zonulin转基因小鼠表现出通过消耗肠道微生物群而改善的行为改变。

IF 3.6 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Tissue Barriers Pub Date : 2022-07-03 Epub Date: 2021-11-14 DOI:10.1080/21688370.2021.2000299
Alba Miranda-Ribera, Gloria Serena, Jundi Liu, Alessio Fasano, Marcy A Kingsbury, Maria R Fiorentino
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引用次数: 7

摘要

肠脑轴假说表明,肠道环境中的相互作用在调节大脑功能中起着关键作用。几项研究指出,肠道-微生物群-大脑之间的联系将肠道屏障受损和肠道微生物群组成改变与涉及神经炎症的神经系统疾病联系起来。增加的肠道通透性允许腔内抗原穿过肠道上皮,并通过血流和受损的血脑屏障(BBB)进入大脑,影响其功能。前触珠蛋白2 (Pre-haptoglobin 2, pHP2)是成熟HP2的前体蛋白,是zonulin结构相关蛋白家族中第一个被发现的成员。pph2在人类中被鉴定为迄今为止唯一的上皮和内皮紧密连接(TJs)的内源性调节因子。我们利用zonulin转基因小鼠(Ztm)表达小鼠pHP2 (zonulin)来确定肠道通透性增加及其与肠道微生物群失调对脑功能和行为的协同作用。本研究表明,Ztm小鼠表现出性别依赖的行为异常,并伴有血脑屏障TJs基因表达改变和脑炎症基因表达增加。Ztm小鼠肠道菌群的抗生素消耗下调了脑炎症标志物,改善了一些焦虑样行为。总的来说,我们表明,肠道通透性和肠道微生物群生态失调的带蛋白依赖性改变与血脑屏障完整性改变、神经炎症和行为改变有关,而这些改变可以通过微生物群消耗部分改善。我们的研究结果表明,在神经行为/神经炎症疾病的背景下,Ztm模型可以作为研究微生物组/肠道和大脑之间相互作用的工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Zonulin-transgenic mouse displays behavioral alterations ameliorated via depletion of the gut microbiota.

The gut-brain axis hypothesis suggests that interactions in the intestinal milieu are critically involved in regulating brain function. Several studies point to a gut-microbiota-brain connection linking an impaired intestinal barrier and altered gut microbiota composition to neurological disorders involving neuroinflammation. Increased gut permeability allows luminal antigens to cross the gut epithelium, and via the blood stream and an impaired blood-brain barrier (BBB) enters the brain impacting its function. Pre-haptoglobin 2 (pHP2), the precursor protein to mature HP2, is the first characterized member of the zonulin family of structurally related proteins. pHP 2 has been identified in humans as the thus far only endogenous regulator of epithelial and endothelial tight junctions (TJs). We have leveraged the Zonulin-transgenic mouse (Ztm) that expresses a murine pHP2 (zonulin) to determine the role of increased gut permeability and its synergy with a dysbiotic intestinal microbiota on brain function and behavior. Here we show that Ztm mice display sex-dependent behavioral abnormalities accompanied by altered gene expression of BBB TJs and increased expression of brain inflammatory genes. Antibiotic depletion of the gut microbiota in Ztm mice downregulated brain inflammatory markers ameliorating some anxiety-like behavior. Overall, we show that zonulin-dependent alterations in gut permeability and dysbiosis of the gut microbiota are associated with an altered BBB integrity, neuroinflammation, and behavioral changes that are partially ameliorated by microbiota depletion. Our results suggest the Ztm model as a tool for the study of the cross-talk between the microbiome/gut and the brain in the context of neurobehavioral/neuroinflammatory disorders.

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来源期刊
Tissue Barriers
Tissue Barriers MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.60
自引率
6.50%
发文量
25
期刊介绍: Tissue Barriers is the first international interdisciplinary journal that focuses on the architecture, biological roles and regulation of tissue barriers and intercellular junctions. We publish high quality peer-reviewed articles that cover a wide range of topics including structure and functions of the diverse and complex tissue barriers that occur across tissue and cell types, including the molecular composition and dynamics of polarized cell junctions and cell-cell interactions during normal homeostasis, injury and disease state. Tissue barrier formation in regenerative medicine and restoration of tissue and organ function is also of interest. Tissue Barriers publishes several categories of articles including: Original Research Papers, Short Communications, Technical Papers, Reviews, Perspectives and Commentaries, Hypothesis and Meeting Reports. Reviews and Perspectives/Commentaries will typically be invited. We also anticipate to publish special issues that are devoted to rapidly developing or controversial areas of research. Suggestions for topics are welcome. Tissue Barriers objectives: Promote interdisciplinary awareness and collaboration between researchers working with epithelial, epidermal and endothelial barriers and to build a broad and cohesive worldwide community of scientists interesting in this exciting field. Comprehend the enormous complexity of tissue barriers and map cross-talks and interactions between their different cellular and non-cellular components. Highlight the roles of tissue barrier dysfunctions in human diseases. Promote understanding and strategies for restoration of tissue barrier formation and function in regenerative medicine. Accelerate a search for pharmacological enhancers of tissue barriers as potential therapeutic agents. Understand and optimize drug delivery across epithelial and endothelial barriers.
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