The Potential Role of Gut-Derived Inflammation in Multiple System Atrophy
The Potential Role of Gut-Derived Inflammation in Multiple System Atrophy
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DOI：
10.3233/jpd-160991
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发表时间：
2017-01-01
影响因子：
5.2
通讯作者：
Keshavarzian, Ali
中科院分区：
文献类型：
--
作者：
Engen, Phillip A.;Dodiya, Hemraj B.;Keshavarzian, Ali
背景资料：最近的证据表明，帕金森病（PD）与肠道微生物群失调、肠道通透性异常和肠道炎症有关。目的：我们的研究旨在确定这些肠道异常是否存在于另一种突触核蛋白病--多系统萎缩（MSA）中。在6名MSA和11名健康对照受试者中，我们对结肠乙状结肠粘膜进行了免疫组织化学研究，以评估肠屏障标志物闭锁小带-1和内毒素相关炎症标志物Toll样受体-4的表达。我们还评估了结肠乙状结肠粘膜和粪便微生物群组成，使用高通量16 S核糖体RNA基因扩增sequencing.Results：MSA科目显示破坏紧密连接蛋白封闭带-1结构的乙状结肠粘膜组织表明肠屏障功能障碍。脂多糖特异性炎症受体Toll样受体-4在MSA的结肠乙状结肠粘膜中显著高于健康对照组。微生物群分析表明，在MSA粪便和粘膜中，来自拟杆菌门（Bacteroidetes）和变形菌门（Proteobacteria）的各种科和属水平分类群中的革兰氏阴性、推定的“促炎”细菌的相对丰度较高。在属的分类水平，推定的“正”丁酸生产细菌在MSA粪便中的丰度较低。预测功能分析表明，与健康对照组相比，MSAfeces中参与代谢的许多基因的相对丰度较低，而MSAfeces和粘膜中参与脂多糖生物合成的基因的相对丰度较高。这项概念验证研究提供了初步证据，表明与PD一样，MSA受试者显示出肠屏障完整性受损的证据，内毒素相关的肠道炎症和促炎性结肠微生物群的标志物增加。
Background: Recent evidence suggests that Parkinson's disease (PD) is associated with intestinal microbiota dysbiosis, abnormal intestinal permeability, and intestinal inflammation.Objective: Our study aimed to determine if these gut abnormalities are present in another synucleinopathy, multiple system atrophy (MSA).Methods: In six MSA and 11 healthy control subjects, we performed immunohistochemistry studies of colonic sigmoid mucosa to evaluate the intestinal barrier marker Zonula Occludens-1 and the endotoxin-related inflammation marker Toll-likereceptor- 4 expression. We also assessed colonic sigmoid mucosal and fecal microbiota compositions using high-throughput 16S ribosomal RNA gene amplicon sequencing.Results: MSA subjects showed disrupted tight junction protein Zonula Occludens-1 structure in sigmoid mucosa tissue suggesting intestinal barrier dysfunction. The lipopolysaccharide specific inflammatory receptor Toll-like-receptor-4 was significantly higher in the colonic sigmoid mucosa in MSA relative to healthy controls. Microbiota analysis suggested high relative abundance of gram-negative, putative "pro-inflammatory" bacteria in various family and genus level taxa, from the phylum Bacteroidetes and Proteobacteria, in MSA feces and mucosa. At the taxonomic level of genus, putative "antiinflammatory" butyrate-producing bacteria were less abundant in MSA feces. Predictive functional analysis indicated that the relative abundance of a number of genes involved in metabolism were lower inMSAfeces, whereas the relative abundance of genes involved in lipopolysaccharide biosynthesis were higher in bothMSAfeces and mucosa compared to healthy controls.Conclusions: This proof-of-concept study provides preliminary evidence that like PD, MSA subjects display evidence of disrupted intestinal barrier integrity, increased marker of endotoxin-related intestinal inflammation, and pro-inflammatory colonic microbiota.