The intestinal microbial metabolite nicotinamide n-oxide prevents herpes simplex encephalitis via activating mitophagy in microglia.
The intestinal microbial metabolite nicotinamide n-oxide prevents herpes simplex encephalitis via activating mitophagy in microglia.
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肠道微生物代谢物烟酰胺 N-氧化物通过激活小胶质细胞的线粒体自噬来预防单纯疱疹脑炎
DOI：
10.1080/19490976.2022.2096989
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发表时间：
2022-01
期刊：
影响因子：
12.2
通讯作者：
Wang, Yifei
中科院分区：
文献类型：
--
作者：
Li, Feng;Wang, Yiliang;Song, Xiaowei;Wang, Zhaoyang;Jia, Jiaoyan;Qing, Shurong;Huang, Lianzhou;Wang, Yuan;Wang, Shuai;Ren, Zhe;Zheng, Kai;Wang, Yifei
单纯疱疹病毒性脑炎（HSE）是单纯疱疹病毒I型（HSV-1）感染的并发症，可导致免疫功能低下的成人和新生儿神经系统疾病甚至死亡。然而，控制HSE结果的内在因素仍不清楚。在这里，我们表明HSE小鼠表现出肠道微生物群失调和代谢物构型和烟酰胺代谢的改变。HSV-1嗜神经性感染激活了小胶质细胞，改变了免疫特性和细胞数量，刺激抗病毒免疫反应，并在HSE中发挥重要作用。此外，通过口服抗生素（ABX）治疗耗尽肠道微生物群引发了小胶质细胞的过度活化，这反过来增强了炎症免疫应答和细胞因子产生，导致聚集的病毒负荷和HSE病理。此外，外源性给予ABX处理或未处理的HSE小鼠烟酰胺N-氧化物（NAMO）（一种来源于肠道微生物群的烟酰胺氧化产物）显著降低了CNS中小胶质细胞介导的促炎反应和有限的HSV-1感染。机制研究表明，HSV-1通过缺陷性线粒体自噬增加线粒体损伤来激活小胶质细胞，而微生物代谢物NAMO恢复NAD+依赖性线粒体自噬以抑制小胶质细胞激活和HSE进展。NAMO还可预防由HSV-1感染或小胶质细胞介导的微环境毒性引发的神经元细胞死亡。最后，我们发现NAMO主要由新霉素敏感细菌产生，尤其是加氏乳杆菌和罗伊氏乳杆菌。总之，这些数据表明，肠道微生物代谢产物通过调节小胶质细胞中的线粒体自噬作为对抗HSE进展的内在限制性因素，这意味着进一步探索细菌或营养方法用于治疗嗜神经病毒相关的神经退行性疾病。
Herpes simplex encephalitis (HSE), a complication of herpes simplex virus type I (HSV-1) infection causes neurological disorder or even death in immunocompromised adults and newborns. However, the intrinsic factors controlling the HSE outcome remain unclear. Here, we show that HSE mice exhibit gut microbiota dysbiosis and altered metabolite configuration and tryptophan-nicotinamide metabolism. HSV-1 neurotropic infection activated microglia, with changed immune properties and cell numbers, to stimulate antiviral immune response and contribute substantially to HSE. In addition, depletion of gut microbiota by oral antibiotics (ABX)-treatment triggered the hyper-activation of microglia, which in turn enhanced inflammatory immune response, and cytokine production, resulting in aggregated viral burden and HSE pathology. Furthermore, exogenous administration of nicotinamide n-oxide (NAMO), an oxidative product of nicotinamide derived from gut microbiota, to ABX-treated or untreated HSE mice significantly diminished microglia-mediated proinflammatory response and limited HSV-1 infection in CNS. Mechanistic study revealed that HSV-1 activates microglia by increasing mitochondrial damage via defective mitophagy, whereas microbial metabolite NAMO restores NAD+-dependent mitophagy to inhibit microglia activation and HSE progression. NAMO also prevented neuronal cell death triggered by HSV-1 infection or microglia-mediated microenvironmental toxicity. Finally, we show that NAMO is mainly generated by neomycin-sensitive bacteria, especially Lactobacillus_gasseri and Lactobacillus_reuteri. Together, these data demonstrate that gut microbial metabolites act as intrinsic restrictive factors against HSE progression via regulating mitophagy in microglia, implying further exploration of bacterial or nutritional approaches for treating neurotropic virus-related neurodegenerative diseases.
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影响因子：
4.3
作者：
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通讯作者：
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影响因子：
64.8
作者：
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DOI：
10.1073/pnas.1019378108
发表时间：
2011-03-29
影响因子：
11.1
作者：
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DOI：
10.1073/pnas.1424775112
发表时间：
2015-02-17
影响因子：
11.1
作者：
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通讯作者：
Chen, Ding-Shinn
影响因子：
7.3
作者：
Grayson MH;Camarda LE;Hussain SA;Zemple SJ;Hayward M;Lam V;Hunter DA;Santoro JL;Rohlfing M;Cheung DS;Salzman NH
通讯作者：
Salzman NH