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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 TNFα, 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.

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Nonsteroidal anti-inflammatory drugs


Hypothalamic–pituitary–adrenal axis


Microbiota–gut–brain axis


Water avoidance stress


Dimethyl sulfoxide


Reverse transcription polymerase chain reaction


Fluorescein isothiocyanate dextran


Terminal restriction fragment length polymorphism


Phosphate-buffered saline


Fecal microbiota transplantation


Toll-like receptor


Gram-positive bacteria


Gram-negative bacteria


NOD-like receptor family pyrin domain containing 6


Corticotropin-releasing hormone


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This study was supported by a Health and Labor Sciences research grant into research on intractable diseases, from the Ministry of Health, Labor and Welfare, Japan (

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Correspondence to Kenichi Yoshikawa.

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Yoshikawa, K., Kurihara, C., Furuhashi, H. et al. Psychological stress exacerbates NSAID-induced small bowel injury by inducing changes in intestinal microbiota and permeability via glucocorticoid receptor signaling. J Gastroenterol 52, 61–71 (2017).

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  • NSAID enteropathy
  • HPA axis
  • Fecal microbiota transplantation
  • Small intestinal permeability
  • Water avoidance stress