Microbiota-Taurine Pathway Links Dietary Fiber to Mucosal Healing.
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Odakura Rina, Seki Natsumi, Nomura Kei, Inoue Yukinobu, Yakabe Kyosuke, Akiyama Masahiro, Yao Takashi, Okano Soh, Suda Wataru, Masuoka Hiroaki, Zhang Xiaochen, Orikasa Masayuki, Omori Masashi, Koma Masao, Maruyama Takafumi, Yanagisawa Naotake, Murakami Takumi, Mori Hiroshi, Toyoda Atsushi, Suzuki Junto, Izuta Honoka, Srirat Tanakorn, Haneda Takeshi, Miki Tsuyoshi, Ito Masahiro, Ito Takashi, Shibuya Tomoyoshi, Katsumata Ryo, Nakato Gaku, Mizutani Sayaka, Yamada Takuji, Sasaki Nobuo, Hase Koji, Fukuda Shinji, Nagahara Akihito, Ishikawa Dai, Kim Yun-Gi
Аннотация
METHODS: We screened fibers in dextran sodium sulfate (DSS)-induced murine colitis and assessed survival, inflammation, barrier function, and epithelial regeneration. Microbiota dependence was evaluated using antibiotics and bacterial supplementation. Metabolites were profiled using capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS), and epithelial programs were analyzed using RNA-seq and colonic organoid injury assays. Slc6a6-/- and Cyp2c55-/- mice were used to determine mechanistic requirements. Translational relevance was examined in a randomized, placebo-controlled trial of UC patients receiving antibiotic-primed fecal microbiota transplantation (A-FMT) followed by alginate or placebo. Clinical outcomes, histology, fecal taurine, and colonic CYP2C18 expression were assessed.
RESULTS: Alginate improved DSS colitis recovery, reducing inflammation, restoring barrier integrity, and enhancing crypt proliferation. Alginate enriched taurine-releasing bacteria, including Bacteroides acidifaciens and Ligilactobacillus murinus, and increased intestinal taurine; antibiotic disruption abrogated these effects. Taurine was required for benefit, as alginate failed in Slc6a6-/- mice. Alginate and taurine induced epithelial Cyp2c55, and protection was lost in Cyp2c55-/- mice and organoids. In the clinical trial, the primary endpoint was not met. However, alginate supplementation was associated with biological changes, including fecal taurine levels and colonic CYP2C18 expression, consistent with preclinical mechanisms.
CONCLUSION: Alginate engages a fiber-microbiota-taurine-epithelial signaling pathway that promotes recovery in preclinical models. The clinical trial did not meet its primary endpoint; however, the biological changes warrant further investigation of alginate as a microbiota-targeted intervention.
CLINICAL TRIAL REGISTRY: jRCTs031200103 (https://jrct.mhlw.go.jp/), registered September 1, 2020: UMIN000041968 (https://www.umin.ac.jp/ctr/index.htm), October 1, 2020.