Urolithin A-mediated augmentation of intestinal barrier function through elevated secretory mucin synthesis

Author:

Yasuda Takeshi,Takagi Tomohisa,Asaeda Kohei,Hashimoto Hikaru,Kajiwara Mariko,Azuma Yuka,Kitae Hiroaki,Hirai Yasuko,Mizushima Katsura,Doi Toshifumi,Inoue Ken,Dohi Osamu,Yoshida Naohisa,Uchiyama Kazuhiko,Ishikawa Takeshi,Konishi Hideyuki,Ukawa Yuichi,Kohara Akiko,Kudoh Masatake,Inoue Ryo,Naito Yuji,Itoh Yoshito

Abstract

AbstractMaintaining the mucus layer is crucial for the innate immune system. Urolithin A (Uro A) is a gut microbiota-derived metabolite; however, its effect on mucin production as a physical barrier remains unclear. This study aimed to elucidate the protective effects of Uro A on mucin production in the colon. In vivo experiments employing wild-type mice, NF-E2-related factor 2 (Nrf2)-deficient mice, and wild-type mice treated with an aryl hydrocarbon receptor (AhR) antagonist were conducted to investigate the physiological role of Uro A. Additionally, in vitro assays using mucin-producing cells (LS174T) were conducted to assess mucus production following Uro A treatment. We found that Uro A thickened murine colonic mucus via enhanced mucin 2 expression facilitated by Nrf2 and AhR signaling without altering tight junctions. Uro A reduced mucosal permeability in fluorescein isothiocyanate-dextran experiments and alleviated dextran sulfate sodium-induced colitis. Uro A treatment increased short-chain fatty acid-producing bacteria and propionic acid concentration. LS174T cell studies confirmed that Uro A promotes mucus production through the AhR and Nrf2 pathways. In conclusion, the enhanced intestinal mucus secretion induced by Uro A is mediated through the actions of Nrf-2 and AhR, which help maintain intestinal barrier function.

Funder

Mitsubishi Tanabe Pharma Corporation

PreMedica, Inc.

EA Pharma Co., Ltd.

Taiyo Kagaku Co., Ltd.

Publisher

Springer Science and Business Media LLC

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