Ross N Butler

Introduction: Delayed gastric emptying occurs frequently in critically ill patients and has the potential to adversely affect both the rate, and extent, of nutrient absorption. However, there is limited information about nutrient absorption in the critically ill, and the relationship between gastric emptying (GE) and absorption has hitherto not been evaluated. The aim of this study was to quantify glucose absorption and the relationships between GE, glucose absorption and glycaemia in critically ill patients. Methods: Studies were performed in nineteen mechanically-ventilated critically ill patients and compared to nineteen healthy subjects. Following 4 hours fasting, 100 ml of Ensure, 2 g 3-O-methyl glucose (3-OMG) and ^99mTc sulphur colloid were infused into the stomach over 5 minutes. Glucose absorption (plasma 3-OMG), blood glucose levels and GE (scintigraphy) were measured over four hours. Data are mean ± SEM. A P-value < 0.05 was considered significant. Results: Absorption of 3-OMG was markedly reduced in patients (AUC₂₄₀: 26.2 ± 18.4 vs. 66.6 ± 16.8; P < 0.001; peak: 0.17 ± 0.12 vs. 0.37 ± 0.098 mMol/l; P < 0.001; time to peak; 151 ± 84 vs. 89 ± 33 minutes; P = 0.007); and both the baseline (8.0 ± 2.1 vs. 5.6 ± 0.23 mMol/l; P < 0.001) and peak (10.0 ± 2.2 vs. 7.7 ± 0.2 mMol/l; P < 0.001) blood glucose levels were higher in patients; compared to healthy subjects. In patients; 3-OMG absorption was directly related to GE (AUC₂₄₀; r = -0.77 to -0.87; P < 0.001; peak concentrations; r = -0.75 to -0.81; P = 0.001; time to peak; r = 0.89-0.94; P < 0.001); but when GE was normal (percent retention₂₄₀ < 10%; n = 9) absorption was still impaired. GE was inversely related to baseline blood glucose, such that elevated levels were associated with slower GE (ret 60, 180 and 240 minutes: r > 0.51; P < 0.05). Conclusions: In critically ill patients; (i) the rate and extent of glucose absorption are markedly reduced; (ii) GE is a major determinant of the rate of absorption, but does not fully account for the extent of impaired absorption; (iii) blood glucose concentration could be one of a number of factors affecting GE.

Newer biological agents that are designed to have multiple effects on a host require better ways to determine both their safety and toxicity. Indeed ecologically potent factors such as agents that can alter the gut milieu and change host responses are now being realized as a viable alternative to more focused pharmaceuticals. Even in the pharmaceutical arena there is a growing awareness of the preventative and therapeutic potential of alternative agents. Probiotics and prebiotics amongst other agents fall into this category and can have both direct and indirect effects on the pathogenesis and progress of disease. This review details some of the new approaches using non-invasive tests to enable firstly a better definition of a stressed through to a damaged gastrointestinal mucosa. They constitute ways to apply dynamic function testing in animal models and humans to provide reference points to which other measurements can be related e.g. altered circulating cytokines, altered gene expression. As such this phenotypic scaffold, alone and combined with newer molecular parameters, will improve our understanding of the interaction of luminal factors within the alimentary tract and the impact that these have on physiologically challenged mucosa and in disease both at the gastrointestinal level and also in remote organs. Practically, the dynamic function tests, primarily breath tests, can now be used as diagnostic and prognostic indicators of the efficacy of new biologics such as probiotics and prebiotics that in part elicit their effects by altering the ecology of particular regions of the intestine.

Small intestinal permeability was employed to assess the efficacy of commercially available yoghurts containing probiotics in a rat model of methotrexate (MTX)-induced mucositis. Male Sprague-Dawley rats were allocated to four groups (n = 8): MTX + water, MTX + cow’s milk yoghurt (CY; fermented with Lactobacillus johnsonii), MTX + sheep’s milk yoghurt (SY; containing Lactobacillus bulgaricus and Streptococcus thermophilus), and saline. Treatment gavage occurred twice daily for 7 days pre-MTX and 5 days post-MTX. Intestinal permeability was assessed on days −7, −1, 2, and 5 of the trial. Intestinal sections were collected at sacrifice for histological and biochemical analyses. Histology revealed that rats receiving CY and SY did not have a significantly damaged duodenum compared to controls. However, an improved small intestinal barrier function was evident, determined by a decreased lactulose/mannitol ratio. Probiotics containing SY and CY may be useful in preventing disruption to intestinal barrier function in MTX-induced mucositis.

The present review is timely owing to the previous paucity of biomarkers, particularly functional noninvasive tests, to evaluate the extent and severity of gastrointestinal toxicity in both animal models of chemotherapy and in cancer patients undergoing chemotherapy. The most recent findings using noninvasive functional biomarkers now allow longitudinal monitoring of the time course of damage and repair that occurs in the gastrointestinal tract following radiotherapy and chemotherapy. This monitoring has in turn enabled collection of objective evidence for efficacy of new antimucositis agents using animal models and, more importantly, for use in future randomized, double-blind, placebo-controlled clinical trials. In the past 12 months the C sucrose breath test has been applied to a series of animal models of chemotherapeutic damage, showing rapid monitoring of the efficacy of particular bioactive molecules is now possible at different stages of the damage and repair cycle. This biomarker has also been applied to childhood cancer studies of mucositis and now needs to be used in adult cancers for eventual adoption in routine clinical management of mucositis. An exciting possibility would be extension of the biomarker use to predict damage in other regions of the gastrointestinal tract, including oral mucosa.

Background: Cholecystokinin (CCK) and peptide YY (PYY) are released in response to intestinal nutrients and play an important physiological role in regulation of gastric emptying (GE). Plasma CCK and PYY concentrations are elevated in critically ill patients, particularly in those with a history of feed intolerance. This study aimed to evaluate the relationship between CCK and PYY concentrations and GE in critical illness. Methods: GE of 100 mL of Ensure^® meal (106 kcal, 21% fat) was measured using a ¹³C-octanoate breath test in 39 mechanically ventilated, critically ill patients (24 males; 55.8 ± 2.7 years old). Breath samples for ¹³CO₂ levels were collected over the course of 4 hours, and the GE coefficient (GEC) (normal = 3.2 to 3.8) was calculated. Measurements of plasma CCK, PYY, and glucose concentrations were obtained immediately before and at 60 and 120 minutes after administration of Ensure. Results: GE was delayed in 64% (25/39) of the patients. Baseline plasma CCK (8.5 ± 1.0 versus 6.1 ± 0.4 pmol/L; P = 0.045) and PYY (22.8 ± 2.2 versus 15.6 ± 1.3 pmol/L; P = 0.03) concentrations were higher in patients with delayed GE and were inversely correlated with GEC (CCK: r = -0.33, P = 0.04, and PYY: r = -0.36, P = 0.02). After gastric Ensure, while both plasma CCK (P = 0.03) and PYY (P = 0.02) concentrations were higher in patients with delayed GE, there was a direct relationship between the rise in plasma CCK (r = 0.40, P = 0.01) and PYY (r = 0.42, P < 0.01) from baseline at 60 minutes after the meal and the GEC. Conclusion: In critical illness, there is a complex interaction between plasma CCK, PYY, and GE. Whilst plasma CCK and PYY correlated moderately with impaired GE, the pathogenetic role of these gut hormones in delayed GE requires further evaluation with specific antagonists.

Background: The purpose of the present paper was to assess the reproducibility of the ¹³C‐urea breath test (¹³C‐UBT) and its ability to reflect the level of Helicobacter pylori‐associated inflammation.Methods: Asymptomatic H. pylori‐positive subjects (n = 21) performed the ¹³C‐UBT six times. The H. pylori‐positive symptomatic subjects (n = 55) performed the ¹³C‐UBT and had antral biopsies taken for histopathology, culture, urease activity assay and myeloperoxidase activity assay.Results: No significant intraindividual variation in ¹³C‐UBT results were observed for the asymptomatic subjects. The ¹³C‐UBT results were significantly higher in symptomatic subjects with a moderate to severe gastritis compared to a mild gastritis and to no inflammation (34.5 ± 4.4 vs 17.7 ± 2.8 vs 1.7 ± 0.1, respectively, P < 0.01). The ¹³C‐UBT results significantly correlated with urease (r = 0.55) and myeloperoxidase activity (r = 0.82) but not with bacterial load.Conclusion: The ¹³C‐UBT is a reproducible determinant of H. pylori infection and non‐invasively assesses the severity of antral inflammation.© 2004 Blackwell Publishing Asia Pty Ltd

Evaluates the sucrose breath test, which for the non-invasive assessment of small intestinal mucosal injury following methotrexate administration in rats. Reliability as an indicator of small intestinal sucrase activity following intestinal damage; Accuracy in determining the severity of intestinal damage that manifest in certain conditions

It is often difficult to assess small bowel recovery in adults with coeliac disease on a gluten-free diet (GFD). This prospective study compares changes in intestinal permeability with changes in intestinal biopsy at various intervals after commencing a GFD. Intestinal permeability was measured by lactulose/rhamnose absorption from 1 week to 24 months after commencing a GFD. Intestinal morphometry was measured by villus area, crypt length and mitotic count per crypt at diagnosis and after commencing a GFD. Median intestinal permeability values decreased from 0.47 (n = 35) at diagnosis to 0.25 (n = 17) after 1 week and to 0.16 (n = 18) after 2 months of a GFD. Rhamnose absorption improved significantly at an early stage, from 6.6% (untreated) to 15.4% at 3 months of a GFD, whereas the decrease in lactulose permeation took longer: from 3.4% (untreated) to 0.8% after 12 months of a GFD. Mean villus area (n = 29) was reduced to 16% of control values at diagnosis, and improved to a maximum of 48% after 6 months on a GFD, but did not change thereafter. Mean crypt length and mitotic count per crypt were increased by 222% and 356% respectively at diagnosis, and these parameters remained elevated at 172% and 216% above control values after 6 months of a GFD. We conclude that intestinal permeability improves within 2 months after starting a GFD, but that measurable intestinal biopsy improvement requires ingestion of a GFD for at least 3-6 months, and even then remains incomplete.