Prevention of NSAID-Enteropathy: A Soluble Problem?

Abstract

Small intestinal injury caused by nonsteroidal anti-inflammatory drugs (NSAIDs), common and clinically significant [1], is difficult to detect and largely asymptomatic, with associated hospital costs and rates of mortality higher than those for NSAID-induced upper gastrointestinal (GI) injury [2]. There are no proven-effective preventative or therapeutic options available to physicians [3]. Indeed, in animal studies, anti-secretory drugs that are commonly used to reduce the incidence of NSAID-induced damage in the upper GI tract [proton pump inhibitors (PPI), histamine H2receptor antagonists (H2RA)] markedly exacerbate NSAID-associated jejunal and ileal damage [4, 5], in part through significant changes to the intestinal microbiota that include a marked reduction in numbers of Bifidobacteria [5], and by increasing the cytotoxicity of bile [6]. A recent capsule endoscopic study of NSAID-enteropathy in patients with arthritis identified the three strongest risk factors for developing severe intestinal damage and reduced hematocrit: use of a PPI, use of an H2RA, and advanced age (odds ratios of 5.2, 4.0, and 4.2, respectively; all p 0.05) [7]. Rodent models have been very useful for studying the pathogenesis of this condition, since the factors contributing to the damage in such models appear to be similar to those in humans: alterations in the intestinal microbiota, enterohepatic circulation of the NSAID, increased cytotoxicity of bile, and other factors [3] (Fig. 1). Although altering the intestinal microbiota with antibiotics and/or reducing the enterohepatic circulation of the NSAID all markedly diminish NSAID-enteropathy in rodents [3], some of these approaches are not viable, nor desirable, therapeutic strategies for humans, since they can also reduce the therapeutic efficacy of the NSAID. Animal studies of prophylaxis with antibiotics have yielded inconsistent or conflicting results [8, 9], further complicated by concern about the development of resistant strains of bacteria, particularly if long-term or repeated use of antibiotics is required for effectiveness [10]. In this issue of Digestive Diseases and Sciences, Satoh et al. [11] report that NSAID-induced intestinal damage in arthritic rats could be markedly reduced or prevented simply through the provision of a diet enriched in soluble fiber. After arthritis had been induced and established in rats by injection of Freund’s adjuvant, the rats were placed on a powdered diet alone, or one supplemented with one of two soluble fibers: pectin or guar gum. Two days later, a 3-day course of indomethacin treatment was started, with blind evaluation of the intestinal damage occurring 1 day after the final treatment. The authors observed a 60–90 % reduction in intestinal damage in the rats receiving the pectinor guar gum-supplemented diets as compared to controls. Importantly, the dietary interventions did not attenuate the desired anti-inflammatory effects of the NSAID. Also, feeding the rats an enriched with insoluble (cellulose-based) dietary fiber diet did not significantly alter the severity of NSAID-induced intestinal damage [11]. There are several potential mechanisms of action that could be invoked to explain the remarkable effectiveness of the diets high in soluble fiber in this rat model. A favorable alteration in the intestinal microbiome would be logical candidate. NSAID administration to rodents substantially alters the numbers and types of bacteria in the intestine; in & John L. Wallace altapharm@hotmail.com