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Br J Clin Pharmacol. 2003 Sep; 56(3): 284–291.
PMCID: PMC1884343

Determining small bowel integrity following drug treatment


Intestinal integrity is maintained by a delicate balance between mucosal defence and luminal aggressors that cause damage if exposed to the mucosa. The intestinal barrier function appears to be the gatekeeper for controlling this balance. It is becoming increasingly clear that if the intestinal barrier is disrupted the consequences are low grade intestinal inflammation which carry with it the risk of significant blood and protein loss both of which may cause clinical management problems. We review the strength and weaknesses of methods for assessing small bowel function that are useful for assessing drug-induced intestinal toxicity. There are a number of imaging methods for assessing intestinal integrity but these do not provide functional information. Intestinal permeability measurements have been optimized for specificity and there are now ways of measuring intestinal permeability regionally, but marker analyses continue to be cumbersome. Recent developments of faecal inflammatory markers make it a matter of routine to assess this in any routine chemical pathology laboratory. Bleeding, protein loss and other complications of inflammation can also be measured with good specificity, but again the methods are cumbersome. Using a combination of functional and imaging techniques it is now possible to characterize and define with precision, the small bowel side-effects of drugs, the best example being the small bowel side-effects of nonsteroidal anti-inflammatory drugs (NSAIDs).

Keywords: drugs, intestinal inflammation, intestinal permeability, intestinal toxicity, NSAIDs


The gastro-intestinal tract forms a barrier between its lumen and the contents therein and the systemic circulation. The lumen contains nutrients, bacteria and their degradation products and other toxins. Remarkably the gastro-intestinal mucosa is able to absorb the nutrients whilst preventing luminal antigens and toxins from breaching the mucosa. Numerous drugs have effects on the function of the gastro–intestinal barrier, certain drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects whilst others may have protective effects.

In this paper we have reviewed the current literature with respect to the methods used to assess small bowel integrity, particularly following drug treatment.

Overview of barrier

The gastro–intestinal barrier can be thought of as having two components; the intrinsic barrier is composed of the epithelial cells lining the digestive tube and the intercellular tight junctions. The extrinsic barrier consists of secretions and other factors that while not physically part of the epithelium protects it from the luminal aggressors

Intrinsic barrier

Epithelial cells linked together by tight junctions form the basis of the gastro–intestinal barrier. Maintenance of the integrity of this layer is vital to preserve access of the luminal contents to the systemic circulation. The delicate balance between cell proliferation and cell death ensures continued cellular integrity of the barrier. Transcellular permeation of macromolecules is severely restricted and is largely determined by the composition of the brush border membrane. Unfortunately there are no reliable noninvasive techniques available to assess this function. The tight junctions are the main determinant of gastrointestinal permeability and there are a number of ways to measure this function.

Changes in intestinal permeability may occur in gastrointestinal diseases of various causes including coeliac and Crohn's disease. Drugs, in particular NSAIDs, also have effects on barrier function.

Extrinsic barrier

Numerous other components including mucus, bicarbonate, cytokines, hormones, prostaglandins, peptides and proteins are essential components of the gastro–intestinal barrier. However it is often difficult to deduct the precise role of each of the above in the pathophysiology of intestinal disease in man.

Mucus overlies the epithelial layer. This is produced by cells of the epithelial layer and serves to prevent colonization of the epithelial surface by pathogenic bacteria. It also prevents exposure of the epithelial cells to certain luminal toxins by restricting their diffusion towards the epithelial surface, particularly lipid soluble compounds. Bicarbonate ions within the mucus allow maintenance of a neutral pH on the luminal surface of the gastric mucosa.

Endocrine and paracrine factors have considerable influence on intestinal integrity by their effect on cell proliferation. Prostaglandins, synthesized from arachadonic acid, particularly prostaglandin E2 and prostacyclin additionally stimulate the secretion of mucus and bicarbonate.

Peptides, such as epidermal growth factor (EGF), produced by salivary glands and transforming growth factor alpha (TGFα) also promote epithelial growth and have been shown to promote ulcer healing in experimental models.

Trefoil proteins, secreted by goblet cells, coat the apical surface of the epithelium. They have been shown to promote epithelial integrity and appear to have a central role in the restitution phase of epithelial damage and repair.

Nitric oxide also has an important role in protecting the mucosa from injury, a phenomenon that is being exploited by the use of NO-releasing NSAIDs. A nitric-oxide excess may, however, be detrimental to the intestinal mucosa.

Anti-microbial peptides secreted by Paneth cells have a broad range of activity against a spectrum of intestinal bacteria, yeasts and protozoa.In conjunction with the gastro-intestinal immune system, which is responsible for the production of a layer of immunoglobulin A (IgA), these protect the mucosa from attack by pathogenic bacteria. If drugs affect the integrity of the epithelial layer, these peptides may become important in limiting the number of intestinal bacteria reaching the exposed mucosa.

Effect of drugs on barrier function and integrity

NSAIDs cause the most widely studied of the drug-induced enteropathies. The pathogenesis has been extensively researched and is well described. In man NSAID enteropathy can be diagnosed by measurement of surrogate markers of inflammation in stools [1], indium-111-labelled white cell excretion [24] or faecal calprotectin [1], at fiberoptic or capsule enteroscopy [58] during surgery [9] or postmortem [10].

We briefly outline the pathogenesis of NSAID-induced enteropathy with a special reference to the noninvasive methods for documenting this damage and its pathogenesis.

Prevalence rates for NSAID-enteropathy range from 8 to 65% depending upon which method is used to assess the inflammation. Faecal inflammatory markers appear to be most sensitive for detection of injury, with reported prevalence rates of 50–65% in patients taking certain NSAIDs [4, 11]. The prevalence and severity of NSAID-related enteropathy appears unrelated to the NSAID taken with the exception that neither aspirin nor nabumetone appear to cause small bowel inflammation in man. The reason for the apparent small bowel tolerability to these two drugs is uncertain, but potentially is of considerable importance.

It is suggested that the development of small intestinal inflammation in patients on NSAIDs is a multistep pathogenic event [12]. In experimental animals, which are generally thought to react to NSAIDs in a similar way to man, there is considerable evidence for the idea that the damage is due to two main actions common to all conventional NSAIDs. One is the ‘topical’ toxicity and the other is due to their inhibition of cyclo-oxygenase (COX).

The topical toxicity of NSAIDs may relate to their detergent action [13], which includes the interaction between NSAIDs and surface membrane phospholipids [14, 15] or their mitochondrial action [12, 1619]. These actions are not mutually exclusive as both are dependent on the physicochemical properties of NSAIDs as weak acids with certain lipid to water solubility characteristics. In the case of the mitochondrial action it is suggested that NSAIDs accumulate within enterocytes during drug absorption, as postulated by the ion trapping hypothesis [20, 21], to reach sufficiently high concentrations as to uncouple mitochondrial oxidative phosphorylation [12, 1619]. In vitro the uncoupling action of NSAIDs relate to their pKa [19]. Uncoupling, in turn, leads to decreased cellular ATP [22, 23], increased intestinal permeability [16, 17, 24, 25] and inflammation without ulcers [26].

Concomitant inhibition of COX is required to convert this to ulcerative damage [26] which may involve intestinal ischaemia due to the recruitment of neutrophils [27, 28] and/or the effect of decreased mucosal prostaglandins on villus contraction and microvascular blood flow [2931]. Identical macroscopic damage can be brought about by dual inhibition of COX-1 and 2 in the absence of the topical effect [32, 33].

The topical action of NSAIDs on the small bowel is evident after ingestion of the drugs as well as after parenteral administration as they are excreted in bile. Aspirin, it is suggested, is largely absorbed before it reaches the small bowel and nabumetone, being a nonacidic pro-NSAID, may be largely devoid of ‘topical’ toxicity. Aspirin and 6-methoxy-6-naphthylacetic acid, the active component of nabumetone, are also unusual amongst conventional NSAIDs in that they are not excreted in bile [34, 35] which is an important mechanism of toxicity [36, 37]. Increased intestinal permeability may therefore be a marker of the ‘topical’ damage of NSAIDs and neither aspirin nor nabumetone increase small intestinal permeability in man or experimental animals [17, 38]. If the intestinal permeability changes are a prerequisite to the inflammatory changes then these findings explain why no significant intestinal inflammation is found in patients taking these drugs long-term.

NSAID enteropathy is thought to be asymptomatic. The clinical implications of NSAID-induced enteropathy are that some patients may have significant bleeding, which may contribute to iron deficiency anaemia, others have a protein loosing enteropathy, which may lead to symptomatic hypoalbuminaemia (peripheral oedema, congestive heart failure, etc.), the occasional patient may develop large ulcers that may radiologically resemble Crohn's disease or even mimic malignancy and some patients develop so called ‘diaphragmatic’ strictures that may require surgery [3946].

Measures of intestinal integrity

Several measures are available to assess intestinal anatomy and function following drug ingestion. Radiological studies [7, 42, 4750] and enteroscopy [5, 7, 8, 5153] can be used to assess anatomical abnormalities such as ulceration and strictures. Small bowel permeability and markers of faecal inflammatory activity may give a more sensitive indication of functional changes.

Functional assessment

Radio-isotope scanning

Initially Bjarnason and others [5456] showed that NSAID intake was associated with intestinal inflammation (studies with indium-111-labelled leucocytes). Expanding these studies it is now clear that 50–70% of patients on conventional NSAIDs have intestinal inflammation [5, 6, 11, 52, 53, 5759].

The kinetics of indium-111 accumulation within the gastrointestinal tract and 99 m technetium-porphyrin scans suggested that the main site of NSAID-induced intestinal inflammation was the mid-small bowel. Further studies [60] assessed the clinical complications of this inflammation. Forty-nine patients on NSAIDs underwent study with the indium-111 labelled leucocyte technique, which localizes this inflammation. At the same time patients underwent study with technetium-99 m-labelled red blood cells (99mTcRBC), which has the potential to localize the site of gastrointestinal bleeding. The results showed identical sites of localization of indium-111-leucocytes and 99mTcRBC in 19 patients on NSAIDs. Intestinal blood loss was quantified by use of chromium-51 labelled RBC, and a significant correlation between blood loss and intestinal inflammation was found. These patients also underwent endoscopy with biopsy and neither the inflammation nor blood loss correlated with the endoscopic features, confirming that NSAID-enteropathy contributed to the bleeding. Intestinal protein loss was assessed in nine patients with chromium-51-labelled albumen; patients with NSAID-enteropathy were found to have a protein-losing enteropathy. Thus the small bowel is shown to be a site of protein and blood loss. The importance of this is somewhat concealed by the fact that most of the publicity of NSAID related gastrointestinal side-effects has been driven by pharmaceuticals with vested commercial interest in agents that protect or heal the gastric side-effects.

Interestingly treatment of rheumatoid arthritis with NSAIDs in combination with sulphasalazine [61] may have beneficial effects not only on the arthritis but also upon NSAID-related enteropathy, faecal excretion of indium-111-labelled leucocytes decreased from a mean of 2.39 (2.22)% to 1.33 (1.13)% (normal less than 1%, P < 0.01). Bleeding was reduced to a similar extent. Similarly co-administration of metronidazole [62] with a constant dose of NSAIDs may have a positive effect on NSAID-enteropathy, as assessed by the faecal excretion of indium-111-labelled neutrophils, and chromium-51-labelled red cells. Such treatment also appears to have a beneficial effect on the anaemia and hypoalbuminaemia [63] associated with NSAID enteropathy.

Other faecal markers

The 111-indium white cell technique is not practical in a busy clinical setting. Alternatives have been sought to diagnose NSAID-enteropathy with greater ease. One such marker is faecal calprotectin which is a neutrophil selective protein that resists metabolic degradation by intestinal bacteria.

Meling [64] studied the use of faecal calprotectin in the assessment of gastrointestinal inflammation following ingestion of NSAIDs. Calprotectin was measured after 14 days of indomethacin or naproxen or 7 days of lornoxicam or naproxen. They found that mean calprotectin rose significantly from 4.7 mg l−1 to 9.0 and 8.0, respectively. Shah showed that the COX-2 selective agent nimesulide did not cause small bowel inflammation in the short-term while naproxen did [65]. Tibble [66] proposed that calprotectin can be used as an accurate and reliable marker of NSAID related enteropathy. Single stool calprotectin was compared with 4 day excretion of indium-111-labelled white cells in 47 patients taking NSAIDs. Four day faecal excretion correlated significantly with faecal calprotectin. Shah also assessed 312 patients with rheumatic disease for which they were taking NSAIDs. Faecal calprotectin was significantly higher in patients on NSAIDs than in controls. Forty-four percent of patients had NSAID-related enteropathy as assessed by this technique. Twenty percent of patients with enteropathy had levels of inflammation comparable with those found in inflammatory bowel disease.

It seems likely that the calprotectin method will be more widely used than the indium-111 -labelled white cell method as a screening test for NSAID-enteropathy. The test is conveniently suited to quantify the damage in clinical research, but we suspect that clinicians would prefer to see the damage, if severe, by enteroscopy or capsule enteroscopy, which is now widely available.


Whilst the effects of NSAIDs on the gastro-duodenal mucosa have been clearly documented for many years the effect of conventional NSAIDs on the small bowel in man was not described until the 1980s. It is suggested from animal studies that increased intestinal permeability following NSAIDs represents to a large extent their topical damage, involving mitochondria, etc. In man it is shown that patients with untreated rheumatoid arthritis and osteoarthrosis have normal intestinal permeability whilst those on NSAIDs have increased intestinal permeability [67]. Volunteer studies [2, 68] assessed the effect of aspirin, ibuprofen and indomethacin on small bowel permeability using the chromium-51-labelled ethylenediaminetetra-acetate (Cr-51-EDTA) permeability test. Intestinal permeability increased significantly from control levels following each drug within 12 h and while the effect was proposed to relate to drug potency to inhibit COX no such measurements were carried out.

Subsequently it was demonstrated that [69] indomethacin significantly increased intestinal permeability to Cr-51-EDTA and the co-administration of rioprostil, misoprostol [70] or ornoprostil [71], significantly decreased the detrimental effect of indomethacin, but did not normalize the intestinal barrier function. However co-administration of carbopol (a polyacrylic acid polymer capable of increasing mucus strength and viscosity) with indomethacin had no protective effect on the potentially deleterious effects of indomethacin [70]. These findings suggested that prostaglandins are important for maintaining small intestinal integrity in man, but prostaglandin deficiency alone was unlikely to explain the NSAID-induced increase in intestinal permeability. Further studies showed that providing the epithelial cells with substrates for glycolysis and the TCA cycle abrogated the indomethacin-induced increase in intestinal permeability [72] in keeping with the possible mitochondrial action of these drugs. Another study showed that the nonacidic pro-NSAID nabumetone had no propensity to increase intestinal permeability when given in the short term [38]. The only controversy relating to the effect of NSAIDs on intestinal permeability is whether aspirin has an effect to increase it [73, 74] or not [2, 68].

Much has been made of the importance of using the correct test dose composition for assessing intestinal permeability namely which markers should be used together and whether osmotic fillers should be used to enhance the sensitivity of the procedure. These problems have now been resolved, but it is worth re-emphasizing that the use of polyethylene glycol 400 is clearly unsuitable for intestinal permeability measurements. Sigthorsson [4] examined small intestinal permeability in a large number of patients on long-term NSAIDs. Sixty-eight patients receiving six different NSAIDs for at least six months underwent small bowel absorption permeability tests with hypo-, iso- and hyper-osmolar solutions of 3–O-methyl-d-glucose, d-xylose, and l-rhamnose. The iso- and hyperosmolar tests showed significant malabsorption associated with NSAID ingestion. Intestinal permeability changes were significantly more pronounced and frequent with the hypo- and hyperosmolar solutions.

The effect of COX-2 selective agents on intestinal integrity is of interest. Collectively the data shows that nimesulide [65], rofecoxib [75] and celecoxib [76] have no significant effect to increase intestinal permeability in the short term. This coincides with their nonacidic nature.

However the purported COX-2 selective agent meloxicam, which is acidic, increases intestinal permeability in volunteers consistently [76]. This is further evidence for the importance of the topical effect in the damage of NSAIDs, but it seems at present that dual inhibition of the COX enzymes is of paramount importance with the topical effect increasing the damage. Whether COX-1inhibition plus the topical effect or COX-2 inhibition plus the topical effect is sufficient to cause damage remains to be determined. Changes in permeability associated with NSAID use resolve on withdrawal of the drug, but may take months to do so after long-term treatment [77]. It is suggested, unlike the short-term endoscopy studies with NSAIDs, that the short-term effects of NSAIDs and COX-2 selective agents predicts the long-term safety, i.e. whether these drugs lead to NSAID-enteropathy when taken long-term.

Other drug-related enteropathies

NSAID-related enteropathy provides an illustration of the methods used to assess small intestinal integrity. Similar methods can be used for other drugs such as methotrexate, which has been shown to induce changes in small bowel permeability [7881] probably relating to small bowel ulceration [82, 83]. Perhaps the most clinically relevant damage to the small intestine, apart from NSAIDs, occurs during chemotherapy. Symptomatic side-effects such as abdominal pain, nausea, vomiting, diarrhoea, etc. are troublesome and may in fact be the rate limiting factor in the administration of these drugs. Relatively little has been done to elucidate the mechanism of the damage in man. It is however, clear that the gastrointestinal side-effects of these drugs may limit the amounts administered.

Similar methods can be used regardless of the drug. Potentially beneficial effects such as those of steroids or dietary modification on inflammatory bowel disease and coeliac disease, respectively, can also be assessed [8491].

Permeability tests were initially pioneered as a noninvasive means of screening for coeliac disease and assessing the success of a gluten free diet in coeliac disease. Faecal markers are increasingly used as a means of noninvasive screening for intestinal inflammation in clinical practice and may provide a simple and accurate reflection of response to drug treatment [92].


Radiology, endoscopy and functional investigations can all be used to assess the potentially detrimental or beneficial effects of drugs on the small bowel although an understanding of the likely effects of groups of drugs and their sites of activity will lead to a more rational use of the available investigations. It is clear that each method has its distinct strengths and weaknesses. Whilst radiology, radio-isotope scanning and enteroscopy may delineate the site and morphology of lesions clearly, they may be less sensitive and more open to subjective interpretation than both faecal markers and permeability tests in detecting more subtle functional abnormalities that often characterize drug-induced enteropathies.


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