Long-term probiotic intervention mitigates memory dysfunction through a novel H3K27me3-based mechanism in lead-exposed rats.,Translational Psychiatry

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Long-term probiotic intervention mitigates memory dysfunction through a novel H3K27me3-based mechanism in lead-exposed rats.
Translational Psychiatry ( IF 5.8 ) Pub Date : 2020-01-22 , DOI: 10.1038/s41398-020-0719-8
Jie Xiao _{1,

2} , Tian Wang _{1,

2} , Yi Xu _{1,

2} , Xiaozhen Gu _{1,

2} , Danyang Li _{1,

2} , Kang Niu _{1,

2} , Tiandong Wang _{1,

2} , Jing Zhao _{1,

2} , Ruiqing Zhou _{1,

2} , Hui-Li Wang _{1,

2}

Affiliation

Chronic lead exposure is associated with the development of neurodegenerative diseases, characterized by the long-term memory decline. However, whether this pathogenesis could be prevented through adjusting gut microbiota is not yet understood. To address the issue, pregnant rats and their female offspring were treated with lead (125 ppm) or separately the extra probiotics (1010 organisms/rat/day) till adulthood. For results, memory dysfunction was alleviated by the treatment of multispecies probiotics. Meanwhile, the gut microbiota composition was partially normalized against lead-exposed rats, which in turn mediated the memory repairment via fecal transplantation trials. In the molecular aspect, the decreased H3K27me3 (trimethylation of histone H3 Lys 27) in the adult hippocampus was restored with probiotic intervention, an epigenetic event mediated by EZH2 (enhancer of zeste homolog 2) at early developmental stage. In a neural cellular model, EZH2 overexpression showed the similar rescue effect with probiotics, whereas its blockade led to the neural re-damages. Regarding the gut-brain inflammatory mediators, the disrupted IL-6 (interleukin 6) expression was resumed by probiotic treatment. Intraperitoneal injection of tocilizumab, an IL-6 receptor antagonist, upregulated the hippocampal EZH2 level and consequently alleviated the memory injuries. In conclusion, reshaping gut microbiota could mitigate memory dysfunction caused by chronic lead exposure, wherein the inflammation-hippocampal epigenetic pathway of IL-6-EZH2-H3K27me3, was first proposed to mediate the studied gut-brain communication. These findings provided insight with epigenetic mechanisms underlying a unique gut-brain interaction, shedding light on the safe and non-invasive treatment of neurodegenerative disorders with environmental etiology.

中文翻译：

长期益生菌干预通过一种新的基于 H3K27me3 的机制在铅暴露的大鼠中减轻记忆功能障碍。

慢性铅暴露与以长期记忆衰退为特征的神经退行性疾病的发展有关。然而，目前尚不清楚是否可以通过调整肠道菌群来预防这种发病机制。为了解决这个问题，怀孕大鼠及其雌性后代接受铅（125 ppm）或单独的额外益生菌（1010 个生物体/大鼠/天）直至成年。结果表明，通过多种益生菌的治疗，记忆功能障碍得到了缓解。同时，针对铅暴露的大鼠，肠道微生物群组成部分正常化，这反过来又通过粪便移植试验介导了记忆修复。在分子方面，通过益生菌干预，成年海马中减少的 H3K27me3（组蛋白 H3 Lys 27 三甲基化）得到恢复，在早期发育阶段由 EZH2（zeste 同源物 2 的增强子）介导的表观遗传事件。在神经细胞模型中，EZH2 过表达显示出与益生菌相似的拯救效果，而其阻断导致神经再损伤。关于肠脑炎症介质，通过益生菌治疗恢复了被破坏的 IL-6（白细胞介素 6）表达。腹腔注射 IL-6 受体拮抗剂托珠单抗可上调海马 EZH2 水平，从而减轻记忆损伤。总之，重塑肠道菌群可以减轻慢性铅暴露引起的记忆功能障碍，其中 IL-6-EZH2-H3K27me3 的炎症-海马表观遗传途径首次被提出来介导所研究的肠-脑交流。

更新日期：2020-01-23

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