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Priming the Pump of a Leaky Gut
Abstract & Commentary
By Malcolm Robinson, MD, FACP, FACG, AGAF, Emeritus Clinical Professor of Medicine, University of Oklahoma College of Medicine, Oklahoma City. Dr. Robinson reports no financial relationship to this field of study.
Synopsis: This is the first study documenting that a PPI compromises the mucosal barrier function of the upper GI tract.
Source: J Mullin, et al. Esomeprazole induces upper gastrointestinal tract transmucosal permeability increase. Aliment Pharmacol Ther 2008;28:1317-1325.
Proton Pump Inhibitors (PPIs) are among the most widely utilized of all drug classes (more than $2 billion spent annually on PPIs in the United States), and they are generally presumed to be as safe as they are effective. The authors of this paper had previously documented that Barrett's esophagus (BE) patients had "leaky" upper gastrointestinal (GI) mucosa as assessed using the widely accepted sucrose permeability test (SPT). Many pharmacological agents that damage the mucosa (e.g., NSAIDs) are known to enhance mucosal permeability. The authors initially hypothesized that the leakiness found in upper GI mucosa in BE might actually be improved by therapy with PPIs (just as PPIs heal damaged esophageal mucosa when used to treat erosive esophagitis or resolve mucosal damage in many gastric and duodenal disorders). Oral sucrose can only be absorbed paracellularly in its disaccharide form (i.e., intact sucrose must pass through leaky intercellular junctions or through actual breaks in the mucosa as would be present in erosions or ulcerations). In the usual digestive setting, sucrose is absorbed through the intestinal mucosa after being enzymatically hydrolyzed to glucose and fructose by sucrase, an enzyme found on the surface of the duodenum. If sucrose as an intact molecule is absorbed through areas of damaged mucosa of the upper GI tract, this undigested sucrose passes unchanged into the urine. An overnight urine specimen after bedtime consumption of 100 g of sucrose in a concentrated sucrose solution can be quantitatively assessed for sucrose as a marker for upper GI mucosal leakage.
In the current study, mucosal permeability was measured in untreated GERD patients at baseline and after 8 weeks of esomeprazole 40 mg daily before breakfast. Eleven of 37 patients screened had > 200 mg of sucrose leak at baseline. This was thought to indicate the likelihood of alternative ongoing pathology, and these patients were excluded. Of the remaining 26 patients, 21 (84%) showed an increased sucrose leak by SPT after 8 weeks of esomeprazole. In this post-treatment group, 14 of the patients had more than 200 mg of sucrose leak, a level others have thought to be indicative of pathophysiology. The average baseline sucrose leak was 72 ± 9 mg vs a mean final sucrose leak of 325 ± 56 mg. This is a 351% increase (P = 0.001). After this group of patients had been studied, a follow-up study of normal healthy individuals was initiated. Volunteers received 1, 2, 3, 5, 7, or 9 days of esomeprazole after a baseline SPT. The final SPT was done on the night following the last dose of esomeprazole. Results indicated a progressive rise in SPT values with increasing duration of esomeprazole therapy (reaching statistical significance after 3 days of therapy). By day 9 of therapy, the SPT was almost 400 mg greater than baseline. By day 4 after the completion and discontinuation of esomeprazole dosing, a follow-up SPT test had returned to baseline. The authors felt that gastric mucosal permeability should be measured after intravenous PPI therapy. It was also mentioned that animal studies had confirmed PPI-enhanced upper GI permeability. It was speculated that PPIs might affect the integrity of the cellular cytoskeleton since they may inhibit other phosphatases in addition to H,K-ATPase. Phosphatases have been implicated in control of tight junction permeability.
Astra Zeneca, maker of esomeprazole, was undoubtedly unhappy about the results of this study. Undoubtedly, they had been hoping to show that their drug led to improvement of pathological upper GI permeability. Instead, a multibillion dollar product has been shown to cause what could be a significant pathophysiologic abnormality of the upper GI mucosal barrier. Although there are no definite clinical abnormalities that can be ascribed to increased mucosal permeability, a number of disease states are apparently related to enhanced mucosal permeability. For example, as already mentioned, NSAIDs cause a quite reproducible increase in upper GI mucosal permeability that can be quantified by the SPT as used in these PPI studies. Crohn's disease is associated with more than normally permeable intestinal mucosa, and healthy relatives of Crohn's disease patients also have statistically increased intestinal mucosal permeability vs healthy control subjects. Defective intestinal barrier function has been linked to such disparate disorders as rheumatoid arthritis and a variety of systemic allergies.
Clearly, the finding of this mucosal effect of esomeprazole may or may not be generalized to other PPIs, but this certainly needs to be explored. More to the point, the clinical implications of dramatically enhanced intestinal permeability need to be carefully analyzed. Pharmaceutical companies seldom fund studies that backfire in the way that seems to have occurred in the present scenario, but there could be a number of valuable consequences that develop in the light of these quite unexpected data.