A host-gut microbial amino acid co-metabolite, p-cresol glucuronide, promotes blood-brain barrier integrity in vivo.

IF 3.6 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Andrew V Stachulski, Tobias B-A Knausenberger, Sita N Shah, Lesley Hoyles, Simon McArthur
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引用次数: 8

Abstract

The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism of the amino acids tyrosine and phenylalanine to p-cresol by gut microbes, and then to p-cresol glucuronide (pCG) by host enzymes. Although such glucuronide conjugates are classically thought to be biologically inert, there is accumulating evidence that this may not always be the case. We investigated the activity of pCG, studying its interactions with the cerebral vasculature and the brain in vitro and in vivo. Male C57Bl/6 J mice were used to assess blood-brain barrier (BBB) permeability and whole-brain transcriptomic changes in response to pCG treatment. Effects were then further explored using the human cerebromicrovascular endothelial cell line hCMEC/D3, assessing paracellular permeability, transendothelial electrical resistance and barrier protein expression. Mice exposed to pCG showed reduced BBB permeability and significant changes in whole-brain transcriptome expression. Surprisingly, treatment of hCMEC/D3 cells with pCG had no notable effects until co-administered with bacterial lipopolysaccharide, at which point it was able to prevent the permeabilizing effects of endotoxin. Further analysis suggested that pCG acts as an antagonist at the principal lipopolysaccharide receptor TLR4. The amino acid phase II metabolic product pCG is biologically active at the BBB, antagonizing the effects of constitutively circulating lipopolysaccharide. These data add to the growing literature showing glucuronide conjugates to be more than merely metabolic waste products and highlight the complexity of gut microbe to host communication pathways underlying the gut-brain axis.

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宿主肠道微生物氨基酸共代谢物对甲酚葡萄糖醛酸,促进体内血脑屏障的完整性。
肠道微生物和宿主过程的顺序活动可以对饲料成分产生强大的调节作用,例如肠道微生物将酪氨酸和苯丙氨酸代谢为对甲酚,然后由宿主酶代谢为对甲酚葡萄糖醛酸盐(pCG)。虽然这种葡萄糖醛酸缀合物通常被认为是生物惰性的,但越来越多的证据表明,情况并非总是如此。我们研究了pCG的活性,研究了它在体外和体内与脑血管系统和大脑的相互作用。雄性C57Bl/6 J小鼠被用来评估血脑屏障(BBB)通透性和全脑转录组学对pCG治疗的反应。然后利用人脑血管内皮细胞系hCMEC/D3进一步探讨其影响,评估细胞旁通透性、跨内皮电阻和屏障蛋白表达。暴露于pCG的小鼠血脑屏障通透性降低,全脑转录组表达显著改变。令人惊讶的是,用pCG治疗hCMEC/D3细胞没有明显的效果,直到与细菌脂多糖共同施用,此时pCG能够阻止内毒素的渗透作用。进一步分析表明pCG作为主要脂多糖受体TLR4的拮抗剂。氨基酸II期代谢产物pCG在血脑屏障中具有生物活性,可拮抗组成循环脂多糖的作用。这些数据增加了越来越多的文献,表明葡萄糖醛酸盐缀合物不仅仅是代谢废物,并且突出了肠道微生物在肠-脑轴下宿主通信途径的复杂性。
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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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