Gut and Liver Depression Promotes the Onset of Irritable Bowel Syndrome through Unique Dysbiosis in Rats
Author Information
Takeshi Takajo1, Kengo Tomita1, Hanae Tsuchihashi2, Shingo Enomoto3, Masaaki Tanichi3, Hiroyuki Toda3, Yoshikiyo Okada1, Hirotaka Furuhashi1, Nao Sugihara1, Akinori Wada1, Kazuki Horiuchi1, Kenichi Inaba1, Yoshinori Hanawa1, Naoki Shibuya1, Kazuhiko Shirakabe1, Masaaki Higashiyama1, Chie Kurihara1, Chikako Watanabe1, Shunsuke Komoto1, Shigeaki Nagao1, Katsunori Kimura2, Soichiro Miura1,4, Kunio Shimizu5, and Ryota Hokari1
1Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, 2Microbiome Group, Basic Microbiology Research Department, Food Microbiology Research Laboratories, R&D Division, Meiji Co., Ltd., Hachiouji, 3Department of Psychiatry, National Defense Medical College, Tokorozawa, 4International University of Health and Welfare Graduate School, Tokyo, and 5Division of Behavioral Sciences, National Defense Medical College Research Institute, Tokorozawa, Japan

Kengo Tomitaa and Ryota Hokarib
Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan
Tel: +81-4-2995-1211 (ext. 2369), Fax: +81-4-2996-5201, E-mail: akengo@ndmc.ac.jp and bryota@ndmc.ac.jp
© The Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer. All rights reserved.

Abstract
Background/Aims: Although studies using conventional animal models have shown that specific stressors cause irritable bowel syndrome (IBS), it is unclear whether depression itself causes IBS. Our aim was to establish a rat model to determine if depression itself promotes the onset of IBS and to elucidate the role of gut microbiota in brain-gut axis pathogenesis during coincident depression and IBS. Methods: Rat models of depression were induced using our shuttle box method of learned helplessness. Visceral hypersensitivity was evaluated by colorectal distension (CRD) to diagnose IBS. Gut microbiota compositions were analyzed using high-throughput sequencing. In the subanalysis of rats without depression-like symptoms, rats with posttraumatic stress disorder (PTSD) were also examined. Results: The threshold value of CRD in depressed rats was significantly lower than that in control rats. Microbial community analysis of cecal microbiota showed that the relative abundance of Clostridiales incertae sedis, the most prevalent microbe, was significantly lower in depressed rats than in control rats. The distribution pattern of the microbiota clearly differed between depressed rats and control rats. Neither visceral hypersensitivity nor the composition of gut microbiota was altered in rats with PTSD-like phenotypes. Conclusions: Our rat model of depression is useful for clarifying the effect of depression on IBS and suggests that depression itself, rather than specific stressors, promotes the onset of IBS. Further, we provided evidence that various psychiatric diseases, viz., depression and PTSD, are associated with unique gut microbiota profiles, which could differentially affect the onset and progression of coincident IBS.
Keywords: Irritable bowel syndrome; Depression; Stress disorders, post-traumatic; Gastrointestinal Microbiome
Abstract
Background/Aims: Although studies using conventional animal models have shown that specific stressors cause irritable bowel syndrome (IBS), it is unclear whether depression itself causes IBS. Our aim was to establish a rat model to determine if depression itself promotes the onset of IBS and to elucidate the role of gut microbiota in brain-gut axis pathogenesis during coincident depression and IBS. Methods: Rat models of depression were induced using our shuttle box method of learned helplessness. Visceral hypersensitivity was evaluated by colorectal distension (CRD) to diagnose IBS. Gut microbiota compositions were analyzed using high-throughput sequencing. In the subanalysis of rats without depression-like symptoms, rats with posttraumatic stress disorder (PTSD) were also examined. Results: The threshold value of CRD in depressed rats was significantly lower than that in control rats. Microbial community analysis of cecal microbiota showed that the relative abundance of Clostridiales incertae sedis, the most prevalent microbe, was significantly lower in depressed rats than in control rats. The distribution pattern of the microbiota clearly differed between depressed rats and control rats. Neither visceral hypersensitivity nor the composition of gut microbiota was altered in rats with PTSD-like phenotypes. Conclusions: Our rat model of depression is useful for clarifying the effect of depression on IBS and suggests that depression itself, rather than specific stressors, promotes the onset of IBS. Further, we provided evidence that various psychiatric diseases, viz., depression and PTSD, are associated with unique gut microbiota profiles, which could differentially affect the onset and progression of coincident IBS.
Keywords: Irritable bowel syndrome; Depression; Stress disorders, post-traumatic; Gastrointestinal Microbiome
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