Zhang Zhongbao, Tan Xiaoqin, Sun Xiaorong, Wei Jianhua, Li Qing X, Wu Zhongyi
Beijing Agro-Biotechnology Research Center, Beijing Academy of Agriculture and Forestry Sciences, Beijing, China.
Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA.
J Nutr. 2022 Jan 11;152(1):140-152. doi: 10.1093/jn/nxab328.
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.
We studied the effects of oral administration of ISO on AD-related markers and the oral and gut microbiota in mice.
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.
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.
The microbiota-gut-brain axis is a potential mechanism by which ISO reduces AD-related markers in AP mice.
越来越多的证据表明，阿尔茨海默病（AD）的发病机制与口腔和肠道微生物群失调之间存在密切关联。最近的研究表明，异荭草素（ISO）具有抗炎作用，并能减轻AD的标志物，据推测这是由口腔和肠道微生物群介导的。
我们研究了口服ISO对小鼠AD相关标志物以及口腔和肠道微生物群的影响。
将8月龄的淀粉样前体蛋白/早老素-1（AP）转基因雄性小鼠随机分为3组，每组15只：单独给予载体（AP）或低剂量ISO（AP + ISO-L；25 mg/kg）或高剂量ISO（AP + ISO-H；50 mg/kg）。年龄匹配的野生型（WT）C57BL/6雄性同窝小鼠用作对照。4组小鼠通过胃内给予ISO或无菌超纯水，持续2个月。采用免疫组织化学和组织化学染色、蛋白质印迹法和酶联免疫吸附测定法分析脑、血清、结肠和肝脏中的AD相关标志物。使用16S核糖体RNA基因测序分析口腔和肠道微生物群。
高剂量ISO治疗使AP小鼠皮质和海马中淀粉样β42阳性沉积分别显著降低38.1%和45.2%（P < 0.05）。与AP组相比，在AP + ISO-L组和AP + ISO-H组中，两种ISO治疗均使脑磷酸化Tau、磷酸化p65、核因子κB抑制蛋白磷酸化水平以及脑和血清中的脂多糖（LPS）和肿瘤坏死因子-α（TNF-α）降低17.9% - 72.5%，并使脑和血清中的白细胞介素-4（IL-4）和白细胞介素-10（IL-10）增加130% - 210%（P < 0.05）。相对于AP组，AP + ISO-L组和AP + ISO-H组的口腔、粪便和盲肠样本中分别有26、25和23种微生物分类群的丰度增加[线性判别分析（LDA）>3.0；P < 0.05]。革兰氏阴性菌、交替单胞菌、弯曲菌目和未培养的拟杆菌属细菌与LPS水平和炎性细胞因子反应呈正相关（rho = 0.28 - 0.59；P < 0.05）。
微生物-肠道-脑轴是ISO降低AP小鼠AD相关标志物的潜在机制。
