Ingvar Bjarnason

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

BACKGROUND It 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. METHODS A systematic search was made through Medline and Embase to identify possible adverse effects of NSAIDs on the large and small intestine. RESULTS Ingested 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. CONCLUSIONS The adverse effects of NSAIDs distal to the duodenum represent a range of pathologies that may be asymptomatic, but some are life threatening.

A simple method for assessing intestinal inflammation in Crohn's disease

BACKGROUND AND AIMS Assessing the presence and degree of intestinal inflammation objectively, simply, and reliably is a significant problem in gastroenterology. We assessed faecal excretion of calprotectin, a stable neutrophil specific marker, as an index of intestinal inflammation and its potential use as a screening test to discriminate between patients with Crohns disease and those with irritable bowel syndrome. METHODS The validity of faecal calprotectin as a marker of intestinal inflammation was assessed in 22 patients with Crohns disease (35 studies) by comparing faecal excretions and concentrations using four day faecal excretion of111indium white cells. A cross sectional study assessed the sensitivity of faecal calprotectin concentration for the detection of established Crohns disease (n=116). A prospective study assessed the value of faecal calprotectin in discriminating between patients with Crohns disease and irritable bowel syndrome in 220 patients referred to a gastroenterology clinic. RESULTS Four day faecal excretion of 111indium (median 8.7%; 95% confidence interval (CI) 7–17%; normal <1.0%) correlated significantly (p<0.0001) with daily (median ranged from 39 to 47 mg; normal <3 mg; r=0.76–0.82) and four day faecal calprotectin excretion (median 101 mg; 95% CI 45–168 mg; normal <11 mg; r=0.80) and single stool calprotectin concentrations (median 118 mg/l; 95% CI 36–175 mg/l; normal <10 mg/l; r=0.70) in patients with Crohns disease. The cross sectional study showed a sensitivity of 96% for calprotectin in discriminating between normal subjects (2 mg/l; 95% CI 2–3 mg/l) and those with Crohns disease (91 mg/l; 95% CI 59–105 mg/l). With a cut off point of 30 mg/l faecal calprotectin has 100% sensitivity and 97% specificity in discriminating between active Crohns disease and irritable bowel syndrome. CONCLUSION The calprotectin method may be a useful adjuvant for discriminating between patients with Crohns disease and irritable bowel syndrome.

Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria.

In contrast with normal subjects where IgA is the main immunoglobulin in the intestine, patients with active inflammatory bowel disease (IBD) produce high concentrations of IgG from intestinal lymphocytes, but the antigens at which these antibodies are directed are unknown. To investigate the specificities of these antibodies mucosal immunoglobulins were isolated from washings taken at endoscopy from 21 control patients with irritable bowel syndrome, 10 control patients with intestinal inflammation due to infection or ischaemia, and 51 patients with IBD: 24 Crohns disease (CD, 15 active, nine quiescent), 27 ulcerative colitis (UC, 20 active, seven inactive). Total mucosal IgG was much higher (p < 0.001) in active UC (median 512 micrograms/ml) and active CD (256 micrograms/ml) than in irritable bowel syndrome controls (1.43 micrograms/ml), but not significantly different from controls with non-IBD intestinal inflammation (224 micrograms/ml). Mucosal IgG bound to proteins of a range of non-pathogenic commensal faecal bacteria in active CD; this was higher than in UC (p < 0.01); and both were significantly greater than controls with non-IBD intestinal inflammation (CD p < 0.001, UC p < 0.01) or IBS (p < 0.001 CD and UC). This mucosal IgG binding was shown on western blots and by enzyme linked immunosorbent assay (ELISA) to be principally directed against the bacterial cytoplasmic rather than the membrane proteins. Total mucosal IgA concentrations did not differ between IBD and controls, but the IgA titres against faecal bacteria were lower in UC than controls (p < 0.01). These experiments show that there is an exaggerated mucosal immune response particularly in active CD but also in UC directed against cytoplasmic proteins of bacteria within the intestinal lumen; this implies that in relapse of IBD there is a breakdown of tolerance to the normal commensal flora of the gut.

Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID induced injury to the rat intestine

Background—The “topical” effect of non-steroidal anti-inflammatory drugs (NSAIDs) seems to be an important cause of NSAID induced gastrointestinal damage. Aim—To examine the possible mechanism of the “topical” phase of damage in the small intestine. Methods—Electron microscopy and subcellular organelle marker enzyme studies were done in rat small intestine after oral administration of indomethacin (doses varied between 5 and 30 mg/kg). The effect of conventional and non-acidic NSAIDs on rat liver mitochondrial respiration was measured in vitro in a Clarke-type oxygen electrode. Results—The subcellular organelle marker enzymes showed mitochondrial and brush border involvement within an hour of indomethacin administration. Electron microscopy showed dose dependent mitochondrial changes following indomethacin administration consistent with uncoupling of oxidative phosphorylation (or inhibition of electron transport) which were indistinguishable from those seen with the uncoupler dinitrophenol. Parenteral indomethacin caused similar changes, but not in rats with ligated bile ducts. A range of NSAIDs, but not paracetamol or non-acidic NSAIDs which have a favourable gastrointestinal tolerability profile, uncoupled oxidative phosphorylation in vitro at micromolar concentrations and inhibited respiration at higher concentrations. In vivo studies with nabumetone and aspirin further suggested that uncoupling or inhibition of electron transport underlies the “topical” phase of NSAID induced damage. Conclusion—Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important component of the “topical” phase of damage induction.

INTESTINAL PERMEABILITY AND INFLAMMATION IN RHEUMATOID ARTHRITIS: EFFECTS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

The suggestion that the intestinal mucosa may be abnormally permeable and a site of absorption of antigens in rheumatoid arthritis was tested by the use of a 51Cr-EDTA (edetic acid) absorption test. 24 patients with rheumatoid arthritis excreted significantly more 51Cr-EDTA than did 34 controls. Intestinal permeability was normal in untreated patients but almost invariably abnormal in patients treated with non-steroidal anti-inflammatory drugs. Studies in patients with osteoarthritis showed that the permeability abnormalities were due to an effect of NSAIDs on both the proximal and the distal intestine and that the effect was systemically mediated. Indium-111-labelled leucocyte scans showed ileocaecal inflammation in 6 of 9 patients on or recently on NSAIDs. Although increased intestinal permeability does not seem to be important in the pathogenesis of rheumatoid arthritis, the administration of NSAIDs may lead to loss of intestinal integrity, thus facilitating antigenic absorption and perhaps contributing to persistence of the disease.

High prevalence of NSAID enteropathy as shown by a simple faecal test

BACKGROUND The diagnosis of non-steroidal anti-inflammatory drug (NSAID) induced enteropathy is difficult, requiring enteroscopy or the use of four day faecal excretion of 111In labelled white cells. AIMS To assess faecal calprotectin (a non-degraded neutrophil cytosolic protein) as a method for diagnosing NSAID enteropathy. METHODS Single stool faecal calprotectin concentrations were compared with the four day faecal excretion of 111In labelled white cells in 47 patients taking NSAIDs. The prevalence and severity of NSAID enteropathy was assessed using this method in 312 patients (192 with rheumatoid arthritis, 65 with osteoarthritis, 55 with other conditions) taking 18 different NSAIDs. RESULTS The four day faecal excretion of 111In white cells correlated significantly with faecal calprotectin concentrations. In the group of 312 patients on NSAIDs faecal calprotectin concentrations were significantly higher than in controls, the prevalence of NSAID enteropathy being 44%. The prevalence and severity of NSAID enteropathy was independent of the particular type or dose of NSAID being taken or other patient variables. CONCLUSIONS Assay of faecal calprotectin provides a simple practical method for diagnosing NSAID enteropathy in man. Forty four per cent of patients receiving these drugs had NSAID induced enteropathy when assessed by this technique; 20% of these had comparable levels of inflammation to that previously reported in patients with inflammatory bowel disease.

Adacolumn, an adsorptive carrier based granulocyte and monocyte apheresis device for the treatment of inflammatory and refractory diseases associated with leukocytes

Abstract:  Apheresis has been recognized both economically and therapeuticallyas a novel approach for the treatment of inflammatory diseases,and certain others, which respond poorly to drug therapy. This reportis about Adacolumn, an adsorptive carrier based granulocyteand monocyte apheresis device with a volume of 335 mL,filled with about 220 g of cellulose acetate beads of 2 mmdiameter as the column adsorptive carriers. Pre‐ and post‐columnleukocyte counts have shown that the carriers adsorb about 65% ofgranulocytes, 55% of monocytes and 2% of lymphocytesfrom the blood in the column. Additionally, after apheresis, thereis a marked decrease in inflammatory cytokines (TNF‐α,IL‐1β, IL‐6 and IL‐8) produced by blood leukocytes,together with down‐modulation of l‐selectinand the chemokine receptor CXCR3. Adacolumn has been used to treatpatients with rheumatoid arthritis, ulcerative colitis and HIV infection. Typicalapheresis sessions have been 4–10, at a frequency of oneor two sessions per week. Treatment of patients with Adacolumn hasbeen associated with very promising efficacy and safety data. Accordingly,in Japan, Adacolumn has been approved by the Ministry of Healthfor the treatment of ulcerative colitis. Furthermore, Adacolumnmet the required quality and safety standards for medical devices andreceived an EC certification (CE‐mark) from TUV in 1999. However,although Adacolumn carriers are very efficient in depleting excessand activated granulocytes and monocytes/macrophages, theclinical efficacy associated with Adacolumn apheresis cannot befully explained on the basis of reducing granulocytes and monocytesper se. Hence, a long lasting effect on inflammatory cytokine generation,chemokine activities or immunomodulation is likely, but the precisemechanisms involved are not fully understood yet.

Effect of non-steroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine.

Intestinal permeability was estimated in healthy subjects after ingestion of aspirin (1.2+1.2 g), ibuprofen (400+400 mg) and indomethacin (75+50 mg) at midnight and an hour before starting a 51chromium labelled ethylenediaminetetraacetate absorption test. Intestinal permeability increased significantly from control levels following each drug and the effect was related to drug potency to inhibit cyclooxygenase. Intestinal permeability increased to a similar extent after oral and rectal administration of indomethacin showing that the effect is systemically mediated. Prostaglandin E2 decreased intestinal permeability significantly but failed to prevent the indomethacin induced increased intestinal permeability. These studies show that non-steroidal anti-inflammatory drugs disrupt the intestinal barrier function in man and suggest that the morphological correlates of the damage may reside at the level of the intercellular junctions.

Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat

The pathogenesis of NSAID‐induced gastrointestinal damage is believed to involve a nonprostaglandin dependent effect as well as prostaglandin dependent effects. One suggestion is that the nonprostaglandin mechanism involves uncoupling of mitochondrial oxidative phosphorylation.