10月12日，北京市农林科学院生物所玉米分子育种研究团队与美国夏威夷大学Qing X. Li教授团队合作，在国际知名医学与食品学期刊Journal of Nutrition（Top期刊，IF5-year：5.07，h-index：240）在线发表题为“Isoorientin Affects Markers of Alzheimer's Disease via Effects on the Oral and Gut Microbiota in APP/PS1 Mice”的研究论文。该研究揭示了玉米花丝天然产物异荭草素，通过调节阿尔茨海默病模型鼠口腔和肠道微生物，进而抑制NF-κB炎症通路，最终通过脑-肠轴来减缓阿尔茨海默病相关病理指标。
阿尔茨海默病是一种慢性神经退行性疾病，逐渐成为继心血管、脑血管疾病、癌症后人类生命的第四大杀手，目前无特效药可治。我们前期研究发现玉米花粉、花丝提取天然产物黄酮类物质异荭草素可以改善阿尔茨海默病相关病理指标，但是异荭草素进入血液含量少，且不能穿过脑屏障，其作用机理不清晰。近期有研究报道，阿尔茨海默病人肠道微生物菌群紊乱，通过调节肠道微生物菌群组成，可以改善阿尔茨海默病患者的症状。
本研究以阿尔茨海默病模型APP/PS1小鼠为研究对象，通过饲喂玉米花丝提取的天然产物异荭草素，探索异荭草素的作用机理。最终发现异荭草素可以抑制模型鼠口腔和肠道有害菌含量、提升益生菌含量，并可以重塑模型鼠口腔和肠道微生物菌群，并使血液和脑组织中LPS（细菌脂多糖，内毒素）的含量显著降低。同时发现异荭草素可以抑制NF-κB炎症通路核心蛋白IκBα和p65的磷酸化，进而抑制炎症相关病理指标IL-6、TNF-α、iNOS和COX-2。相关性分析发现，益生菌含量与抑炎因子IL-4和IL-10呈现正相关，有害菌含量与促炎因子IL-6、TNF-α等程现正相关。试验结果最终发现，饲喂异荭草素后，模型鼠脑内阿尔茨海默病典型病理指标β淀粉样蛋白（Aβ42）和磷酸化Tau蛋白（p-Tau）含量显著下降。
综合所有试验结果，初步推测异荭草素减缓阿尔茨海默病相关病理指标的机理为：通过调节口腔和肠道微生物菌群结构，降低血清和脑组织中LPS的含量，进而抑制LPS诱导的NF-κB炎症通路，最终通过脑-肠轴来调节并减缓阿尔茨海默病相关病理指标。
北京市农林科学院生物所张中保副研究员和广州中医药大学谭小琴博士为共同第一作者，吴忠义研究员、魏建华研究员和夏威夷大学Qing X. Li教授为通讯作者，论文第一通讯单位为北京市农林科学院。该研究得到院科技创新能力建设专项、国家基金培育专项及北京市金桥种子资金资助。
图1 异荭草素减缓阿尔茨海默病相关病理指标通路图
图2 异荭草素可以重塑阿尔茨海默病模型鼠口腔和肠道微生物菌群
图3 饲喂异荭草素后，模型鼠脑内Aβ42和p-Tau含量显著下降
摘要原文
Isoorientin Affects Markers of Alzheimer's Disease via Effects on the Oral and Gut Microbiota in APP/PS1 Mice
Zhongbao Zhang, Xiaoqin Tan, Xiaorong Sun, Jianhua Wei, Qing X Li, Zhongyi Wu
ABSTRACT
Background
There is growing evidence of strong associations between the pathogenesis of Alzheimer's disease (AD) and dysbiotic oral and gut microbiota. Recent studies demonstrated that isoorientin (ISO) is anti-inflammatory and alleviates markers of AD, which were hypothesized to be mediated by the oral and gut microbiota.
Objectives
We studied the effects of oral administration of ISO on AD-related markers and the oral and gut microbiota in mice.
Methods
Eight-month-old amyloid precursor protein/presenilin-1 (AP) transgenic male mice were randomly allocated to 3 groups of 15 mice each: vehicle (AP) alone or with a low dose of ISO (AP + ISO-L; 25 mg/kg) or a high dose of ISO (AP+ISO-H; 50 mg/kg). Age-matched wild-type (WT) C57BL/6 male littermates were used as controls. The 4 groups were treated intragastrically with ISO or sterilized ultrapure water for 2 months. AD-related markers in the brain, serum, colon, and liver were analyzed with immunohistochemical and histochemical staining, Western blotting, and ELISA. Oral and gut microbiotas were analyzed using 16S ribosomal RNA gene sequencing.
Results
The high-dose ISO treatment significantly decreased amyloid beta 42–positive deposition by 38.1% and 45.2% in the cortex and hippocampus, respectively, of AP mice (P<0.05). Compared with the AP group, both ISO treatments reduced brain phospho-Tau, phosphor-p65, phosphor–inhibitor of NF-κB, and brain and serum LPS and TNF-α by 17.9%–72.5% and increased brain and serum IL-4 and IL-10 by 130%–210% in the AP + ISO-L and AP + ISO-H groups (P<0.05). Abundances of 26, 25, and 23 microbial taxa in oral, fecal and cecal samples, respectively, were increased in both the AP + ISO-L and AP+ISO-H groups relative to the AP group [linear discriminant analysis (LDA)>3.0;P<0.05]. Gram-negative bacteria,Alteromonas,Campylobacterales,and uncultured Bacteroidales bacterium were positively correlated (rho=0.28–0.59; P<0.05) with the LPS levels and responses of inflammatory cytokines.
Conclusions
The microbiota-gut-brain axis is a potential mechanism by which ISO reduces AD-related markers in AP mice.
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文章来源于北京市农林科学院 。图片来源于 Journal of Nutrition官网。点击下方 阅读原文，即可查看英文摘要原文。
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