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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Partially hydrolyzed guar gum attenuates non-alcoholic fatty liver disease in mice through the gut-liver axis
Shun Takayama, Kazuhiro Katada, Tomohisa Takagi, Takaya Iida, Tomohiro Ueda, Katsura Mizushima, Yasuki Higashimura, Mayuko Morita, Tetsuya Okayama, Kazuhiro Kamada, Kazuhiko Uchiyama, Osamu Handa, Takeshi Ishikawa, Zenta Yasukawa, Tsutomu Okubo, Yoshito Itoh, Yuji Naito
Shun Takayama, Kazuhiro Katada, Tomohisa Takagi, Takaya Iida, Tomohiro Ueda, Katsura Mizushima, Tetsuya Okayama, Kazuhiro Kamada, Kazuhiko Uchiyama, Takeshi Ishikawa, Yoshito Itoh, Yuji Naito, Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
Tomohisa Takagi, Department of Medical Innovation and Translational Medical Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
Yasuki Higashimura, Department of Food Science, Ishikawa Prefectural University, Nonoichi 921-8836, Japan
Mayuko Morita, Department of Health Care Nutrition, Showa Gakuin Junior College, Ichikawa 272-0823, Japan
Osamu Handa, Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki 701-0192, Japan
Zenta Yasukawa, Tsutomu Okubo, Department of Nutrition, Taiyo Kagaku Co. Ltd, Yokkaichi 510-0844, Japan
Author contributions: Takayama S performed the research, analyzed the data, and wrote the manuscript; Katada K designed the research study, and wrote the manuscript; Higashimura Y performed the biostatistical analysis, and critically reviewed the manuscript; Takagi T, Iida T, Ueda T, Mizushima K, Morita M, Okayama T, Kamada K, Uchiyama K, Handa O, Ishikawa T, Yasukawa Z, Okubo T, Itoh Y, and Naito Y contributed to data collection and interpretation, and critically reviewed the manuscript; all authors approved the final version of the manuscript, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Supported by Scientific Research (KAKENHI) (C), No. 25460958; Japan Society for the Promotion of Science, No. 20K11513; and Adaptable and Seamless Technology Transfer Program through target driven R&D from the Japan Agency for Medical Research and Development.
Institutional review board statement: At our institution, the attached “Institutional Animal Care and Use Committee Approval Form” also serves as the Institutional Review Board Approval Form. The study was reviewed and approved by the Institutional Review Board at Kyoto Prefectural University of Medicine.
Institutional animal care and use committee statement: All procedures involving animal subject is approved by the Animal Care Committee of the Kyoto Prefectural University of Medicine, Kyoto, Japan, No. M2020-126.
Conflict-of-interest statement: All authors have nothing to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Kazuhiro Katada, MD, PhD, Assistant Professor, Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. katada@koto.kpu-m.ac.jp
Received: February 6, 2021
Peer-review started: February 6, 2021
First decision: February 27, 2021
Revised: March 12, 2021
Accepted: April 21, 2021
Article in press: April 21, 2021
Published online: May 14, 2021
BACKGROUND
The gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis. Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver disease (NAFLD) by modulating gut microbiota. Partially hydrolyzed guar gum (PHGG), a water-soluble dietary fiber, has been reported to alleviate the symptoms of various intestinal diseases and metabolic syndromes. However, its effects on NAFLD remain to be fully elucidated.
AIM
To determine whether treatment with PHGG attenuates NAFLD development in mice through the gut-liver axis.
METHODS
Seven-week-old male C57BL/6J mice with increased intestinal permeability were fed a control or atherogenic (Ath) diet (a mouse model of NAFLD) for 8 wk, with or without 5% PHGG. Increased intestinal permeability was induced through chronic intermittent administration of low-dose dextran sulfate sodium. Body weight, liver weight, macroscopic findings in the liver, blood biochemistry [aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total cholesterol, triglyceride, free fatty acids, and glucose levels], liver histology, myeloperoxidase activity in liver tissue, mRNA expression in the liver and intestine, serum endotoxin levels in the portal vein, intestinal permeability, and microbiota and short-chain fatty acid (SCFA) profiles in the cecal samples were investigated.
RESULTS
Mice with increased intestinal permeability subjected to the Ath diet showed significantly increased serum AST and ALT levels, liver fat accumulation, liver inflammatory (tumor necrosis factor-α and monocyte chemotactic protein-1) and fibrogenic (collagen 1a1 and α smooth muscle actin) marker levels, and liver myeloperoxidase activity, which were significantly attenuated by PHGG treatment. Furthermore, the Ath diet combined with increased intestinal permeability resulted in elevated portal endotoxin levels and activated toll-like receptor (TLR) 4 and TLR9 expression, confirming that intestinal permeability was significantly elevated, as observed by evaluating the lumen-to-blood clearance of fluorescein isothiocyanate-conjugated dextran. PHGG treatment did not affect fatty acid metabolism in the liver. However, it decreased lipopolysaccharide signaling through the gut-liver axis. In addition, it significantly increased the abundance of cecal Bacteroides and Clostridium subcluster XIVa. Treatment with PHGG markedly increased the levels of SCFAs, particularly, butyric acid, acetic acid, propionic acid, and formic acid, in the cecal samples.
CONCLUSION
PHGG partially prevented NAFLD development in mice through the gut-liver axis by modulating microbiota and downstream SCFA profiles.
Core Tip: The gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis, including non-alcoholic fatty liver disease (NAFLD). Here, by using a mouse model of NAFLD induced by an atherogenic diet combined with increased intestinal permeability, we report that partially hydrolyzed guar gum (PHGG), a water-soluble dietary fiber, prevented NAFLD development in mice partially through the gut-liver axis by modulating the microbiota and downstream short-chain fatty acid profiles, highlighting that treatment with PHGG might show great promise as a therapeutic strategy for NAFLD.
