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益生菌改善高脂膳食结构下小鼠肠道微生态异常及其干预结直肠癌发生的研究

Effects of probiotics on the intestinal microecological abnormalities and colorectal cancer of mice induced by high-fat diet

摘要:

目的:建立高脂饮食和益生菌干预的结直肠癌小鼠模型,探讨益生菌干预高脂膳食结构下肠道微生态异常及结直肠癌发生的疗效。方法:8周龄雄性C57BL/6J小鼠40只随机分为4组,每组10只:高脂饮食组(HFD)、高脂饮食+益生菌干预组(HFD+P组)、普通饮食组(ND组)、普通饮食+益生菌干预组(ND+P组),益生菌组给予益生菌制剂灌胃,实验期间采用氧化偶氮甲烷(AOM)联合葡聚糖硫酸钠(DSS)诱导小鼠肠癌模型,定期记录小鼠体质量并评估机体状态。促癌前后小鼠粪便通过16S rDNA高通量测序分析评估菌群结构变化。实验结束收集小鼠肠组织并记录附睾脂肪质量及肿瘤负荷。采用Alpha多样性指数对每组小鼠肠道的菌群丰度和多样性进行分析(Chao1指数越高,菌群丰度越高;Simpson指数越大,多样性越低)。利用Beta多样性分析4组间肠道菌群分布差异的显著性(当 R>0,说明菌群在组间的分布差异大于组内差异)。 结果:实验15周后,HFD组、HFD+P组、ND组和ND+P组小鼠体质量分别为(33.70±0.52)g、(28.70±0.32)g、(25.90±0.34)g和(25.60±0.40)g,差异有统计学意义( F=700.89, P<0.01),其中HFD组体质量分别高于ND组和HFD+P组,而HFD+P组体质量又高于ND组,差异均有统计学意义(均 P<0.01)。HFD组、HFD+P组、ND组和ND+P组小鼠附睾周围脂肪重量分别为(1.36±0.15)g、(0.67±0.08)g、(0.58±0.10)g和(0.54±0.05)g,4组间比较差异有统计学意义( F=114.03, P<0.01),两两比较提示,HFD组附睾周围脂肪重量分别高于ND组和HFD+P组,差异均有统计学意义(均 P<0.017),且HFD+P组与ND组附睾周围脂肪重量相当( P=0.09)。饮食干预条件下,HFD组、HFD+P组、ND组和ND+P组的Chao1指数分别为217.62、235.32、301.51和305.71,Simpson指数分别为0.93、0.89、0.91和0.90。通过Beta多样性分析显示,4组组间菌群分布差异大于组内差异,差异有统计学意义( R=0.655, P=0.001)。物种丰度分析显示,与ND组比较,在门水平层面,HFD组小鼠肠道菌群中拟杆菌门和厚壁菌门等菌群的比例更高,而疣微菌门等菌群的比例更低;在属水平层面,HFD组中拟杆菌属和颤杆菌克属等菌群的比例更高,而艾克曼菌属和拟普雷沃菌属等菌群的比例更低。经过益生菌干预后,上述菌群除了拟普雷沃菌属外,均有改善。HFD组、HFD+P组、ND组和ND+P组小鼠肿瘤数量分别为(4.63±1.19)个、(2.33±0.52)个、(2.56±0.73)个和(2.38±0.52)个,差异有统计学意义( F=14.92, P<0.01)。 结论:益生菌治疗可通过调节肠道菌群紊乱来减轻HFD引起的小鼠肥胖和菌群失调,有助于降低结直肠癌发生的风险。

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abstracts:

Objective:To establish the mice colorectal cancer (CRC) model induced by AOM/DSS with the intervention of high fat diet and probiotics, and to explore the potential mechanism of probiotics intervention in regulating intestinal flora disturbance and antitumor efficiency.Methods:Forty 8-week-old male C57BL/6J mice were randomly divided into 4 groups with 10 mice in each group: HFD group, HDF with probiotics intervention (HFD+P) group, normal diet (ND) group, normal diet with probiotics intervention (ND+P) group. The probiotic groups were administered with probiotics preparation by gavage. During the experiment, AOM/DSS was used to induce mouse colorectal cancer model. The mouse body weight was regularly recorded and the body status was evaluated weekly. High-throughput 16S rDNA sequencing was used to analyze the changes of fecal flora in bacterial structure before and after cancer induction. At the end of the experiment, intestinal tissues of mice were collected and the epididymis adipose mass (EAM) and tumor burden were recorded. The Alpha diversity index was used to analyze the abundance and diversity of the intestinal flora (higher chaol index means higher abundance of bacteria and greater Simpson index means lower diversity in flora structure). The Beta diversity index was used to analyze the significance of the difference in the distribution of intestinal flora among the four groups (When R>0, the difference in the distribution of bacteria among the groups is greater than the difference within the group).Results:After 15 weeks of experiment, the body weight of mice in HFD group, HFD+P group, ND group and ND+P group was (33.70±0.52) g, (28.70±0.32) g, (25.90±0.34) g and (25.60±0.40) g, whose difference was statistically significant ( F=700.89, P<0.01). The body weight of HFD group was higher than that of ND group and HFD+P group while the body weight of HFD+P group was still higher than that of ND group, and the differences were statistically significant (all P<0.017). The average EAM of HFD group, HFD+P group, ND group and ND+P group was (1.36±0.15) g, (0.67±0.08) g, (0.58±0.10) g and (0.54±0.05) g, whose difference was statistically significant ( F=114.03, P<0.01). Pairwise comparisons showed that EAM in HFD group was higher than that in ND group and HFD+P group respectively, with statistically significant difference (both P<0.01), while average EAM of HFD+P group was similar to ND group ( P=0.09). Under the diet intervention, the Chao1 index of HFD group, HFD+P group, ND group and ND+P group was 217.62, 235.32, 301.51 and 305.71 respectively, and the Simpson index was 0.93, 0.89, 0.91 and 0.90. At the same time, the Anosim analysis of Beta diversity analysis showed that the difference in the flora distribution among four groups was greater than the difference with in each group with statistically significant difference ( R=0.655, P=0.001). Species abundance analysis revealed that, compared with ND group, at phylum level, HFD group had a higher proportion of Bacteroides phylum and Firmicutes phylum in the intestinal flora and lower proportion of Verrucomicrobia; at genus level, the proportion of Bacteroides and Oscillibacter in HFD group was higher while the proportion of Akkermansia and Alloprevotella was lower. After the intervention of probiotics, the flora mentioned above was improved significantly except for Alloprevotella. The average number of tumor in HFD group, HFD+P group, ND group and ND+P group was 4.63±1.19, 2.33±0.52, 2.56±0.73 and 2.38±0.52 with statistically significant difference ( F=14.92, P<0.01). Conclusion:Probiotics therapy can reduce obesity and flora imbalance caused by HFD and reduce the incidence of CRC by regulating intestinal flora disturbance.

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