Tryptophan metabolite norharman secreted by cultivated Lactobacillus attenuates acute pancreatitis as an antagonist of histone deacetylases.
Tryptophan metabolite norharman secreted by cultivated Lactobacillus attenuates acute pancreatitis as an antagonist of histone deacetylases.
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DOI：
10.1186/s12916-023-02997-2
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发表时间：
2023-08-28
期刊：
影响因子：
9.3
通讯作者：
Xiang, Hong
中科院分区：
文献类型：
--
作者：
Zhou, Qi;Tao, Xufeng;Guo, Fangyue;Wu, Yu;Deng, Dawei;Lv, Linlin;Dong, Deshi;Shang, Dong;Xiang, Hong
急性胰腺炎（AP）患者表现出与严重程度相关的肠道微生物群的特定表型。肠道微生物群和宿主主要通过代谢物相互作用;遗憾的是，对它们在AP生物网络中的作用知之甚少。本研究探讨了肠细菌代谢产物如何调节AP加重时的先天免疫系统。在AP中，通过微生物组学检测肠道微生物群的变化，并通过液相色谱-串联质谱法（LC-MS/MS）鉴定色氨酸的乳酸菌代谢物。采用LC-MS/MS法检测乳酸菌与色氨酸共同培养后的代谢产物，并以脂多糖（LPS）刺激的RAW264.7细胞和雨蛙肽+LPS诱导的AP小鼠模型，研究norharman对AP形成过程中M1巨噬细胞活化的影响。此外，RNA测序和脂质代谢组学用于筛选诺哈曼的治疗靶点和途径。用共聚焦显微镜观察脂筏的结构。应用分子对接技术预测了去甲哈曼与HDAC的相互作用。采用荧光素酶报告基因分析和染色质免疫沉淀（ChIP）技术探讨norharman促进Rftn 1表达的直接机制。此外，使用骨髓特异性Rftn 1敲除小鼠来验证Rftn 1的作用和norharman的逆转作用。AP诱导肠道菌群及其代谢产物功能障碍，导致乳酸杆菌介导的色氨酸代谢途径受到抑制。乳酸菌代谢产物色氨酸，norharman，抑制炎症因子的释放在体外和体内，由于其最佳的抑制作用M1巨噬细胞。Norharman能维持脂筏的完整性，恢复脂代谢紊乱，从而阻断AP加重时的多种炎症反应。norharman的作用机制是通过抑制组蛋白去乙酰化酶（HDACs）的活性，增加组蛋白H3在赖氨酸9/14（H3 K9/14）的乙酰化，从而增加Rftn 1（Raftlin 1）的转录水平，抑制M1巨噬细胞的活化。肠道细菌代谢产物norharman可降低HDACs活性，增加Rftn 1的H3 K9/14乙酰化，从而抑制M1巨噬细胞活化，恢复脂质代谢平衡，减轻多种炎症反应。因此，norharman可能是一个很有前途的前体药物，以阻止AP加重。在线版本包含补充材料，可通过10.1186/s12916-023-02997-2获得。
Patients with acute pancreatitis (AP) exhibit specific phenotypes of gut microbiota associated with severity. Gut microbiota and host interact primarily through metabolites; regrettably, little is known about their roles in AP biological networks. This study examines how enterobacterial metabolites modulate the innate immune system in AP aggravation. In AP, alterations in gut microbiota were detected via microbiomics, and the Lactobacillus metabolites of tryptophan were identified by liquid chromatography-tandem mass spectrometry (LC–MS/MS). By culturing Lactobacillus with tryptophan, differential metabolites were detected by LC–MS/MS. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells and mice with cerulein plus LPS-induced AP were used to evaluate the biological effect of norharman on M1 macrophages activation in AP development. Further, RNA sequencing and lipid metabolomics were used for screening the therapeutic targets and pathways of norharman. Confocal microscopy assay was used to detect the structure of lipid rafts. Molecular docking was applied to predict the interaction between norharman and HDACs. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to explore the direct mechanism of norharman promoting Rftn1 expression. In addition, myeloid-specific Rftn1 knockout mice were used to verify the role of Rftn1 and the reversed effect of norharman. AP induced the dysfunction of gut microbiota and their metabolites, resulting in the suppression of Lactobacillus-mediated tryptophan metabolism pathway. The Lactobacillus metabolites of tryptophan, norharman, inhibited the release of inflammatory factor in vitro and in vivo, as a result of its optimal inhibitory action on M1 macrophages. Moreover, norharman blocked multiple inflammatory responses in AP exacerbation due to its ability to maintain the integrity of lipid rafts and restore the dysfunction of lipid metabolism. The mechanism of norharman’s activity involved inhibiting the enzyme activity of histone deacetylase (HDACs) to increase histone H3 at lysine 9/14 (H3K9/14) acetylation, which increased the transcription level of Rftn1 (Raftlin 1) to inhibit M1 macrophages’ activation. The enterobacterial metabolite norharman can decrease HDACs activity to increase H3K9/14 acetylation of Rftn1, which inhibits M1 macrophage activation and restores the balance of lipid metabolism to relieve multiple inflammatory responses. Therefore, norharman may be a promising prodrug to block AP aggravation. The online version contains supplementary material available at 10.1186/s12916-023-02997-2.
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影响因子：
5.1
作者：
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通讯作者：
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影响因子：
30.5
作者：
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通讯作者：
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影响因子：
11.4
作者：
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通讯作者：
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