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GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3.
Mucosal Immunology ( IF 8 ) Pub Date : 2018-05-01 , DOI: 10.1038/mi.2017.118
Ye Zhao 1, 2 , Feidi Chen 3 , Wei Wu 2, 4 , Mingming Sun 2, 4 , Anthony J Bilotta 2 , Suxia Yao 2 , Yi Xiao 2, 5 , Xiangsheng Huang 2 , Tonyia D Eaves-Pyles 2 , George Golovko 6 , Yuriy Fofanov 6 , Warren D'Souza 7 , Qihong Zhao 8 , Zhanju Liu 4 , Yingzi Cong 2, 3
Affiliation  

The antimicrobial peptides (AMP) produced by intestinal epithelial cells (IEC) play crucial roles in the regulation of intestinal homeostasis by controlling microbiota. Gut microbiota has been shown to promote IEC expression of RegIIIγ and certain defensins. However, the mechanisms involved are still not completely understood. In this report, we found that IEC expression levels of RegIIIγ and β-defensins 1, 3, and 4 were lower in G protein-coupled receptor (GPR)43-/- mice compared to that of wild-type (WT) mice. Oral feeding with short-chain fatty acids (SCFA) promoted IEC production of RegIIIγ and defensins in mice. Furthermore, SCFA induced RegIIIγ and β-defensins in intestinal epithelial enteroids generated from WT but not GPR43-/- mice. Mechanistically, SCFA activated mTOR and STAT3 in IEC, and knockdown of mTOR and STAT3 impaired SCFA induction of AMP production. Our studies thus demonstrated that microbiota metabolites SCFA promoted IEC RegIIIγ and β-defensins in a GPR43-dependent manner. The data thereby provide a novel pathway by which microbiota regulates IEC expression of AMP and intestinal homeostasis.

中文翻译:

GPR43 通过激活 mTOR 和 STAT3 介导微生物代谢物 SCFA 对肠上皮细胞抗菌肽表达的调节。

肠上皮细胞(IEC)产生的抗菌肽(AMP)通过控制微生物群在调节肠道稳态中发挥着至关重要的作用。肠道微生物群已被证明可以促进 RegIIIγ 和某些防御素的 IEC 表达。然而,所涉及的机制仍不完全清楚。在本报告中,我们发现与野生型 (WT) 小鼠相比, G 蛋白偶联受体 (GPR)43 -/-小鼠中 RegIIIγ 和 β-防御素 1、3 和 4 的 IEC 表达水平较低。口服短链脂肪酸 (SCFA) 促进小鼠 IEC 产生 RegIIIγ 和防御素。此外,SCFA 在 WT 而非 GPR43 -/-小鼠产生的肠上皮肠样细胞中诱导 RegIIIγ 和 β-防御素。从机制上讲,SCFA 激活 IEC 中的 mTOR 和 STAT3,而 mTOR 和 STAT3 的敲除会损害 SCFA 对 AMP 产生的诱导。因此,我们的研究表明,微生物代谢物 SCFA 以 GPR43 依赖性方式促进 IEC RegIIIγ 和 β-防御素。因此,这些数据提供了微生物群调节 AMP 的 IEC 表达和肠道稳态​​的新途径。
更新日期:2018-02-07
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