Fröhlich Esther E, Farzi Aitak, Mayerhofer Raphaela, Reichmann Florian, Jačan Angela, Wagner Bernhard, Zinser Erwin, Bordag Natalie, Magnes Christoph, Fröhlich Eleonore, Kashofer Karl, Gorkiewicz Gregor, Holzer Peter
Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
Brain Behav Immun. 2016 Aug;56:140-55. doi: 10.1016/j.bbi.2016.02.020. Epub 2016 Feb 23.
Emerging evidence indicates that disruption of the gut microbial community (dysbiosis) impairs mental health. Germ-free mice and antibiotic-induced gut dysbiosis are two approaches to establish causality in gut microbiota-brain relationships. However, both models have limitations, as germ-free mice display alterations in blood-brain barrier and brain ultrastructure and antibiotics may act directly on the brain. We hypothesized that the concerns related to antibiotic-induced gut dysbiosis can only adequately be addressed if the effect of intragastric treatment of adult mice with multiple antibiotics on (i) gut microbial community, (ii) metabolite profile in the colon, (iii) circulating metabolites, (iv) expression of neuronal signaling molecules in distinct brain areas and (v) cognitive behavior is systematically investigated. Of the antibiotics used (ampicillin, bacitracin, meropenem, neomycin, vancomycin), ampicillin had some oral bioavailability but did not enter the brain. 16S rDNA sequencing confirmed antibiotic-induced microbial community disruption, and metabolomics revealed that gut dysbiosis was associated with depletion of bacteria-derived metabolites in the colon and alterations of lipid species and converted microbe-derived molecules in the plasma. Importantly, novel object recognition, but not spatial, memory was impaired in antibiotic-treated mice. This cognitive deficit was associated with brain region-specific changes in the expression of cognition-relevant signaling molecules, notably brain-derived neurotrophic factor, N-methyl-d-aspartate receptor subunit 2B, serotonin transporter and neuropeptide Y system. We conclude that circulating metabolites and the cerebral neuropeptide Y system play an important role in the cognitive impairment and dysregulation of cerebral signaling molecules due to antibiotic-induced gut dysbiosis.
新出现的证据表明，肠道微生物群落的破坏（生态失调）会损害心理健康。无菌小鼠和抗生素诱导的肠道生态失调是建立肠道微生物群与大脑关系因果关系的两种方法。然而，这两种模型都有局限性，因为无菌小鼠的血脑屏障和脑超微结构会发生改变，而且抗生素可能直接作用于大脑。我们假设，只有系统地研究成年小鼠经多种抗生素灌胃治疗对（i）肠道微生物群落、（ii）结肠中的代谢物谱、（iii）循环代谢物、（iv）不同脑区神经元信号分子的表达以及（v）认知行为的影响，才能充分解决与抗生素诱导的肠道生态失调相关的问题。在所使用的抗生素（氨苄青霉素、杆菌肽、美罗培南、新霉素、万古霉素）中，氨苄青霉素有一定的口服生物利用度，但不会进入大脑。16S rDNA测序证实了抗生素诱导的微生物群落破坏，代谢组学研究表明，肠道生态失调与结肠中细菌衍生代谢物的消耗以及血浆中脂质种类和转化的微生物衍生分子的改变有关。重要的是，抗生素治疗的小鼠在新物体识别方面存在障碍，但空间记忆不受影响。这种认知缺陷与认知相关信号分子表达的脑区特异性变化有关，特别是脑源性神经营养因子、N-甲基-D-天冬氨酸受体亚基2B、5-羟色胺转运体和神经肽Y系统。我们得出结论，循环代谢物和大脑神经肽Y系统在抗生素诱导的肠道生态失调导致的认知障碍和大脑信号分子失调中起重要作用。
