Shingo Takashima1, Fumio Tanaka1, Yunosuke Kawaguchi2, Yuki Usui3, Kosuke Fujimoto2,4, Yuji Nadatani1, Koji Otani1, Shuhei Hosomi1, Yasuaki Nagami1, Noriko Kamata1, Koichi Taira1, Tetsuya Tanigawa1, Toshio Watanabe1, Seiya Imoto5, Satoshi Uematsu2,4, Yasuhiro Fujiwara1. 1. Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan. 2. Department of Immunology and Genomics, Osaka City University Graduate School of Medicine, Osaka, Japan. 3. Division of Systems Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 4. Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 5. Division of Health Medical Data Science, Health Intelligence Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Abstract
BACKGROUND: Intestinal permeability and psychological stress are considered the key mechanism(s) in functional dyspepsia (FD). Although proton pump inhibitors (PPIs) are commonly used for the treatment of FD, the effect of PPIs on intestinal permeability has not been elucidated. This study investigated the effect of PPI on intestinal permeability under stressed conditions. METHODS: C57BL/6J mice were subjected to water avoidance stress (WAS) and administered rabeprazole (40 mg/kg) or vehicle treatment (VT). We then evaluated intestinal permeability both in vivo and ex vivo using plasma fluorescein isothiocyanate-dextran and by assessing the paracellular permeability and transepithelial electrical resistance (TEER) in an Ussing chamber, respectively. Furthermore, we evaluated the effect of PPI-treated fecal microbiota transplant (FMT) on intestinal permeability in vivo. Microbiota profiles of donor feces were assessed by 16S rRNA gene analysis using MiSeq and QIIME2. KEY RESULTS: In the WAS treatment, PPI significantly enhanced intestinal permeability in vivo compared to that in VT. Moreover, PPI significantly increased paracellular permeability and decreased TEER in the duodenum and jejunum, respectively, compared to those in VT under stressed conditions. Moreover, both vasoactive intestinal peptide (VIP) receptor antagonist and ketotifen significantly reversed the effect of PPI on intestinal permeability. Furthermore, PPI-treated FMT significantly increased the intestinal permeability in vivo compared to that in vehicle-treated FMT. Proton pump inhibitors treatment altered the gut microbiota composition, indicating that PPI induced dysbiosis. CONCLUSIONS AND INFERENCES: Under stressed conditions, PPI enhances intestinal permeability via dysbiosis of gut microbiota. Vasoactive intestinal peptide and mast cells are also implicated in the underlying mechanisms.
BACKGROUND: Intestinal permeability and psychological stress are considered the key mechanism(s) in functional dyspepsia (FD). Although proton pump inhibitors (PPIs) are commonly used for the treatment of FD, the effect of PPIs on intestinal permeability has not been elucidated. This study investigated the effect of PPI on intestinal permeability under stressed conditions. METHODS: C57BL/6J mice were subjected to water avoidance stress (WAS) and administered rabeprazole (40 mg/kg) or vehicle treatment (VT). We then evaluated intestinal permeability both in vivo and ex vivo using plasma fluorescein isothiocyanate-dextran and by assessing the paracellular permeability and transepithelial electrical resistance (TEER) in an Ussing chamber, respectively. Furthermore, we evaluated the effect of PPI-treated fecal microbiota transplant (FMT) on intestinal permeability in vivo. Microbiota profiles of donor feces were assessed by 16S rRNA gene analysis using MiSeq and QIIME2. KEY RESULTS: In the WAS treatment, PPI significantly enhanced intestinal permeability in vivo compared to that in VT. Moreover, PPI significantly increased paracellular permeability and decreased TEER in the duodenum and jejunum, respectively, compared to those in VT under stressed conditions. Moreover, both vasoactive intestinal peptide (VIP) receptor antagonist and ketotifen significantly reversed the effect of PPI on intestinal permeability. Furthermore, PPI-treated FMT significantly increased the intestinal permeability in vivo compared to that in vehicle-treated FMT. Proton pump inhibitors treatment altered the gut microbiota composition, indicating that PPI induced dysbiosis. CONCLUSIONS AND INFERENCES: Under stressed conditions, PPI enhances intestinal permeability via dysbiosis of gut microbiota. Vasoactive intestinal peptide and mast cells are also implicated in the underlying mechanisms.
Authors: Mijeong Son; I Seul Park; Soochan Kim; Hyun Woo Ma; Ji Hyung Kim; Tae Il Kim; Won Ho Kim; Jaeyong Han; Seung Won Kim; Jae Hee Cheon Journal: Front Immunol Date: 2022-05-25 Impact factor: 8.786
Authors: Denise Battaglini; Chiara Robba; Andrea Fedele; Sebastian Trancǎ; Samir Giuseppe Sukkar; Vincenzo Di Pilato; Matteo Bassetti; Daniele Roberto Giacobbe; Antonio Vena; Nicolò Patroniti; Lorenzo Ball; Iole Brunetti; Antoni Torres Martí; Patricia Rieken Macedo Rocco; Paolo Pelosi Journal: Front Med (Lausanne) Date: 2021-06-04