基于16S rRNA测序的2型糖尿病db/db小鼠模型口腔菌群差异分析

doi:10.12300/j.issn.1674-5817.2024.119

实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (2): 147-157.DOI: 10.12300/j.issn.1674-5817.2024.119

基于16S rRNA测序的2型糖尿病db/db小鼠模型口腔菌群差异分析

潘钱家¹, 葛峻沂¹, 胡楠², 华飞³, 顾敏¹()

^1.苏州大学附属第三医院, 常州市第一人民医院口腔科, 常州 213003
^2.苏州大学附属第三医院, 常州市第一人民医院药学部, 常州 213003
^3.苏州大学附属第三医院, 常州市第一人民医院内分泌科, 常州 213003

收稿日期:2024-08-21 修回日期:2024-12-24 出版日期:2025-04-25 发布日期:2025-04-25
通讯作者: 顾敏（1987—），女，博士，副主任医师，研究方向：口腔菌群。E-mail：gumin106@163.com。ORCID： 0000-0001-6162-2792
作者简介:潘钱家（2000—），男，硕士研究生，医师，研究方向：口腔菌群。E-mail：2743297453@qq.com
基金资助:
2022年常州市“十四五”卫生健康高层次人才培养工程“拔尖人才-顾敏”(KY20221388);2023年常州市卫健委科技项目立项项目（青年项目）“类脑仿生深度学习在口腔智齿智能化检测中的高效应用”(QN202310);2023年苏州大学研究生教育改革成果奖培育项目“基于循证医学PICOS模式的CBL在口腔专业研究生培养中的探索应用”(KY20231517)

Differential Analysis of Oral Microbiota in db/db Mouse Model of Type 2 Diabetes Utilizing 16S rRNA Sequencing

PAN Qianjia¹, GE Junyi¹, HU Nan², HUA Fei³, GU Min¹()

^1.Department of Stomatology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Changzhou 213003, China
^2.Department of Pharmacy, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Changzhou 213003, China
^3.Department of Endocrinology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Changzhou 213003, China

Received:2024-08-21 Revised:2024-12-24 Published:2025-04-25 Online:2025-04-25
Contact: GU Min (ORCID: 0000-0001-6162-2792), E-mail: gumin106@163.com

摘要/Abstract

摘要：

目的研究db/db小鼠口腔菌群的改变，为探寻2型糖尿病与口腔微生态的联系提供实验基础。方法选取8只10周龄雄性db/db小鼠为糖尿病实验组，8只10周龄雄性db/m小鼠为正常对照组。适应性喂养5 d后，在相同饲料饲养的第6天和第37天行尾静脉采血，测定两组小鼠的空腹血糖（fasting blood glucose，FBG）水平和口服葡萄糖耐量（oral glucose tolerance test，OGTT），以验证糖尿病模型的可靠性。在相同饲料饲养的第15天采集两组小鼠两侧颊黏膜、舌背与舌腹、口底黏膜、上腭硬区黏膜、上下颌牙龈的龈上区域的口腔菌群样本，提取口腔微生物的基因组DNA后，使用GeneAmp 9700热循环仪对其中16S核糖体RNA（16S ribosomal RNA，16S rRNA）基因的V3～V4 区进行扩增，然后在Illumina MiSeq平台上通过双标引扩增和测序对口腔菌群结构进行评估，然后应用QIIME（version 1.6.0）软件进行生物信息学分析。结果实验开始后第6天和第37天的FBG水平和OGTT检测结果均显示db/db小鼠比db/m小鼠表现出明显的2型糖尿病症状。α多样性分析显示两组小鼠的口腔菌群在多样性上无显著差异（P＞0.05），而在丰富度上差异显著（P＜0.05）。主坐标分析显示db/db小鼠的口腔菌群结构与db/m小鼠存在显著差异（P＜0.05），物种组成分析以及LEfSe分析显示db/db小鼠口腔菌群在门水平以变形菌门（p_Proteobacteria）为主的相对丰度显著上升（P＜0.05），而在属水平上变形杆菌属（g_Proteus）和肠球菌属（g_Enterococcus）的相对丰度极显著上升（P＜0.001）。结论 2型糖尿病db/db小鼠的口腔菌群结构和丰富度均较血糖正常的对照小鼠出现了显著变化。

关键词: 2型糖尿病, db/db小鼠, 口腔菌群, 16S rRNA测序

Abstract:

Objective To investigate the changes in oral microbiota of db/db mice and provide an experimental basis for exploring the relationship between type 2 diabetes mellitus and oral microecology. Methods Eight 10-week-old male db/db mice were designated as the diabetes experimental group (db/db group), while eight 10-week-old male db/m mice were assigned as the normal control group (db/m group). After a 5-day adaptive feeding period, tail venous blood samples were collected on the 6th and 37th days, and fasting blood glucose (FBG) levels and oral glucose tolerance test (OGTT) were performed for both groups to verify the reliability of the diabetes model. On the 15th day of feeding with the same diet, oral microbiota samples were collected from the buccal mucosa, dorsal and ventral tongue surfaces, oral floor mucosa, hard palate mucosa, and the gingival areas of both the upper and lower jaws of the two groups. Genomic DNA from the oral microbiota was extracted, and the V3-V4 regions of the 16S ribosomal RNA (16S rRNA) gene were amplified using a GeneAmp 9700 thermocycler. The composition of the oral microbiota was evaluated through double-labelled amplification and sequencing on the Illumina MiSeq platform, followed by bioinformatics analysis using QIIME software(version 1.6.0). Results The FBG levels and OGTT results on the 6th and 37th days after the start of the experiment indicated that db/db mice exhibited more pronounced symptoms of type 2 diabetes compared to db/m mice. Alpha diversity (α diversity) analysis showed no significant difference in the diversity of oral microbiota between the two groups (P>0.05); however, there was a significant difference in richness (P<0.05). Principal coordinate analysis(PCoA) revealed differences in the oral microbiota composition between the db/db group and db/m group (P<0.05). Species composition analysis and LEfSe analysis demonstrated that the relative abundance of oral microbiota in db/db group mice, predominantly composed of p_Proteobacteria, increased significantly at the phylum level (P<0.05). At the genus level, the relative abundances of g_Proteus and g_Enterococcus showed a significant increase (P<0.001). Conclusion The composition and diversity of oral microbiota in db/db mice with type 2 diabetes mellitus significantly differed from those without the disease.

Key words: Type 2 diabetes, db/db mouse, Oral microbiota, 16S rRNA sequencing analysis

中图分类号:

Q95-33

潘钱家,葛峻沂,胡楠,等. 基于16S rRNA测序的2型糖尿病db/db小鼠模型口腔菌群差异分析[J]. 实验动物与比较医学, 2025, 45(2): 147-157. DOI: 10.12300/j.issn.1674-5817.2024.119.

PAN Qianjia,GE Junyi,HU Nan,et al. Differential Analysis of Oral Microbiota in db/db Mouse Model of Type 2 Diabetes Utilizing 16S rRNA Sequencing[J]. Laboratory Animal and Comparative Medicine, 2025, 45(2): 147-157. DOI: 10.12300/j.issn.1674-5817.2024.119.

图/表 5

图1 db/db小鼠及db/m小鼠的血糖相关指标差异注：A，禁食12 h的空腹血糖（FBG）浓度；B，0~2 h的口服葡萄糖耐量（OGTT）分析；C，OGTT试验的曲线下面积（AUC）。db/db小鼠为糖尿病实验组；db/m小鼠为正常对照组，每组8只。*P＜0.05，**P＜0.01，***P＜0.001。

Figure 1 Comparison of blood glucose indices in db/db mice and db/m miceNote：A， The concentration of fasting blood glucose （FBG） levels after a 12-hour fasting period； B， Analysis of oral glucose tolerance test （OGTT） from 0-2 hours； C， Area under the curve （AUC） of the OGTT. Db/db mice served as the diabetic group， while db/m mice were the normal controls， n=8 per group. *P＜0.05， **P＜0.01， ***P＜0.001.

图2 db/db小鼠及db/m小鼠口腔菌群结构的PCoA分析和 LEfSe分析注：A，db/db小鼠和db/m小鼠之间的主坐标分析；B，基于LEfSe的支系图是从门级到属级的结果（p表示门水平，c表示纲水平，o表示目水平，f表示科水平，g表示属水平）。db/db小鼠为糖尿病实验组；db/m小鼠为正常对照组，每组8只。

Figure 2 PCoA and LEfSe analysis of oral microbiota composition in db/db mice and db/m miceNote：A， Principal coordinate analysis （PCoA） between db/db mice and db/m mice； B， LEfSe-derived cladogram showing taxonomic differences from phylum to genus level （p for phylum； c for class； o for order； f for family； g for genus）. Db/db mice served as the diabetic model， while db/m mice were the normal controls， n=8 per group.

表1 db/db小鼠及db/m小鼠口腔菌群的α多样性分析 (n=8, xˉ±s)

Table 1 Alpha (α) diversity analysis of oral microbiota in db/db mice and db/m mice

指标 Index	db/m	db/db	P value
观察物种指数 Sobs	10.25±8.43	77.25±29.33	0.049^*
香农指数^# Shannon^#	2.40 (2.25~2.48)	2.32 (2.23~2.51)	0.529
辛普森指数 Simpson	0.18±0.04^*	0.16±0.04	0.499
基于丰度的覆盖估计值 ACE	105.56±8.34	79.49±30.06	0.045^*
Chao1丰富度估计量 Chao1	105.67±9.78	79.25±30.42	0.046^*
测序覆盖度 Coverage	0.999 9	1.000 0	0.458

图3 db/db小鼠与db/m小鼠口腔微生物菌群在门水平上的差异注：A～B，db/db组和db/m组口腔微生物在门水平上的群落组成直方图；C，变形杆菌门的相对丰度。db/db小鼠为糖尿病实验组；db/m小鼠为正常对照组，每组8只。*P＜0.05。

Figure 3 Comparison of oral microbiota between db/db mice and db/m mice at the phylum levelNote：A-B， Phylum-level community composition of oral microbiota in db/db and db/m groups； C， Relative abundance of p_Proteobacteria. db/db mice served as the diabetic model， while db/m mice were the normal controls， n=8 per group. *P＜0.05.

图4 db/db小鼠及db/m小鼠的口腔微生物菌群在属水平上的差异注：A，db/db和db/m组唾液微生物群中50种优势物种的相对丰度热图；B～M，葡萄球菌属、鼠杆菌属、链球菌属、气球菌属、棒杆菌属、嗜冷咸海鲜球菌属、肠球菌属、变形杆菌属、副拟杆菌属、瘤胃球菌科下未分类属、肠杆菌属、假芽孢杆菌属水平的相对丰度。正态分布的数据由条形图表示，非正态分布的数据用箱线图表示。db/db小鼠为糖尿病实验组；db/m小鼠为正常对照组，每组8只。*P<0.05，**P<0.01，***P<0.001。

Figure 4 Differences in oral microbiota composition between db/db mice and db/m mice at the genus levelNote： A， Heatmap showing the relative abundance of the top 50 dominant species in the saliva microbiota （db/db vs. db/m）； B-M， Relative abundance of the following genera： g_Staphylococcus， g_Muribacter， g_Streptococcus， g_Aerococcus， g_Corynebacterium， g_Jeotgalicoccus， g_Enterococcus， g_Proteus， g_Parabacteroides， g_Ruminococcaceae， g_Enterorhabdus， and g_Fictibacillus. Normally distributed data are presented as bar plots， and non-normally distributed data as box plots. Db/db mice served as the diabetic model， while db/m mice were the normal controls， n=8 per group. *P < 0.05， **P < 0.01， ***P < 0.001.

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基于16S rRNA测序的2型糖尿病db/db小鼠模型口腔菌群差异分析

Differential Analysis of Oral Microbiota in db/db Mouse Model of Type 2 Diabetes Utilizing 16S rRNA Sequencing

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