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Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction.

ABSTRACT: The large intestinal epithelial cells and immune cells are exposed to a variety of molecules derived from commensal microbiota that can activate innate receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible gene-I-like receptors (RLRs). Although the activation of these receptors is known to be critical for homeostasis of the large intestine, the underlying gene regulatory mechanisms are not well understood. Here, we show that IFN regulatory factor (IRF)3 is critical for the suppression of dextran sulfate sodium-induced colitis. IRF3-deficient mice exhibited lethal defects in the inflammatory and recovery phases of the colitis, accompanied by marked defects in the gene induction for thymic stromal lymphopoietin (TSLP), a cytokine known to be essential for protection of the large intestine. We further provide evidence that DNA and RNA of the large intestinal contents are critical for Tslp gene induction via IRF3 activation by cytosolic nucleic acid receptors. We also demonstrate that IRF3 indeed activates the gene promoter of Tslp via IRF-binding sequences. This newly identified intestinal gene regulatory mechanism, wherein IRF3 activated by microbiota-derived nucleic acids plays a critical role in intestinal homeostasis, may have clinical implication in colonic inflammatory disorders.

SUBMITTER: Negishi H

PROVIDER: S-EPMC3529020 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction.

Negishi Hideo H Miki Shoji S Sarashina Hana H Taguchi-Atarashi Naoko N Nakajima Akira A Matsuki Kosuke K Endo Nobuyasu N Yanai Hideyuki H Nishio Junko J Honda Kenya K Taniguchi Tadatsugu T

Proceedings of the National Academy of Sciences of the United States of America 20121203 51

The large intestinal epithelial cells and immune cells are exposed to a variety of molecules derived from commensal microbiota that can activate innate receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible gene-I-like receptors (RLRs). Although the activation of these receptors is known to be critical for homeostasis of the large intestine, the underlying gene regulatory mechanisms are not well understood. Here, we show that IFN regulatory factor (IRF)3 is critical for the su ...[more]

PMID: 23213237

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Project description:With the increased demand for safe and sustainable alternatives to growth promoting antibiotics in the livestock industry, oregano essential oils (OEO) and Lactobacillus reuteri (LR) have been examined as alternatives to antibiotics for growth promotion and to improve animal health and performance. However, the mechanism underlying the OEO and LR mediation of sheep growth remains unknown. In this study, 16S rRNA gene sequencing and untargeted metabolomics were used to determine the role of the gut microbiota in the growth improvements observed. The potential modulating roles of intestinal microbial metabolites of OEO and LR to intestinal health were systematically explored as well. It was observed that both OEO and LR had greater average daily gain (ADG) and lower F/G ratio. Furthermore, OEO also appeared to have produced a greater amylase enzyme activity and mucin gene expression in the jejunal mucosa. It was also observed that OEO reduced serum IL-2 and TNF-β as well as mRNA levels of NF-κB p65, toll-like receptor-4 (TLR-4), and IL-6 in the jejunal mucosa. Moreover, dietary OEO supplementation increased the abundances of Ruminococcus, Bifidobacterium and Enterococcus, while the relative abundances of Succiniclasticum, Marvinbryantia and Streptococcus were enriched in LR group. Spearman's correlation analysis revealed that the abundances of Bifidobacterium, Ruminococcus and Enterococcus were positively correlated with the mRNA expression of mucins. Moreover, the relative abundance of Enterococcus was positively correlated with amylase activity. Metabolomics analysis indicated that OEO and LR increased the levels of indole acetaldehyde and indole-3-acetic acid through the tryptophan metabolism pathway. It was observed that LR also decreased the inflammatory metabolites including tryptamine and 5-hydroxyindole-3-acetic acid. Collectively, these results suggested that OEO exerted a beneficial effect on growth performance and the mucosal barrier, affected tryptophan metabolism and improved the intestinal microbiota of sheep.

Dataset Information

Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction.

Publications

Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction.

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