Establishment and evaluation of a mouse model of human gut microbiota transplanted from patients of coronary heart disease
Received:July 09, 2019  
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DOI:10. 3969 / j.issn.1005-4847. 2019. 06. 005
KeyWord:coronary heart 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
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
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
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
袁建松 中国医学科学院阜外心血管医院,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 mouse model of human flora-associated (HFA)from patients of coronary heart disease via fecal microbiota transplantation. Methods Twenty-eight female germ-free (GF) C57BL/6J mice were divided into the healthy control (CON) and coronary heart disease (CAD) groups. Eight-week-old mice were orally inoculated with 0. 4 mL of stool suspension from healthy participants or CAD patients to build 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 blood lipid, cholesterol, myocardial enzymes and cytokine levels. Coronary arteries were collected, processed and stained with hematoxylin and eosin (H&E) for pathological examination. Results The average body weight of the CAD group was significantly higher than that of the CON group ( P <0. 05) from 5 weeks post-inoculation. α-diversity analysis showed that the Simpson ( P <0. 05, P <0. 01), Chao1 ( P <0. 05) and ACE indices ( P <0. 05) were significantly lower in the CAD group than that in the CON group. The Shannon index ( P <0. 05, P <0. 01) was higher in the CAD group than in the CON group at 6 and 10 weeks post-inoculation. The intestinal florae were mainly comprised of the phyla Firmicutes, Proteobacteria, Bacteroidetes, Verrucomicrobia, Fusobacteria, Actinobacteria, Cyanobacteria and Tenericutes. At six weeks post-inoculation, the relative abundances of Firmicutes and Tenericutes were lower ( P <0. 05), and those of Bacteroidetes and Verrucomicrobia were higher ( P <0. 01) in the CAD group than in the CON group. At ten weeks post-inoculation, the relative abundance of Firmicutes ( P <0. 01) was lower, and the relative abundances of Bacteroidetes and Verrucomicrobia ( P <0. 01) were higher in the CAD group than in the CON group. β- diversity analysis showed that the CON and CAD 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 serum levels of TG ( P <0. 05, P <0. 01), TC ( P <0. 05), LDH ( P <0. 01, P <0. 0001) and CK ( P <0. 01, P <0. 05) were significantly higher in the CAD group than in the CON group at 6 and 10 weeks post-inoculation. LDL-C levels were significantly higher ( P <0. 05) in the CAD group than in the CON group at 10 weeks post-inoculation. IL-6 levels were higher at 6 weeks ( P <0. 05) and lower at 10 weeks ( P <0. 01) post-inoculation in the CAD group than in the CON group. The IL-2, IL-4, IL-5 and IL-1β levels were significantly higher ( P < 0. 0001, P < 0. 05, P < 0. 0001, P < 0. 01, respectively) in the CAD group than in the CON group at 10 weeks post-inoculation. IL-12p70, TNF-α and INF-γ levels did not differ between the CAD and CON groups. Pathological examination using HE staining of the coronary arteries showed no obvious atherosclerotic changes (e.g., foam cell infiltration). Conclusions A mouse model of HFA from CAD patients was established via fecal microbiota transplantation. The main advantages of using bacteria from CAD patients are that the GF mice were well colonized, and the animals have similar body weights and serum levels of blood lipid, cholesterol and cytokines.
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