Sa1960 Risk of Upper Gastrointestinal Complications and the Use of Individual NSAIDs: A Nested Case-Control Study From the Sos Project

Background . Proton pump inhibitors (PPIs) are commonly coprescribed to reduce gastroduodenal injury caused by Non Steroidal Anti-Inflammatory Drugs (NSAIDs). However, while suppression of gastric acid secretion by PPIs is highly effective in reducing gastric injury, PPIs might worsen intestinal injury caused by non selective COX inhibitors. This so-called NSAIDs-PPIs enteropathy has been linked to development of an altered microbiota. Aims. To investigate whether probiotics prevent development of intestinal injury in a model of NSAIDs-PPIs enteropathy.Methods. Mice administered with omeprazole 10 mg/kg (ip twice daily) for 9 days, treated with naproxen (50 mg/kg per os) on the final 4 days. The probiotic VSL#3 at the dose of 18 x109 UCF daily (per os) was administered for 9 days. Small intestinal damage was scored, changes in hematocrit, gastric pH, intestinal expression of IL-1 β, and TNFαmRNA were measured. Change in small intestinal microbiota was assessed by terminal restriction fragment lenght polymorphisms (T-RFLP). To produce terminal restriction fragments the 16S rRNA was amplified and digested with HaeIII. Results. Treating mice with omeprazole increased significantly gastric pH from 2,43±0,29 to 3,66±0,2 (naproxen +omeprazole group) and 3,9 ±0,18 (naproxen + omeprazole +VSL#3 group) and reduced significantly the severity of gastric injury score (mm of lesion) from 20,17±4,8 (naproxen group) to 6±1,15 (naproxen+ omeprazole group) and 7±2,4 (naproxen+ omeprazole+VSL#3 group). In contrast, intestinal injury (mm of lesion) caused by naproxen was exacerbated by omeprazole administration from 37,5±12,12 (naproxen group) to 84,17±11,56 (naproxen + omeprazole group; P,0.05). This effect was reversed by VSL#3. Naproxen alone and naproxen + omeprazole increased the ileal expression of IL-1 β and TNF α, two markers of mucosal inflammation. This effect was reversed by VSL#3. Finally, VSL#3 administration resulted in a robust colonization of small intestine as assessed by T-RFLP. Conclusions. Omeprazole exacerbates naproxen -induced intestinal damage at least in part because of significant shifts in enteric microbiota. VSL#3 has been shown effective in reducing intestinal injury caused by indomethacin in human (APT32:209) and might hold utility in the prevention of NSAIDs-PPIs enteropathy.