointestinal and urinary tract symptoms were conducted in a population-based cohort comprising patients with long-standing type 1 diabetes and matched control persons. Three different questionnaires were sent by mail to diabetic patients and control persons. After a mean duration of 28.7±2.6 years, compared to the controls the diabetic patients showed an almost 10 times higher mortality, a lower employment rate and greater need for welfare benefits. These differences were mainly due to diabetic late complications. Education, housing conditions, life-style, civil state, alcohol and smoking habits were similar in the two groups. The prevalence of gastrointestinal symptoms was significantly higher in the diabetic patients than in the controls, and this was found to be attributable to the female diabetic patients. Female diabetic patients had been treated with antibiotics for urinary tract infections more often than controls, they experienced more social problems than controls in daily life because of urinary tract problems and used clamps to prevent wetting more often than did controls. </p><p>Body composition and bone mineral density were evaluated in parts of the cohort with long-standing type 1 diabetes and control persons in another population-based cohort comprising diabetic females aged 16-19 years with type 1 diabetes since childhood and matched controls. Besides a tendency to reduced abdominal fat mass in diabetic males, no difference was observed in fat mass, muscle mass or bone mineral density between the patients with long-standing type 1 diabetes and controls. Significant correlations were found between insulin dosage and whole body fat mass in diabetic females and between serum cholesterol levels and abdominal fat mass in diabetic males. The female adolescents had a higher body mass index than the controls, and their overweight was shown to consist almost entirely of an increased fat mass. The distribution of fat, expressed as abdominal-to-leg ratio, correlated significantly to HbA1c and daily dosage of insulin. Bone mineral density did not differ between the groups. IGF I was significantly lower both in patients with long-standing type 1 diabetes and in the adolescent diabetic females compared with their matched controls.</p>