[HTML][HTML] Intestinal barrier regulates immune responses in the liver via IL-10–producing macrophages

N Taniki, N Nakamoto, PS Chu, Y Mikami, T Amiya… - JCI insight, 2018 - ncbi.nlm.nih.gov
N Taniki, N Nakamoto, PS Chu, Y Mikami, T Amiya, T Teratani, T Suzuki, T Tsukimi…
JCI insight, 2018ncbi.nlm.nih.gov
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 …
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.
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