Psychological stress exacerbates NSAID-induced small bowel injury by inducing changes in intestinal microbiota and permeability via glucocorticoid receptor signaling

Nonsteroidal anti-inflammatory drugs (NSAIDs) are popular painkillers, but they have serious side effects, not only in the upper gastrointestinal tract but also in the small intestine. It is well known that psychological stress may exacerbate various gastrointestinal diseases. The aim of this study was to determine whether psychological stress exacerbates NSAID enteropathy and to determine the possible underlying mechanisms for this. Experiment 1: mice were exposed to water avoidance stress (WAS) or sham stress for 1 h per day for 8 consecutive days, and then enteropathy was induced by indomethacin. Experiment 2: cecal contents from stress (-) or (+) mice were transplanted into mice that had received antibiotics and in which NSAID enteropathy had been induced without WAS. Experiment 3: mifepristone, a glucocorticoid receptor antagonist, was injected before WAS for 8 days. Small intestinal injury, mRNA expression of TNF alpha, intestinal permeability, and the microbial community were assessed. Psychological stress exacerbated NSAID enteropathy and increased intestinal permeability. Psychological stress induced changes in the ileal microbiota that were characterized by increases in the total number of bacteria and the proportion of Gram-negative bacteria. The increased susceptibility to NSAIDs and intestinal permeability due to WAS was transferable via cecal microbiota transplantation. The increased permeability and aggravation of NSAID enteropathy caused by WAS were blocked by the administration of mifepristone. This study demonstrated a relationship between NSAID enteropathy and psychological stress, and showed the utility of studying the intestinal microbiota in order to elucidate the pathophysiology of NSAID enteropathy. It also showed the impact of stress on the intestinal microbiota and the mucosal barrier in gastrointestinal diseases.