title: Psychological stress exacerbates NSAID-induced small bowel injury by inducing changes in intestinal microbiota and permeability via glucocorticoid receptor signaling.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan. kyoshikawa@jikei.ac.jp.|Division of Gastroenterology and Hepatology, Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan. kyoshikawa@jikei.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshikawa
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Kurihara
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Furuhashi
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takajo
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Maruta
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yasutake
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sato
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Narimatsu
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Yoshikiyo
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Higashiyama
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Watanabe
authors.affiliation: Department of Endoscopic and Photodynamic Medicine, National Defense Medical College, Saitama, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Komoto
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Department of Endoscopic and Photodynamic Medicine, National Defense Medical College, Saitama, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nagao
authors.affiliation: National Defense Medical College, Saitama, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Miura
authors.affiliation: Division of Gastroenterology and Hepatology, Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Tajiri
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hokari
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D004195:Disease Models, Animal; D000069196:Gastrointestinal Microbiome; D007213:Indomethacin / Q000009:adverse effects; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000382:microbiology / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction; D013315:Stress, Psychological / Q000150:complications*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D007213:Indomethacin
keywords: Fecal microbiota transplantation; HPA axis; NSAID enteropathy; Small intestinal permeability; Water avoidance stress