David B. Silk

The effect of tacrolimus (FK506) on intestinal barrier function and cellular energy production in humans

BACKGROUND & AIMS The maintenance of the intestinal mucosal barrier may be energy dependent. Tacrolimus is a potent immunosuppressive drug that decreases mitochondrial adenosine triphosphate production and increases intestinal permeability in animals. METHODS Twelve liver graft recipients receiving tacrolimus, 9 healthy volunteers, and 5 liver graft recipients not receiving immunosuppression underwent a combined absorption-permeability-mitochondrial function test using 5 g lactulose, 1 g L-rhamnose, 0.5 g D-xylose, 0.2 g 3-O-methyl-D-glucose, 1 mg/kg 2-keto[1-13C]isocaproic acid ([13C]KICA), and 20 mg/kg L-leucine. The respiratory quotient and resting energy expenditure were measured by indirect calorimetry. Tacrolimus pharmacokinetic profiles and levels of endotoxin and IgM and IgG endotoxin core antibodies were determined. RESULTS Tacrolimus inhibited the decarboxylation of [13C]KICA, the resting energy expenditure, and the respiratory quotient in an exposure-dependent manner, suggesting an inhibition of mitochondrial respiration. Tacrolimus inhibited intestinal absorptive capacity in an exposure-dependent manner. Tacrolimus-treated patients had an increased intestinal permeability and significantly higher endotoxin levels compared with healthy volunteers. CONCLUSIONS Tacrolimus inhibits cellular energy production in humans at clinically relevant doses. This is associated with an increased intestinal permeability, endotoxemia, and an impaired intestinal absorptive capacity.

Systematic review and meta-analysis: the clinical and physiological effects of fibre-containing enteral formulae

Background  Enteral nutrition can be associated with gastrointestinal side effects and fibre supplementation has been proposed as a means to normalize bowel function.

Effect of peptide chain length on absorption of egg protein hydrolysates in the normal human jejunum

The influence of the peptide chain length of partial enzymic hydrolysates of protein on nitrogen and amino acid absorption was studied in 12 subjects using a jejunal perfusion technique. Three hydrolysates of egg white and an equivalent amino acid mixture were perfused at 30 mmol/L and 100 mmol/L in two separate experiments. Two hydrolysates (OH1 and OH2) contained mainly dipeptides and tripeptides, whereas the third (OH3) comprised tripeptide to pentapeptides as judged chromatographically. Nitrogen absorption was significantly slower from the higher chain length mixture, OH3, than from the short chain mixtures, OH1 and OH2, at both concentrations. Similarly, several amino acid residues were absorbed less well from OH3 than from OH1 and OH2. These data demonstrate that the chain length of heterogeneous mixtures of peptides affects absorption of nitrogen and individual amino acid residues, and suggest that brush border hydrolysis of tetrapeptides and pentapeptides limits absorption from enzymic hydrolysates of protein which simulate the composition of the postprandial luminal contents.

Assessment of an Automated Chemiluminescence Nitrogen Analyzer for Routine Use in Clinical Nutrition

An automated method of chemiluminescence analysis of nitrogen used routinely for 4 yr. Liquid samples (urine, enteral, and parenteral feeds) required simple dilution, whereas feces required a modified acid-digestion procedure, before analysis. For urine samples, the coefficient of variation was within batch from 0.9-3.6%, and between batch 4.3-7.6%. At a sample injection rate of 2 microliter/sec, the useful dynamic range, for urine diluted 1:200, was 0-14 g N/liter. Precision for fecal nitrogen analysis was 3.8-6.7% for samples of low to high nitrogen content. The correlation between this technique and an established Kjeldahl method for fecal analysis was studied (r = 0.96, slope = 1.30). The discrepancy between the methods was due to inefficient conversion of nitrogen to NH4+ during Kjeldahl digestion of feces, rather than systematic errors in chemiluminescence analysis. Reliability was as good as for other automated clinical analyzers and sample cost was ca. 0.22 pounds. It has proved possible to analyze approximately 80 samples in the working day. The efficiency of measuring 24-hr urine urea-nitrogen (UUN) and total urine nitrogen (TUN) in patients on general wards was measured. Results were obtained on 87% of TPN days, but large variations were noted in UUN/TUN from less than 30% to greater than 90% (average 75.7%) in patients receiving TPN, and from less than 55% to 100% (average 83.8%) in patients receiving enteral nutrition. In contrast, UUN/TUN was 87.0% and 84.0% in healthy subjects, fasted or receiving iv nutrition, respectively. We therefore expect that clinical nutritionists will find increasing applications for this method of nitrogen analysis.

Spontaneous transpyloric passage and performance of 'fine bore' polyurethane feeding tubes: a controlled clinical trial.

Certain groups of patients requiring enteral nutritional support are at increased risk of regurgitation and pulmonary aspiration of feed. Positioning of enteral feeding tubes distal to the pylorus has been advocated as a method of reducing such complications. Various techniques have been suggested to achieve postpyloric siting. Reports have indicated that lengthening the tube or altering the distal end tip configuration, by varying the tip profile or by the addition of a weight, may facilitate spontaneous transpyloric passage of the tube. This prospective controlled clinical study using three new polyurethane tubes demonstrates that the frequency of spontaneous transpyloric passage of the tube is not affected by tip profile or by the addition of a weight. Indeed, with all three tube designs only about one-third had passed spontaneously through the pylorus at 24 hr. Once through the pylorus the unweighted tube stayed in position significantly longer than the weighted tubes (p less than 0.005). We suggest that in those patients requiring post-pyloric feeding, endoscopic or fluoroscopic techniques should be used to position the tubes at the time of insertion, and that an unweighted tube should be used to prolong tube usage.

Lactitol, a new hydrogenated lactose derivative: intestinal absorption and laxative threshold in normal human subjects

In the first part of the study, the absorption of lactitol, a new disaccharide analogue of lactose, was studied using an in vivo jejunal perfusion technique in man. Intestinal uptake of lactitol from isotonic solutions containing 10, 30, 60, and 100 mmol lactitol/l was insignificant. In the second part of the study the laxative threshold of lactitol was determined and compared with that of sorbitol in a double-blind, randomized, cross-over study on twenty-one normal subjects. Laxative threshold was considered to be either the maximum dose tolerated without unacceptable diarrhoea or gastrointestinal side effects, or when the maximum dose in the study was reached. Increasing amounts of lactitol, sorbitol or placebo were administered in two divided doses each day until subjects developed diarrhoea or severe gastrointestinal side effects. The laxative threshold of lactitol (74 (SE 5) g/d) was similar to that of sorbitol (71 (SE 5) g/d). These findings indicate that lactitol is not absorbed by the human small intestine. Although diarrhoea or other gastrointestinal side effects occurred as the dose was increased, 40 g lactitol/d was well tolerated.

Peptides in human nutrition

CONCLUSIONS AND PERSPECTIVES . A P P L I C A T I O N OF P E P T I D E S TO I N T R A V E N O U S N U T R I T I O N . EVIDENCE FOR ENDOGENOUS HYDROLYSIS OF CIRCULATING PEPTIDES . TRANSLOCATION OF PEPTIDES ACROSS THE GASTROINTESTINAL BARRIER 88 88 88 88 89 89 89 90 90 91 92 92 92 92 93 93 93 THE ROLE O F THE KIDNEY IN DISPOSAL O F CIRCULATING PEPTIDES . INFUSION STUDIES W I T H SYNTHETIC DIPEPTIDES . LARGE-SCALE USE OF INTRAVENOUS PROTEIN HYDROLYSATES . Comparison with free amino acids. Peptiduria .

Global metabolic phenotyping in an experimental laparotomy model of surgical trauma.

Surgical trauma initiates a complex series of metabolic host responses designed to maintain homeostasis and ensure survival. (1)H NMR spectroscopy was applied to intraoperative urine and plasma samples as part of a strategy to analyze the metabolic response of Wistar rats to a laparotomy model. Spectral data were analyzed by multivariate statistical analysis. Principal component analysis (PCA) confirmed that surgical injury is responsible for the majority of the metabolic variability demonstrated between animals (R² Urine = 81.2% R² plasma = 80%). Further statistical analysis by orthogonal projection to latent structure discriminant analysis (OPLS-DA) allowed the identification of novel urinary metabolic markers of surgical trauma. Urinary levels of taurine, glucose, urea, creatine, allantoin, and trimethylamine-N-oxide (TMAO) were significantly increased after surgery whereas citrate and 2-oxoglutarate (2-OG) negatively correlated with the intraoperative state as did plasma levels of betaine and tyrosine. Plasma levels of lipoproteins such as VLDL and LDL also rose with the duration of surgery. Moreover, the microbial cometabolites 3-hydroxyphenylpropionate, phenylacetylglycine, and hippurate correlated with the surgical insult, indicating that the gut microbiota are highly sensitive to the global homeostatic state of the host. Metabonomic profiling provides a global overview of surgical trauma that has the potential to provide novel biomarkers for personalized surgical optimization and outcome prediction.

Impact of irritable bowel syndrome on personal relationships and working practices.

Objective To determine the impact of irritable bowel syndrome on personal relationships and working practices. Patients and methods A 60-item questionnaire about personal relationships, working practices and treatment was sent to 3090 subscribers of the IBS Bulletin, a quarterly educational publication. A total of 1855 completed questionnaires were returned. Analysis was restricted to 1597 questionnaires (86.1%), returned by respondents in whom the diagnosis of irritable bowel syndrome had been made by a general practitioner or hospital specialist. Results Of these respondents, 57% were aged 55 or over and the male to female ratio was 1:3.4. On average, respondents had suffered from irritable bowel syndrome for 16.6 years, with 57% reporting their symptoms daily, 25% weekly and 14% monthly. Of the married or cohabiting respondents, 19% stated that their partner experienced difficulties in having a personal relationship with them and 45% stated that irritable bowel syndrome interfered with their sex life. Irritable bowel syndrome had caused 12% of respondents to give up work altogether, while 47% of employed respondents reported having lost time off work, although only 35% of these respondents gave irritable bowel syndrome as the reason. In contrast employers, when informed of the diagnosis of irritable bowel syndrome, accepted these symptoms as a valid reason for absence in 61% of instances. Over half of those employed (53%) suffered embarrassment using toilets at work and 32% stated that irritable bowel syndrome had stopped them from applying for promotion or a new job. At the time of completing the questionnaire, 80% of respondents were actually taking some form of treatment. Smooth-muscle relaxants and fibre supplements remained the commonest treatments prescribed. Conclusion Irritable bowel syndrome impacts significantly on personal relationships and working practices. Items that stimulate responsiveness in the areas of personal relationships and working practices should be included in the construction of disease-specific questionnaires used to assess the impact of new treatments for irritable bowel syndrome on health-related quality of life.

Retrograde (ascending) bacterial contamination of enteral diet administration systems

A prospective clinical study in three phases was performed to determine whether it was possible that enteral diet containers could become contaminated as a result of endogenous organisms ascending retrogradely from the enteral feeding tube via the giving set, and if this did occur whether the incidence could be altered by modifying enteral delivery systems. Each phase observed patients on enteral feeding over a 48-hour study period (phase I, n = 18; phase II, n = 17; phase III, n = 18). Each patient was prescribed an enteral diet of 2 L/24 h administered by continuous pump infusion from a closed 1-L sterile diet container. Four containers were used for each patient, and one giving set was used in the 48-hour period. Diet samples were taken at 12-hour intervals: two from the giving set before and after flushing with residual diet, and one from the diet container. Phases differed only in the design of the giving set: phase I had no drip chamber, phase II had a drip chamber, phase III had a drip chamber and an anti-reflux ball valve at the distal end. Both phase I and III had greater numbers of giving set samples colonized at 24, 36, and 48 hours. In phase I, 3 of 14 sterile diet containers were colonized with greater than 10(4) colony-forming organisms/mL of diet at 48 hours. Only phase II had no organisms contaminating the containers at 48 hours. We conclude that the retrograde spread of organisms from patient to sterile diet container does occur in clinical practice, and that a drip chamber in the giving set may prevent the problem.(ABSTRACT TRUNCATED AT 250 WORDS)