Center for Paediatric and Adolescent Gastroenterology

North Adelaide, Australia

Center for Paediatric and Adolescent Gastroenterology

North Adelaide, Australia

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Howarth G.S.,University of Adelaide | Howarth G.S.,Center for Paediatric and Adolescent Gastroenterology | Wang H.,University of Adelaide
Nutrients | Year: 2012

Although gut diseases such as inflammatory bowel disease, mucositis and the alimentary cancers share similar pathogenetic features, further investigation is required into new treatment modalities. An imbalance in the gut microbiota, breached gut integrity, bacterial invasion, increased cell apoptosis to proliferation ratio, inflammation and impaired immunity may all contribute to their pathogenesis. Probiotics are defined as live bacteria, which when administered in sufficient amounts, exert beneficial effects to the gastrointestinal tract. More recently, probiotic-derived factors including proteins and other molecules released from living probiotics, have also been shown to exert beneficial properties. In this review we address the potential for probiotics, with an emphasis on probiotic-derived factors, to reduce the severity of digestive diseases and further discuss the known mechanisms by which probiotics and probiotic-derived factors exert their physiological effects. © 2013 by the authors; licensee MDPI, Basel, Switzerland.


Prisciandaro L.D.,University of Adelaide | Prisciandaro L.D.,Center for Paediatric and Adolescent Gastroenterology | Prisciandaro L.D.,The Queen Elizabeth Hospital | Geier M.S.,South Australian Research And Development Institute | And 5 more authors.
Critical Reviews in Food Science and Nutrition | Year: 2011

Although chemotherapy remains the current best practice for the treatment of neoplasia, the severity of its associated sideeffects continues to impact detrimentally on the quality of life. Mucositis can affect both the oral cavity and intestine, and represents one of the most common side-effects of chemotherapy. It is characterized by ulceration, inflammation, diarrhoea, and intense abdominal pain. Despite extensive research thereremains no definitive therapy for mucositis. This may be due to the multiple factors which contribute to its pathogenesis, including up-regulation of pro-inflammatory cytokines, increased apoptosis of epithelial cells, alteration of the gastrointestinal microbiota, and damage to the epithelium. Although employed increasingly in other gastrointestinal disorders, probiotics are yet to be comprehensively investigated in the treatment or prevention of chemotherapy-induced mucositis. Probiotic-based therapies have been shown to exert beneficial effects, including modulation of the microbiota and inhibition of pro-inflammatory cytokines. This review outlines the current evidence supporting the use of probiotics in intestinal mucositis, and suggests further research directions for the future. © Taylor and Francis Group, LLC.


Wang H.,University of Adelaide | Geier M.S.,University of Adelaide | Geier M.S.,South Australian Research And Development Institute | Howarth G.S.,University of Adelaide | Howarth G.S.,Center for Paediatric and Adolescent Gastroenterology
Critical Reviews in Food Science and Nutrition | Year: 2016

Mucositis, characterized by ulcerative lesions along the alimentary tract, is a common consequence of many chemotherapy regimens. Chemotherapy negatively disrupts the intestinal microbiota, resulting in increased numbers of potentially pathogenic bacteria, such as Clostridia and Enterobacteriaceae, and decreased numbers of “beneficial” bacteria, such as Lactobacilli and Bifidobacteria. Agents capable of restoring homeostasis in the bowel microbiota could, therefore, be applicable to mucositis. Prebiotics are indigestible compounds, commonly oligosaccharides, that seek to reverse chemotherapy-induced intestinal dysbiosis through selective colonization of the intestinal microbiota by probiotic bacteria. In addition, evidence is emerging that certain prebiotics contribute to nutrient digestibility and absorption, modulate intestinal barrier function through effects on mucin expression, and also modify mucosal immune responses, possibly via inflammasome-mediated processes. This review examines the known mechanisms of prebiotic action, and explores their potential for reducing the severity of chemotherapy-induced mucositis in the intestine. © 2016, Copyright © Taylor and Francis Group, LLC.


Lange B.,University of Adelaide | Currie K.-L.,Flinders University | Howarth G.S.,University of Adelaide | Howarth G.S.,Center for Paediatric and Adolescent Gastroenterology | And 3 more authors.
Aquaculture | Year: 2014

Summer mortality (SM) in greenlip abalone (Haliotis laevigata Donovan) heavily affects productivity of land-based abalone farms in Southern Australia. It has been associated with conditions of high water temperature (>. 23. °C), low dissolved oxygen levels, and a range of other stressful factors in the culture water during summer months. This study aimed to alleviate mortality experienced by abalone at high water temperatures (26. °C), by dietary intervention using grape seed extract (GSE) and dried Ulva lactuca Linnaeus, two products which contain antioxidative and bioactive compounds. These products were formulated into a commercial abalone diet at levels of 5 and 30%. The diets were fed to 3-year-old greenlip abalone (26.8. g; 57.9. mm) at a water temperature of 22 or 26. °C for 38. days. No mortalities were observed at 22. °C. Compared to the unaltered commercial diet, both GSE and dried U. lactuca additive diets significantly increased the survival of abalone at the 26. °C water temperature (P<. 0.05). GSE addition also significantly increased serum superoxide dismutase activity, feed intake, and meal acceptance of the abalone (P<. 0.05). These results demonstrate the potential for GSE or dried U. lactuca to act as dietary additives to reduce mortality and improve productivity on abalone farms subjected to high summer water temperatures. © 2014.


Cheah K.Y.,University of Adelaide | Cheah K.Y.,Center for Paediatric and Adolescent Gastroenterology | Howarth G.S.,Center for Paediatric and Adolescent Gastroenterology | Howarth G.S.,University of Adelaide | Bastian S.E.P.,University of Adelaide
PLoS ONE | Year: 2014

Objective: Mucositis is a serious disorder of the gastrointestinal tract that results from cancer chemotherapy. We investigated the effects of increasing grape seed extract doses on the severity of chemotherapy in a rat model and its coincident impact on chemotherapeutic effectiveness in colon cancer cells. Design: Female Dark Agouti rats were gavaged with grape seed extract (400-1000 mg/kg) or water (day 3-11) and were injected intraperitoneally with 5-Fluorouracil (150 mg/kg) or saline (control) on day 9 to induce mucositis. Daily metabolic data were collected and rats were sacrificed on day 12. Intestinal tissues were collected for histological and myeloperoxidase analyses. Caco-2 cell viability was examined in response to grape seed extract in combination with 5-Fluorouracil by 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl- tetrazolium bromide) assay. Results: Compared with 5-Fluorouracil controls, grape seed extract (400-1000 mg/kg) significantly decreased the histological damage score (P<0.05) in the jejunum. Grape seed extract (1000 mg/kg) increased jejunal crypt depth by 25% (P<0.05) in 5-Fluorouracil treated rats compared to 5-Fluorouracil controls, and attenuated the 5-Fluorouracil -induced reduction of mucosal thickness (25%, P<0.05). Grape seed extract (600 mg/kg) decreased myeloperoxidase activity by 55% (P<0.01) compared to 5-Fluorouracil controls. Grape seed extract was more effective at ameliorating 5-Fluorouracil induced intestinal injury, with effects most pronounced in the proximal jejunum. Grape seed extract (10-25 μg/mL) significantly enhanced the growth-inhibitory effects of 5-Fluorouracil by 26% (P<0.05) in Caco-2 cells and was more potent than 5- Fluorouracil at 50-100 mg/mL. Conclusion: Grape seed extract may represent a new therapeutic option to decrease the symptoms of intestinal mucositis while concurrently impacting on the viability of colon cancer cells. © 2014 Cheah et al.


Cheah K.Y.,University of Adelaide | Cheah K.Y.,Center for Paediatric and Adolescent Gastroenterology | Howarth G.S.,Center for Paediatric and Adolescent Gastroenterology | Howarth G.S.,University of Adelaide | And 4 more authors.
PLoS ONE | Year: 2014

Objective: Grape seed procyanidins (PC) are flavan-3-ol oligomers and polymers known for their biological activity in the gut. Grape seed extract (GSE) have been reported to reduce intestinal injury in a rat model of mucositis. We sought to investigate effects of purified PC fractions differing in mean degree of polymerization (mDP) combined with 5-Fluorouracil (5-FU) chemotherapy on the viability of colon cancer cells (Caco-2). Design: SixPC fractions (F1-F6) were isolated from Cabernet Sauvignon seeds at two ripeness stages: pre-veraison unripe (immature) and ripe (mature), utilizing step gradient, low-pressure chromatography on a Sephadex LH-20 resin. Fractions were tested on Caco-2 cells, alone and in combination with 5-FU. Eluted fractions were characterized by phloroglucinolysis and gel permeation chromatography. Cell viability was determined by the 3-(4,5-Dimethylthiazol-2yl)-2,5- diphenyltetrazolium bromide) (MTT) assay. Results: All isolated fractions significantly reduced Caco-2 cell viability compared to the control (P<0.05), but F2 and F3 (mDP 2-6) were the most active fractions (immature F2 = 32% mDP 2.4, F3 = 35% mDP 5.8 and mature F2 = 13% mDP 3.6 and F3 = 17% mDP 5.9; percentage of viable cells remaining) on Caco-2 cells. When combined with 5-FU, immature fractions F1-F3 enhanced the cell toxicity effects of 5-FU by 27-73% (P<0.05). Mature seed PC fractions (F1-F4) significantly enhanced the toxicity of 5-FU by 60-83% against Caco-2 cells (P<0.05). Moreover, some fractions alone were more potent at decreasing viability in Caco-2 cells (P<0.05; immature fractions = 65-68% and mature fractions = 83-87%) compared to 5-FU alone (37%). Conclusions: PCs of mDP 2-6 (immature F1-F3 and mature F1 and F4)not only enhanced the impact of 5-FU in killing Caco-2 cells, but also surpassed standard 5-FU chemotherapy as an anti-cancer agent.The bioactivity of PC is therefore attributed primarily to lower molecular weight PCs. © 2014 Cheah et al.


Tooley K.L.,Center for Paediatric and Adolescent Gastroenterology | Howarth G.S.,Center for Paediatric and Adolescent Gastroenterology | Howarth G.S.,University of Adelaide | Lymn K.A.,Center for Paediatric and Adolescent Gastroenterology | And 2 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2010

Purpose: In order to determine the sensitivity and specificity of the test and to optimize experimental conditions utilizing the SBT in a rat model of chemotherapy-induced small intestinal damage. Methods: Initially, a 13C-sucrose dose-response study was performed in rats to determine an optimal sucrose concentration for the SBT; then applied to assess chemotherapy-induced intestinal damage. A further study was conducted to establish a SBT time-course of methotrexate-induced small intestinal damage and repair. Animals were killed at 96 or 144 h. Results: A sucrose concentration of 0.25 g/ml was optimal (20% CV) for reproducibility and detection of intestinal damage. Maximal damage occurred at 72 h, small intestinal repair was initiated by 96 h and continued at 144 h post-MTX, as determined by the SBT and confirmed by biochemical analyses. Levels of sensitivity and specificity for the SBT were 98 and 94%, respectively. Conclusions: The SBT is a reliable non-invasive marker of small intestinal health and damage with a high degree of sensitivity and specificity. © 2009 Springer-Verlag.


Lindsay R.J.,University of Adelaide | Geier M.S.,South Australian Research And Development Institute | Yazbeck R.,Flinders University | Yazbeck R.,Center for Paediatric and Adolescent Gastroenterology | And 3 more authors.
British Journal of Nutrition | Year: 2010

Mucositis resulting from cancer chemotherapy is a serious disorder of the alimentary tract. Emu oil has demonstrated anti-inflammatory properties in animal models of arthritis and wound healing; however, its effects on the intestine remain unknown. We investigated emu oil for its potential to decrease the severity of mucositis in a rat model. Female Dark Agouti rats (110-150g) were orogastrically gavaged with emu oil (05 or 1ml) or water (1ml) for 5d before intraperitoneal injection of 5-fluorouracil (5-FU, 150mg/kg) or saline (control), and this was continued up to the day of sacrifice (48, 72 and 96h post 5-FU administration). Histological (villus height, crypt depth (CD) and disease severity score) and biochemical (myeloperoxidase (MPO) activity) parameters were determined in intestinal tissues collected at sacrifice. Sucrase activity in vivo was quantified by the sucrose breath test. Activated neutrophil activity (MPO) in the ileum was significantly decreased by emu oil (05ml, 451 (sem 168)U/g and 1ml, 503 (sem 213)U/g) compared with 5-FU-treated controls (1724 (sem 431)U/g) 96h post 5-FU administration. There were also significant increases in CD (152 (sem 8)m) in the ileum of rats that receivied 1ml emu oil at 96h compared with 5-FU-treated controls (CD (106 (sem 12)m)). Emu oil did not affect sucrase activity. Emu oil decreased acute ileal inflammation, and improved mucosal architecture in the intestine during recovery from chemotherapy in rats. Further studies investigating the potential benefits of emu oil as a nutritional supplement for the treatment of intestinal disorders are indicated. Copyright © The Authors 2010.


Whittaker A.L.,University of Adelaide | Howarth G.S.,University of Adelaide | Howarth G.S.,Center for Paediatric and Adolescent Gastroenterology
Applied Animal Behaviour Science | Year: 2014

The understanding and recognition of pain in laboratory rats and mice has advanced considerably in recent times. However, there is evidence that despite these advances, analgesics are still relatively underutilised in these species. One possible contributing influence to this is the difficulty in assessing pain reliably and objectively in these prey species. This review presents the current scientific knowledge on behavioural methods of pain assessment in laboratory rats and mice. The focus is on measures of spontaneous behaviour, since these will find greatest utility in clinical pain management.A range of behavioural pain assessment tools are discussed and difficulties in study interpretation are highlighted. Such methods include locomotor activity, pain specific behaviour identification and the novel facial pain recognition methods developed more recently. Practical problems associated with the techniques are discussed and gaps in the scientific knowledge are identified. A substantial body of information on behavioural signs of acute pain has been collected. Developing awareness and attention to this amongst research workers would improve its application to practice. However, use of techniques for objective measurement can be laborious, subject to variability and confounded by experimental procedures. The increased availability of automated behavioural monitoring systems will reduce these concerns, but it still remains imperative that researchers perform behavioural pilot studies to elucidate behaviours of interest specific to their animal model.Few murine studies of behavioural pain assessment have been performed and this is an area that needs further investigation. Additionally, whilst acute post-operative pain scales in rats have been fairly well-characterised, these should be tested in different acute pain models to determine their reproducibility. Few tools for assessment of chronic pain, such as that arising from inflammatory or neoplastic disease, exist in both of the species examined. Pain-specific behavioural identification is the more widely tested method in the face of chronic pain. However, studies to date have yielded few reliable and consistent behaviours indicative of this category of pain. This is an area in which future studies and funding should be directed, given the significant number of laboratory animals that are likely to experience such pain states. Greater collaboration between ethologists and scientists using animal models should be established in order to improve animal welfare and advance scientific knowledge in this area. © 2013 Elsevier B.V.


Cheah K.Y.,University of Adelaide | Bastian S.E.P.,University of Adelaide | Acott T.M.V.,University of Adelaide | Abimosleh S.M.,Center for Paediatric and Adolescent Gastroenterology | And 5 more authors.
Digestive Diseases and Sciences | Year: 2013

Background: Grape seed extract (GSE) constitutes a rich source of procyanidins. GSE has been demonstrated to exert encouraging anti-inflammatory and anti-ulcer properties in experimental settings, although its effects on inflammation of the colon remain undefined. Aim: To determine the effects of GSE in a rat model of dextran sulphate sodium (DSS) for ulcerative colitis. Methods: Male Sprague-Dawley rats were gavaged daily (days 0-10) with GSE (400 mg/kg). Ulcerative colitis was induced by substituting DSS (2 % w/v) for drinking water from days 5-10. A sucrose breath test was performed on day 11 to determine small bowel function and intestinal tissues were collected for histological analyses. Statistical analysis was by one-way or repeated-measures ANOVA and p < 0.05 was considered significant. Results: Compared to DSS-treated controls, GSE significantly decreased ileal villus height (14 %; p < 0.01) and mucosal thickness (13 %; p < 0.01) towards the values of normal controls. GSE reduced qualitative histological severity score (p < 0.05) in the proximal colon, although no significant effect was evident in the distal colon. However, GSE failed to prevent DSS-induced damage to the crypts of both colonic regions. Administration of GSE did not negatively impact metabolic parameters, nor did it induce any deleterious gastrointestinal side effects in healthy animals. Conclusions: GSE decreased the severity of selected markers of DSS-induced colitis in the distal ileum and proximal colon, suggesting the potential as an adjuvant therapy for the treatment of ulcerative colitis. Future studies of GSE should investigate alternative delivery methods and treatment regimens, further seeking to identify the individual bioactive factors. © 2012 Springer Science+Business Media New York.

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