Andrew Macpherson

Intestinal permeability: An overview

The noninvasive assessment of intestinal permeability in humans has a 20-year history. Because the tests are increasingly used in clinical practice and research and because there is much controversy, we reviewed the literature and outlined the potential and possible shortcomings of these procedures. Data was obtained from personal files and from a systemic search through MEDLINE and EMBASE. The principle of the differential urinary excretion of orally administered test markers is explained with reference to the desired physicochemical properties of the markers and how the principle can be exploited to allow assessment of various other gastrointestinal functions. The use of intestinal permeability tests for diagnostic screen for small bowel disease and assessment of responses to treatment, the pathogenesis of disease, normal intestinal physiology, and the effect of drugs and toxins on the intestine is described and reviewed. The controversy surrounding the anatomic location of the permeation pathways that the markers use is highlighted. Noninvasive tests of intestinal permeability have fulfilled early promises of usefulness in clinical practice and research. There is now a need for integrated research into the basic mechanisms of regulatory control of the intestinal barrier function.

Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans

BACKGROUNDnIt is not widely appreciated that nonsteroidal anti-inflammatory drugs (NSAIDs) may cause damage distal to the duodenum. We reviewed the adverse effects of NSAIDs on the large and small intestine, the clinical implications and pathogenesis.nnnMETHODSnA systematic search was made through Medline and Embase to identify possible adverse effects of NSAIDs on the large and small intestine.nnnRESULTSnIngested NSAIDs may cause a nonspecific colitis (in particular, fenemates), and many patients with collagenous colitis are taking NSAIDs. Large intestinal ulcers, bleeding, and perforation are occasionally due to NSAIDs. NSAIDs may cause relapse of classic inflammatory bowel disease and contribute to serious complications of diverticular disease (fistula and perforation). NSAIDs may occasionally cause small intestinal perforation, ulcers, and strictures requiring surgery. NSAIDs, however, frequently cause small intestinal inflammation, and the associated complications of blood loss and protein loss may lead to difficult management problems. The pathogenesis of NSAID enteropathy is a multistage process involving specific biochemical and subcellular organelle damage followed by a relatively nonspecific tissue reaction. The various possible treatments of NSAID-induced enteropathy (sulphasalazine, misoprostol, metronidazole) have yet to undergo rigorous trials.nnnCONCLUSIONSnThe adverse effects of NSAIDs distal to the duodenum represent a range of pathologies that may be asymptomatic, but some are life threatening.

In siblings with similar genetic susceptibility for inflammatory bowel disease, smokers tend to develop Crohn's disease and non-smokers develop ulcerative colitis

Background and aims: Smoking tobacco has opposite effects on the different forms of inflammatory bowel disease (IBD). It predisposes to the development of Crohns disease (CD) yet is associated with a reduced incidence of ulcerative colitis (UC). We have studied sib pairs discordant for both smoking and IBD phenotype (UC or CD) to investigate whether smoking determines the type of IBD that develops in individuals with very similar genetic susceptibility. Patients: Smoking habits and disease characteristics were analysed in 242 IBD pedigrees (658 patients). Within this group there were 339 affected sibling pairs of whom 89 were discordant for smoking when diagnosed. Results: Smoking at diagnosis was associated with development of CD (odds ratio (OR) 3.55; 95% confidence limits 2.50–5.02; p<0.001) in all of the familial patients, with increases when analysed for ileocaecal disease, fibrostenosis, and intestinal resection. Smokers were also protected from UC (OR 0.28; 0.2–0.4; p<0.001). Of 89 sibling pairs discordant for smoking at diagnosis, 23 were also discordant for disease type—in 21 of these, CD occurred in the smoker and UC in the non-smoker (OR 10.5; 2.6–92; p<0.0001). Conclusions: Smoking is a strong environmental risk factor for Crohns disease and increases the likelihood of needing surgery. However, sib pairs who are discordant for both smoking and IBD type almost always show CD in the smoker and UC in the non-smoker, and so in some cases tobacco consumption acts on IBD genetic predisposition to shift the phenotype from UC towards CD. The explanation of part of the apparent “protective” effect of smoking on sporadic UC may be that the form of IBD that develops in a proportion of smokers is not UC but CD.

The effect of intestinal hypoperfusion on intestinal absorption and permeability during cardiopulmonary bypass

BACKGROUND/AIMSnMean arterial pressure is reduced during hypothermic cardiopulmonary bypass. The aim of this study was to assess whether this was associated with intestinal hypoperfusion and whether it affected intestinal absorption and permeability.nnnMETHODSnTwenty-six patients undergoing coronary artery bypass grafting underwent an intestinal absorption-permeability test involving ingestion of 3-O-methyl-D-glucose, D-xylose, L-rhamnose, and lactulose. Ingestion took place 2 days before, within 3 hours, and 5 days after hypothermic cardiopulmonary bypass. Hemodynamic parameters and gastric mucosal laser Doppler blood flow were measured perioperatively in eight patients.nnnRESULTSnHypothermic (28 degrees C), nonpulsatile cardiopulmonary bypass resulted in a 25% reduction in mean blood pressure, 10% reduction in cardiac index, and a 46% reduction in gastric mucosal laser Doppler blood flow. There was 85.4%, 85.5%, and 73.6% reduction (P < 0.01) in active (3-O-methyl-D-glucose) and passive (D-xylose) carrier-mediated transport and passive, nonmediated transcellular (L-rhamnose) transport in the immediate postoperative period, respectively. The differential urine excretion of lactulose/L-rhamnose increased sixfold. All parameters returned to control levels by the fifth postoperative day.nnnCONCLUSIONSnCardiopulmonary bypass, while maintaining generally acceptable levels of hemodynamic performance, is associated with significant intestinal hypoperfusion and malabsorption of monosaccharides, which may have implications for enteral drug treatment in the immediate postoperative period.

Intestinal toxicity of non-steroidal anti-inflammatory drugs

We review the adverse effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the small and large intestine. NSAIDs cause small intestinal inflammation in 65% of patients receiving the drugs long-term. The clinical implications of NSAID-induced enteropathy are that patients bleed and lose protein from the inflammatory site, contributing to iron deficiency and hypoalbuminemia, respectively. Some patients develop intestinal strictures, which may require surgery, and the occasional one may develop discrete ulcers with perforations. There are a number of therapeutic options available to treat the enteropathy and the attendant complications, including antibiotics, sulphasalazine and misoprostol. The colon, by comparison, is only rarely affected by NSAIDs, but colitis is well recognized and NSAIDs may be an important factor in diverticular complications and the relapse of inflammatory bowel disease. There is an association between NSAID intake and appendicitis in the elderly.

Ethanol-induced smooth and skeletal muscle myopathy: use of animal studies

This article reviews the effects of ethanol on skeletal and smooth muscle. A brief summary of its clinical effects is provided, with a rationale for the use of suitable animal models to study ethanol-induced myotoxicity. Practical details are given for the animal feeding techniques to examine the chronic effects of ethanol toxicity. Information on acute ethanol dosage experiments are also provided. Our results have indicated that ethanol causes net loss of both skeletal and smooth muscle protein and an effect on protein synthesis and/or degradation was implicated. The theoretical and practical basis of measuring protein synthesis in intact laboratory animals is reviewed. However, there are no reliable methods for measuring rates of protein breakdown in vivo. The combined results of our studies indicated that disturbances in protein synthesis were causal mechanisms for ethanol-induced myo-dysfunction. Acute ethanol exposure was largely characterised by reductions in fractional rates of skeletal and smooth muscle contractile protein synthesis. The dominant characteristics of chronic treatments were loss of skeletal and smooth muscle proteins and RNA. Further laboratory animal studies will eventually elucidate the molecular mechanisms of these changes and provide valuable information on the regulation of protein mass.

Pouch permeability: breaching barriers to understanding pouchitis?

Background-Villous atrophy, mucin changes (colonic metaplasia), and chronic inflammation occur to varying degrees in all patients with ileal pouchanal anastomosis whereas acute inflammation (pouchitis) affects a subgroup of patients with prior ulcerative colitis. Aim-To measure epithelial barrier function looking for possible functional adaptation in ileal pouch mucosa. Patients-Patients with an ileal pouch prior to ileostomy closure (n=12), functioning pouch (n=14), pouchitis (n=8), and ulcerative colitis (n=12) were assessed. Methods- 51 Cr-EDTA was administered into the pouch or rectum and urinary recovery over 24 hours was taken as an indication of permeability (barrier function). Histological analysis of pouch biopsy specimens was undertaken. Results-Mucosal permeability is decreased from median 9.4% (range 5.4% to 39.1%) to 1.4% (range 0.38% to 2.2%) after ileostomy closure (p<0.002) with levels being negatively correlated with two histological parameters of colonic metaplasia - mucin changes (p=0.03) and villous atrophy (p=0.05). Pouchitis was associated with increased permeability 5.9% (1.9% to 19.5%) compared with healthy pouch 1.4% (0.35 to 2.2%) (p<0.006). Conclusion-Despite the presence of chronic inflammation in the mature pouch functional adaptation with reduced permeability occurs in conjunction with colonic metaplasia.

Biochemical and Genetic Studies in ALDH1-Deficient Subjects

At least nine isoenzymes of aldehyde dehydrogenase (E.C.1.2.1.3.) have been identified in man based on their enzymatic characteristics and physiochemical properties (Yoshida et al., 1990). Liver mitochondrial aldehyde dehydrogenase (ALDH2) probably plays a major role in acetaldehyde metabolism as its low km (1–2μM) is compatible with the circulating acetaldehyde levels after alcohol ingestion in both normal subjects and alcohol abusers (Arthur et al.,1984: Schumate et al., 1967; Kelding et al., 1983; Mezey and Tubon, 1971; Peters et al.,1987). The ALDH2 gene is 44 kbp in length and contains at least 12 exons which encode 517 amino acid residues (Hsu et al., 1988). These precisely match the reported protein sequence of ALDH2 (Hempel et al., 1985). A point mutation (C→A) leads to the formation of an enzymatically inactive subunit in exon 12 of the genetic sequence (Yoshida et al., 1984). This occurs in over 50% of Orientals (Goedde et al., 1979) and such individuals suffer an alcohol-flush reaction after ingestion of small amounts of ethanol. This is attributable to high circulating acetaldehyde concentrations (in excess of 15 µmol) and causes clinical symptoms such as increase in blood pressure and pulse rate (Wolffe, 1973).