Intestinal barrier regulates immune responses in the liver via IL-10-producing macrophages

Nobuhito Taniki, Nobuhiro Nakamoto, Po Sung Chu, Yohei Mikami, Takeru Amiya, Toshiaki Teratani, Takahiro Suzuki, Tomoya Tsukimi, Shinji Fukuda, Akihiro Yamaguchi, Shunsuke Shiba, Rei Miyake, Tadashi Katayama, Hirotoshi Ebinuma, Takanori Kanai

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The gut-liver axis is of clinical importance as a potential therapeutic target in a wide range of liver diseases; however, the mechanisms underlying interactions between microbial products and immune responses in the liver remain unknown. In this study, we demonstrated that IL-10-producing macrophages contribute to immune tolerance in the inflamed liver under intestinal barrier disruption in a murine tandem model of dextran sulfate sodium (DSS) colitis and concanavalin A (Con A) hepatitis. Intestinal barrier disruption protected mice from subsequent liver injury, and the severity of colitis directly affected susceptibility to such injury. The protective effect of DSS-Con A was canceled in gut-sterilized mice, suggesting that gut microbiota play a substantial role in this process. Altered gut microbiota and their metabolites, along with a disrupted intestinal barrier, directly gave rise to immunological permissiveness in the inflamed liver. We identified 1-methylnicotinamide (1-MNA) as a candidate metabolite capable of suppressing liver injury with the potential to induce IL-10-producing macrophages. Consistently, expression of nicotinamide N-methyltransferase, which converts nicotinamide to 1-MNA, was upregulated in the liver of DSS-Con A mice, and this effect was abrogated by gut sterilization. Collectively, our results provide a mechanistic insight into the regulation of immunological balance in the liver via the gut-liver axis.

Original languageEnglish
JournalJCI Insight
Volume3
Issue number12
DOIs
Publication statusPublished - 2018 Jun 21

Keywords

  • Hepatitis
  • Hepatology
  • Immunology
  • Macrophages
  • Tolerance

ASJC Scopus subject areas

  • Medicine(all)

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    Taniki, N., Nakamoto, N., Chu, P. S., Mikami, Y., Amiya, T., Teratani, T., Suzuki, T., Tsukimi, T., Fukuda, S., Yamaguchi, A., Shiba, S., Miyake, R., Katayama, T., Ebinuma, H., & Kanai, T. (2018). Intestinal barrier regulates immune responses in the liver via IL-10-producing macrophages. JCI Insight, 3(12). https://doi.org/10.1172/jci.insight.91980