Establishment of a human flora-associated mouse model correlated with Alzheimer’s disease
Received:June 02, 2020  
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DOI:10. 3969 / j.issn.1005-4847. 2021. 01. 008
KeyWord:Alzheimer’s disease; intestinal flora; germ-free mice; human flora-associated animal
                       
AuthorInstitution
朱华 卫健委人类疾病比较医学重点实验室,中国医学科学院医学实验动物研究所,北京协和医学院比较医学中心, 北京
刘小海 中国医学科学院 北京协和医院,北京
李卓 卫健委人类疾病比较医学重点实验室,中国医学科学院医学实验动物研究所,北京协和医学院比较医学中心, 北京
郭亚茜 卫健委人类疾病比较医学重点实验室,中国医学科学院医学实验动物研究所,北京协和医学院比较医学中心, 北京
杜晓鹏 卫健委人类疾病比较医学重点实验室,中国医学科学院医学实验动物研究所,北京协和医学院比较医学中心, 北京
苏磊 卫健委人类疾病比较医学重点实验室,中国医学科学院医学实验动物研究所,北京协和医学院比较医学中心, 北京
李永宁 中国医学科学院 北京协和医院,北京
秦川 卫健委人类疾病比较医学重点实验室,中国医学科学院医学实验动物研究所,北京协和医学院比较医学中心, 北京
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Abstract:
       Objective To establish and evaluate a human flora-associated ( HFA) mouse model from patients with Alzheimer’ s disease (AD) via fecal microbiota transplantation. Methods Twenty-eight female germ-free (GF) C57BL/ 6J mice were divided into a healthy control CON group and an AD group. Six-week-old mice were orally inoculated with a 0. 4 mL mixed stool suspension from 3 healthy participants CON or 3 AD patients to establish the HFA mouse model. At 6 and 10 weeks post-inoculation, fresh fecal samples were collected and examined for the V3 region of the 16S rDNA gene. Blood sera were collected and examined for Aβ and cytokine levels. Brain samples were collected, processed and stained with immunohistochemistry (IHC) for pathological examination. Results There was no difference in average body weight between the two groups. Alpha-diversity analysis showed that the Simpson’s Diversity Index (P< 0. 05, P< 0. 01) was significantly lower in the AD group than CON group. At 6 and 10 weeks post-inoculation, the abundance-based coverage estimator (P< 0. 05), Chao1 index (P< 0. 05) and Shannon function (P< 0. 05, P< 0. 01) were higher in the AD group than the CON group. At the family level at 6 and 10 weeks post-inoculation, the relative abundances of Bacteriaceae were higher (P< 0. 01, P< 0. 05), while those of Lachnospiraceae (P< 0. 001) and Peptostreptococcaceae (P< 0. 05, P< 0. 01) were lower in the AD group compared with the CON group. At the genus level, Bacteroides (P< 0. 01, P< 0. 05) were higher in the AD group the AD group than the CON group. The relative abundances of Clostridioides (P< 0. 01, P< 0. 05), Lachnoclostridium (P< 0. 01, P< 0. 0001) and Parasutterella (P< 0. 01, P< 0. 001) were lower in the AD group than the CON group. β-diversity analysis showed that the CON and AD groups were distributed in different quadrants, but the same groups at different stages were distributed in the same quadrants, with a significant difference between the groups ( P< 0. 05). The Aβ40 level in serum ( P< 0. 05) and cerebral homogenates ( P< 0. 01) were significantly higher in the AD group than the CON group at 10 weeks post-inoculation. In the AD group, the interleukin (IL) - 1β level was lower at 6 weeks ( P< 0. 05), the IL-10 level was higher at 10 weeks ( P< 0. 01), and the transforming growth factor-β level was lower at 6 weeks (P< 0. 01) post-inoculation post-inoculation compared with the CON group. Pathological examination using IHC staining of the brain showed no senile plaques. Conclusions An HFA mouse model derived from AD patients was established via fecal microbiota transplantation. The main advantage of using bacteria from AD patients was that the GF mice were well colonized.
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