Membrane lipid remodeling eradicates Helicobacter pylori by manipulating the cholesteryl 6'-acylglucoside biosynthesis

IF 9 2区 医学 Q1 CELL BIOLOGY
Lih-Lih Ong, Hau-Ming Jan, Hong-Hanh Thi Le, Tsai-Chen Yang, Chou-Yu Kuo, Ai-Feng Feng, Kwok-Kong Tony Mong, Chun-Hung Lin
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Abstract

Helicobacter pylori, the main cause of various gastric diseases, infects approximately half of the human population. This pathogen is auxotrophic for cholesterol which it converts to various cholesteryl α-glucoside derivatives, including cholesteryl 6’-acyl α-glucoside (CAG). Since the related biosynthetic enzymes can be translocated to the host cells, the acyl chain of CAG likely comes from its precursor phosphatidylethanolamine (PE) in the host membranes. This work aims at examining how the acyl chain of CAG and PE inhibits the membrane functions, especially bacterial adhesion. Eleven CAGs that differ in acyl chains were used to study the membrane properties of human gastric adenocarcinoma cells (AGS cells), including lipid rafts clustering (monitored by immunofluorescence with confocal microscopy) and lateral membrane fluidity (by the fluorescence recovery after photobleaching). Cell-based and mouse models were employed to study the degree of bacterial adhesion, the analyses of which were conducted by using flow cytometry and immunofluorescence staining, respectively. The lipidomes of H. pylori, AGS cells and H. pylori–AGS co-cultures were analyzed by Ultraperformance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS) to examine the effect of PE(10:0)2, PE(18:0)2, PE(18:3)2, or PE(22:6)2 treatments. CAG10:0, CAG18:3 and CAG22:6 were found to cause the most adverse effect on the bacterial adhesion. Further LC–MS analysis indicated that the treatment of PE(10:0)2 resulted in dual effects to inhibit the bacterial adhesion, including the generation of CAG10:0 and significant changes in the membrane compositions. The initial (1 h) lipidome changes involved in the incorporation of 10:0 acyl chains into dihydro- and phytosphingosine derivatives and ceramides. In contrast, after 16 h, glycerophospholipids displayed obvious increase in their very long chain fatty acids, monounsaturated and polyunsaturated fatty acids that are considered to enhance membrane fluidity. The PE(10:0)2 treatment significantly reduced bacterial adhesion in both AGS cells and mouse models. Our approach of membrane remodeling has thus shown great promise as a new anti-H. pylori therapy.
膜脂重塑通过操纵胆固醇-6'-酰基葡萄糖苷的生物合成根除幽门螺旋杆菌
幽门螺杆菌是导致各种胃病的主要原因,感染了大约一半的人口。这种病原体对胆固醇具有辅助营养作用,可将胆固醇转化为各种胆固醇α-葡萄糖苷衍生物,包括胆固醇6'-酰基α-葡萄糖苷(CAG)。由于相关的生物合成酶可以转移到宿主细胞中,CAG 的酰基链很可能来自宿主膜中的前体磷脂酰乙醇胺(PE)。这项工作旨在研究 CAG 和 PE 的酰基链如何抑制膜功能,尤其是细菌粘附。研究人员利用 11 种不同酰基链的 CAG 研究了人胃腺癌细胞(AGS 细胞)的膜特性,包括脂质筏聚集(通过共聚焦显微镜的免疫荧光监测)和侧膜流动性(通过光漂白后的荧光恢复)。在研究细菌粘附程度时,采用了细胞模型和小鼠模型,分别使用流式细胞仪和免疫荧光染色法进行分析。利用超高效液相色谱-串联质谱(UPLC-MS/MS)分析了幽门螺杆菌、AGS细胞和幽门螺杆菌-AGS共培养物的脂质体,研究了PE(10:0)2、PE(18:0)2、PE(18:3)2或PE(22:6)2处理的效果。结果发现,CAG10:0、CAG18:3 和 CAG22:6 对细菌粘附的影响最大。进一步的 LC-MS 分析表明,PE(10:0)2 的处理会产生抑制细菌粘附的双重效果,包括生成 CAG10:0 和膜成分的显著变化。最初(1 小时)的脂质组变化涉及将 10:0 的酰基链纳入二氢和植物鞘氨醇衍生物以及神经酰胺。相反,16 小时后,甘油磷脂中的长链脂肪酸、单不饱和脂肪酸和多不饱和脂肪酸明显增加,这些脂肪酸被认为能增强膜的流动性。在 AGS 细胞和小鼠模型中,PE(10:0)2 处理都能显著降低细菌的粘附性。因此,我们的膜重塑方法有望成为一种新型的抗幽门螺杆菌疗法。
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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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