Bacterial O-GlcNAcase genes abundance decreases in ulcerative colitis patients and its administration ameliorates colitis in mice.
Bacterial O-GlcNAcase genes abundance decreases in ulcerative colitis patients and its administration ameliorates colitis in mice.
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溃疡性结肠炎患者中细菌 O-GlcNAcase 基因丰度降低，其给药可改善小鼠结肠炎
DOI：
10.1136/gutjnl-2020-322468
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发表时间：
2021-10
期刊：
影响因子：
24.5
通讯作者：
Cao H
中科院分区：
文献类型：
--
作者：
He X;Gao J;Peng L;Hu T;Wan Y;Zhou M;Zhen P;Cao H
目的O-连接N-乙酰氨基葡萄糖化（O-GlcNAc ylation，O-GlcNAc）是由O-GlcNAc酶（O-GlcNAc ase，OGA）和O-GlcNAc转移酶（O-GlcNAc transferase，OGT）控制的一种重要的真核蛋白质翻译后修饰，在调节肠道炎症反应中起重要作用。肠道微生物群编码参与O-GlcNAc酰化的各种酶。然而，这些酶的特性、丰度和功能尚不清楚。设计我们首先研究了细菌OGA和OGT的结构和分类分布。然后，我们进行宏基因组分析，以探讨OGA基因在健康样本和不同疾病的丰度。最后，我们采用体外和体内实验来确定细菌OGA水解宿主细胞中O-GlcNAc化蛋白并抑制肠道炎症反应的作用和机制。结果我们发现OGA中富含拟杆菌门和厚壁菌门，而不是OGT。大多数细菌OGA是分泌型酶，具有与人OGA相同的保守催化结构域。对1999个包含6种疾病的宏基因组样本的汇总分析显示，细菌OGA基因在健康人肠道中以高丰度保守，并且仅在溃疡性结肠炎中减少。体外研究表明，细菌OGA可以水解宿主细胞中的O-GlcNAc酰化蛋白，包括O-GlcNAc酰化的NF-κB-p65亚基，这对激活NF-κB信号通路非常重要。体内研究表明，肠道细菌源性OGA可以通过水解O-GlcNAc酰化蛋白质来保护小鼠免受化学诱导的结肠炎症。结论我们的研究结果揭示了一种以前未被认识到的酶活性，肠道微生物群通过这种酶活性影响肠道生理学，并强调细菌OGA是结肠炎症的一种有前途的治疗策略。
Objective O-linked N-acetylglucosaminylation (O-GlcNAcylation), controlled by O-GlcNAcase (OGA) and O-GlcNAc transferase (OGT), is an important post-translational modification of eukaryotic proteins and plays an essential role in regulating gut inflammation. Gut microbiota encode various enzymes involved in O-GlcNAcylation. However, the characteristics, abundance and function of these enzymes are unknown. Design We first investigated the structure and taxonomic distribution of bacterial OGAs and OGTs. Then, we performed metagenomic analysis to explore the OGA genes abundance in health samples and different diseases. Finally, we employed in vitro and in vivo experiments to determine the effects and mechanisms of bacterial OGAs to hydrolyse O-GlcNAcylated proteins in host cells and suppress inflammatory response in the gut. Results We found OGAs, instead of OGTs, are enriched in Bacteroidetes and Firmicutes, the major bacterial divisions in the human gut. Most bacterial OGAs are secreted enzymes with the same conserved catalytic domain as human OGAs. A pooled analysis on 1999 metagenomic samples encompassed six diseases revealed that bacterial OGA genes were conserved in healthy human gut with high abundance, and reduced exclusively in ulcerative colitis. In vitro studies showed that bacterial OGAs could hydrolyse O-GlcNAcylated proteins in host cells, including O-GlcNAcylated NF-κB-p65 subunit, which is important for activating NF-κB signalling. In vivo studies demonstrated that gut bacteria-derived OGAs could protect mice from chemically induced colonic inflammation through hydrolysing O-GlcNAcylated proteins. Conclusion Our results reveal a previously unrecognised enzymatic activity by which gut microbiota influence intestinal physiology and highlight bacterial OGAs as a promising therapeutic strategy in colonic inflammation.
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影响因子：
64.8
作者：
通讯作者：
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TAB1 的 O-GlcNAc 酰化调节 TAK1 介导的细胞因子释放。
影响因子：
11.4
作者：
Pathak, Shalini;Borodkin, Vladimir S.;Albarbarawi, Osama;Campbell, David G.;Ibrahim, Adel;van Aalten, Daan M. F.
通讯作者：
van Aalten, Daan M. F.
影响因子：
16.8
作者：
Dennis, RJ;Taylor, EJ;Davies, GJ
通讯作者：
Davies, GJ
影响因子：
5.2
作者：
Hart GW
通讯作者：
Hart GW
影响因子：
64.8
作者：
Lloyd-Price, Jason;Arze, Cesar;Yajnik, Vijay
通讯作者：
Yajnik, Vijay