摘要
目的
探究凝结魏茨曼氏菌(Weizmannia coagulans) BC-G44对抗生素相关性腹泻(antibiotic-associated diarrhea, AAD)大鼠模型结肠菌群结构、屏障功能和炎症反应的影响。
方法
选取30只5周龄、体重相近的Sprague-Dawley (SD)大鼠,随机分为对照组(Con组)、模型组(Mod组)、低剂量凝结魏茨曼氏菌组(LBC-G44组)、中剂量凝结魏茨曼氏菌组(MBC-G44组)和高剂量凝结魏茨曼氏菌组(HBC-G44组)等5组(n=6),试验包括建模期(7 d)和恢复期(12 d)。在建模期,Con组大鼠每天灌胃2 mL生理盐水,Mod、LBC-G44、MBC-G44和HBC-G44组大鼠则灌胃含克林霉素、氨苄西林和链霉素的混合溶液(2 mL/d)以诱导AAD。在恢复期,Con和Mod组继续灌胃生理盐水,而LBC-G44、MBC-G44和HBC-G44组分别灌胃1
结果
在建模期第7天,与Con组相比,Mod、LBC-G44、MBC-G44和HBC-G44组大鼠出现显著腹泻、体重下降和采食量减少的现象(P<0.05);在第19天,与Mod组对比,MBC-G44和HBC-G44组结肠黏膜厚度和杯状细胞数量显著增加(P<0.05)。HBC-G44组结肠食糜中拟杆菌属(Bacteroides)的相对丰度和乳酸浓度提高(P<0.05),结肠黏膜中d-乳酸(d-lactic acid, d-LA)和二胺氧化酶(diamine oxidase, DAO)浓度也提高(P<0.05),结肠黏膜中Claudin-1、Occludin和MUC2的相对mRNA表达量上调(P<0.05)。同时,与Mod组相比,MBC-G44和HBC-G44组结肠黏膜中Toll样受体4 (Toll-like receptor 4, TLR4)和核因子κB (nuclear factor-kappa B, NF-κB)基因的相对mRNA表达量下调(P<0.05),且结肠黏膜中肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)和白细胞介素-1β (interleukin-1 beta, IL-1β)含量降低(P<0.05)。
结论
W. coagulans BC-G44能够改善抗生素诱导的大鼠结肠损伤,调节结肠微生物群组成和代谢产物,增强肠道屏障功能并减轻肠道炎症反应,从而有效缓解AAD症状。
抗生素在畜牧业中广泛被应用于预防和治疗细菌性疾
肠道菌群结构的变化通常伴随着代谢物的显著变化,尤其是短链脂肪酸(short-chain fatty acid, SCFAs)水平的变化。研究表明,SCFAs能够促进肠上皮细胞的增殖与分化,上调紧密连接蛋白的表达,从而增强肠道屏障功能,防止病原体和毒素穿透肠壁引发炎症反
益生菌作为重要的干预措施,在调节肠道菌群结构、抑制病原菌[如Clostridium difficile、肺炎克雷伯菌(Klebsiella pneumoniae)]过度增殖方面表现出积极作
然而,W. coagulans BC-G44在AAD治疗中的具体作用机制仍需深入研究。本研究采用氨苄西林、链霉素和克林霉素的混合溶液建立大鼠AAD模型,旨在进一步探讨W. coagulans BC-G44对结肠菌群结构、屏障功能和炎症反应的影响,为其在AAD治疗中的应用提供理论依据。
1 材料与方法
1.1 细菌菌株和培养
本研究所用的W. coagulans BC-G44菌株(简称BC-G44)由均瑶润盈生物科技(上海)有限公司提供。菌株冻干粉于-20 ℃保存,以确保其稳定性和活性。使用前,将BC-G44冻干粉溶于2 mL生理盐水中,根据试验需求分别配制成1×1
1.2 动物实验设计
本实验严格遵循南京农业大学实验动物中心的管理规定,已获得南京农业大学实验动物福利与伦理委员会的批准(审核编号:NJAU.No20230329036)。SPF级Sprague-Dawley (SD)大鼠由北京维通利华试验动物技术有限公司提供;试验所用克林霉素、氨苄西林和链霉素分别购自山东方明药业集团股份有限公司、重庆迪康长江制药有限公司和河北远征药业有限公司。
经过7 d的适应期后,将30只体重为(253.20±1.62) g的大鼠随机分为对照组(Con组)、模型组(Mod组)、低剂量BC-G44组(LBC-G44组)、中剂量BC-G44组(MBC-G44组)和高剂量BC-G44组(HBC-G44组)等5组,每组6只,试验分为建模期(7 d)和恢复期(12 d)。通过连续7 d每日灌胃2 mL含1 200 mg/kg体重的克林霉素、1 332 mg/kg体重的氨苄西林和666 mg/kg体重的链霉素的生理盐水溶液,建立AAD模
1.3 样品采集
在试验第19天,所有大鼠经过12 h禁食后被处死。采集结肠中段约2-3 cm的组织样本,立即置于4%多聚甲醛溶液中固定,用于后续组织形态学测定及分析。同时采集大鼠的结肠食糜和黏膜样本,迅速保存在液氮中以备后续分析。
1.4 测定指标和方法
1.4.1 生长性能
从试验第1-19天,每隔2 d在早上8点记录大鼠的体重、采食量和饮水量。在试验结束后计算各组大鼠的平均日增重、采食量及饮水量,并分析其组间差异。
1.4.2 腹泻评估
腹泻程度依据粪便形态和粪便含水量进行评估。根据Chen
粪便含水量=×100% | (1) |
式中:A1为粪便湿重;A2为粪便干重。
1.4.3 结肠组织形态结构观察
将固定在4%多聚甲醛中的结肠组织去除多余部分后,采用乙醇梯度脱水处理。脱水后的组织进行石蜡包埋并切成3 μm厚的切片。使用高碘酸-希夫染色法(periodic acid-Schiff stain, PAS)染色后封固,使用虚拟显微镜(奥林巴斯BX51)观察肠道切片的形态结构和杯状细胞分布。每张切片随机选择6个视野进行观察,采用随机数表法选取,以确保数据采集的随机性和代表性。使用Image Pro Plus 6.0软件测定各视野的黏膜厚度、隐窝深度和杯状细胞数,每个指标选择视野中3个不同位置的平均值进行计算。
1.4.4 结肠黏膜相关参数测定
称取0.1 g结肠黏膜样本置于1.5 mL离心管中,加入900 µL生理盐水进行均质化处理。以4 ℃、3 500 r/min离心15 min,收集上清液以备后续检测。使用BCA试剂盒(北京兰杰柯科技有限公司)测量样品蛋白浓度,并根据蛋白标准曲线进行校准。根据ELISA试剂盒(南京建成生物工程研究所有限公司)说明书的要求,测定样品中二胺氧化酶(diamine oxidase, DAO)、肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)、白细胞介素-6 (interleukin-6, IL-6)、白细胞介素-10 (interleukin-10, IL-10)、白细胞介素-1β (interleukin-1 beta, IL-1β)和分泌型免疫球蛋白A (secretory immunoglobulin A, sIgA)的水平浓度。d-乳酸(d-lactic acid, d-LA)浓度通过比色法检测,具体操作根据乳酸试剂盒(南京建成生物工程研究所有限公司)的说明书进行。
1.4.5 结肠黏膜屏障及炎症相关基因mRNA表达
使用RT-qPCR测定紧密连接蛋白基因(ZO-1、Claudin-1、Occludin)、NF-κB信号通路相关基因(TLR4、NF-κB、MyD88)及黏蛋白基因(MUC1、MUC2、MUC4)的相对mRNA水平,以β-肌动蛋白(β-actin)作为内参基因。首先,使用TRIzol试剂(南京诺唯赞生物科技股份有限公司)从结肠黏膜中提取总RNA,并用微量分光光度计(ThermoFisher Scientific公司)测定RNA浓度。随后,将1 μg总RNA逆转录为cDNA,储存于-80 ℃冰箱中备用。RT-qPCR试验使用ChamQ SYBR qPCR Master Mix试剂盒(南京诺唯赞生物科技股份有限公司)进行反应。引物由生工生物工程(上海)股份有限公司设计和合成(
Gene | Primer sequences (5′→3′) | GenBank accession number |
---|---|---|
β-actin | F: GGTGTGATGGTGGGTATGGG | XM_031144.3 |
R: CAGTTGGTGACAATGCCGTG | ||
ZO-1 | F: CTGAGCCCCCTAGTGATGTG | XM_017588934.1 |
R: TCACAGTGTGGCAAGCGTAG | ||
Claudin-1 | F: AAACTCCGCTTTCTGCACCT | NM_031699.2 |
R: GTGCTGACGATAGAGCCGAT | ||
Occludin | F: GGATTGAGCCCGAGTGGAAAG | NM_031329.2 |
R: AAGGACTTCCCAGAGTGCAGA | ||
TLR4 | F: CCTTTTCATCTCTGCCTTCACTAC | NM_001293316.1 |
R: GGGACACCACGACAATAACCT | ||
NF-κB | F: CCCATGTAGACAGCACCACCTATGAT | NM_001048232.1 |
R: ACAGAGGCTCAAAGTTCTCCACCA | ||
MyD88 | F: TCGACGCCTTCATCTGCTAC | XM_006244087.3 |
R: CCATGCGACGACACCTTTTC | ||
MUC1 | F: GTGCCGCTGCCCACAACCTG | XM_001926883.4 |
R: AGCCGGGTACCCCAGACCCA | ||
MUC2 | F: GGTCATGCTGGAGCTGGACAGT | XM_003122394.1 |
R: TGCCTCCTCGGGGTCGTCAC | ||
MUC4 | F: GATGCCCTGGCCACAGAA | XM_021068274.1 |
R: TGATTCAAGGTAGCATTCATTTGC |
β-actin: Beta-actin; ZO-1: Zonula occludens-1; Occludin: Zonula occludens; Claudin-1: Zonula occludens protein-1; TLR4: Toll-like receptor 4; NF-κB: Nuclear factor kappa-B; MyD88: Myeloid differentiation primary response gene 88; MUC1: Mucin 1; MUC2: Mucin 2; MUC4: Mucin 4.
1.4.6 结肠食糜微生物16S rRNA基因测序
称取0.2 g的大鼠结肠食糜于2 mL离心管中,参照马岩
1.4.7 结肠食糜中乳酸和短链脂肪酸测定
称取0.1 g结肠食糜于1.5 mL离心管中,加入0.9 mL双蒸水,涡旋混匀后制成10%的匀浆液。以4 ℃、12 000 r/min离心10 min,收集上清液用于乳酸测定。乳酸浓度按照乳酸试剂盒(南京建成生物工程研究所有限公司)说明书进行测定。另取0.1 g结肠食糜样本,加入1 mL双蒸水,涡旋混匀后以12 000 r/min离心10 min,取700 µL上清液,加入140 µL偏磷酸巴豆酸溶液混匀后,置于-20 ℃过夜。样本解冻后,以4 ℃、12 000 r/min离心15 min,通过0.22 μm针式滤器过滤,滤液保存备用。短链脂肪酸含量使用气相色谱仪(Shimadzu公司)测定。仪器参数为毛细管柱30 m×0.32 mm×0.25 μm (Agilent Technologies公司),柱温130 ℃,汽化温度180 ℃,氢火焰离子化检测器温度180 ℃,载气为氮气,压力60 kPa,氢气压力50 kPa,氧气压力50 kPa。
1.5 数据统计分析
数据使用Excel 2021进行初步整理,统计分析采用SPSS 26.0软件。组间差异通过单因素方差分析(analysis of variance, ANOVA)进行检测,并进行Duncan多重比较检验。对于不符合正态分布的数据,使用Kruskal-Wallis检验进行分析。数据以“平均值±标准误”表示,P<0.05表示差异显著,P≥0.05则表示无显著差异。
2 结果与分析
2.1 W.coagulans BC-G44对AAD模型大鼠生长性能的影响
如
Items | Con | Mod | LBC-G44 | MBC-G44 | HBC-G44 | P-value |
---|---|---|---|---|---|---|
Body weight (g) | ||||||
1 d | 251.8±3.7 | 254.8±3.4 | 253.8±5.5 | 254.0±2.5 | 251.5±3.6 | 0.965 |
7 d | 319.2±6.9a | 294.0±2.7b | 292.0±8.9b | 283.3±5.9b | 287.2±7.1b | 0.007 |
19 d | 404.2±12.9a | 363.2±9.7b | 365.3±12.7b | 361.3±4.8b | 347.3±8.1b | 0.008 |
Average daily gain (g/d) | ||||||
1-7 d | 9.6±0.6a | 5.6±0.8b | 5.5±0.7b | 4.2±0.8b | 5.1±0.6b | <0.001 |
7-19 d | 7.1±0.5 | 5.8±0.9 | 6.1±0.4 | 6.5±0.5 | 5.0±0.4 | 0.132 |
Data are presented as mean±SE. Different superscript letters (a, b, and c) indicate statistically significant differences (P<0.05), n=6. The same as below.

图1 Weizmannia coagulans BC-G44对AAD模型大鼠生长性能的影响
Figure 1 Effect of Weizmannia coagulans BC-G44 on growth performance of AAD model rats. A: Feed intake; B: Water intake; C: Fecal score; D: Fecal water content.
2.2 W.coagulans BC-G44对AAD模型大鼠结肠形态和杯状细胞的影响
如
Items | Con | Mod | LBC-G44 | MBC-G44 | HBC-G44 | P-value |
---|---|---|---|---|---|---|
Mucosal thickness (μm) | 341.6±4.6a | 237.2±15.1c | 266.0±6.6b | 314.9±3.7a | 327.0±10.2a | 0.001 |
Crypt depth (μm) | 71.6±3.7b | 81.3±4.7b | 86.0±8.7b | 104.9±6.0a | 107.0±9.1a | 0.002 |

图2 Weizmannia coagulans BC-G44对AAD 模型大鼠结肠杯状细胞的影响
Figure 2 Effect of Weizmannia coagulans BC-G44 on colonic goblet cells of AAD model rats. A: Morphological analysis of the colon by PAS staining, the length of the yellow line indicates the mucosal thickness, and the length of the green line indicates the crypt depth. B: Goblet cell numbers. Different letters (a, b, and c) indicate statistically significant differences (P<0.05). Error bars represent the mean±SE. The same as below.
2.3 W.coagulans BC-G44对AAD模型大鼠结肠菌群多样性和组成的影响
2.3.1 结肠菌群α多样性和β多样性分析
如

图3 Weizmannia coagulans BC-G44对AAD模型大鼠结肠菌群α多样性与β多样性的影响
Figure 3 Effect of Weizmannia coagulans BC-G44 on the alpha diversity and beta diversity of colonic microbiota in AAD model rats. A: Shannon index; B: Simpson index; C: Chao1 index; D: ACE index; E: Beta diversity.
2.3.2 W.coagulans BC-G44对AAD模型大鼠结肠菌群组成的影响
如

图4 Weizmannia coagulans BC-G44对AAD模型大鼠结肠菌群门水平的影响
Figure 4 Effect of Weizmannia coagulans BC-G44 on the phylum level of colonic microbiota in AAD model rats. A: Microbial compositions in different experimental groups at the phylum levels; B: Effect of antibiotics and BC-G44 on the relative abundance of microbial communities in chyme samples.
本研究在属水平上对各组间的菌群组成进行了分析,结果如

图5 Weizmannia coagulans BC-G44对AAD模型大鼠结肠菌群属水平的影响
Figure 5 Effect of Weizmannia coagulans BC-G44 on the genus level of colonic microbiota in AAD model rats. A: Microbial compositions in different experimental groups at the genus levels; B: Effect of antibiotics and BC-G44 on the relative abundance of microbial communities in chyme samples.
2.4 W.coagulans BC-G44对AAD模型大鼠结肠菌群代谢产物的影响
如

图6 Weizmannia coagulans BC-G44对AAD模型大鼠结肠食糜短链脂肪酸和乳酸浓度的影响
Figure 6 Effects of Weizmannia coagulans BC-G44 on concentrations of short chain fatty acids and lactate in the colonic chyme of AAD model rats. A: Acetate; B: Propionate; C: Butyrate; D: Isovalerate; E: Total SCFAs; F: Lactate.
2.5 W.coagulans BC-G44对AAD模型大鼠结肠屏障功能的影响
如

图7 Weizmannia coagulans BC-G44对AAD模型大鼠结肠屏障功能的影响
Figure 7 Effect of Weizmannia coagulans BC-G44 on colonic barrier function in AAD model rats. A: Effect of antibiotics and BC-G44 on colonic permeability (D-LA and DAO); B: Effect of antibiotics and BC-G44 on the expression of tight junction protein genes (ZO-1, Claudin-1, and Occludin) and mucin genes (MUC1, MUC2, and MUC4) in colonic mucosa.
2.6 W.coagulans BC-G44对AAD模型大鼠结肠炎症反应的影响
如

图8 Weizmannia coagulans BC-G44对AAD模型大鼠结肠炎症反应的影响
Figure 8 Effect of Weizmannia coagulans BC-G44 on colonic inflammatory response in AAD model rats. A: Effect of antibiotics and BC-G44 on cytokine (IL-6, TNF-α, IL-1β, and IL-10) and slgA content in colonic mucosa; B: Effect of antibiotics and BC-G44 on the relative expression of TLR4/MyD88/NF-κB pathway related genes.
2.7 W.coagulans BC-G44对代谢物与屏障功能指标之间相关性分析的影响
如

图9 Weizmannia coagulans BC-G44对代谢物与屏障功能指标之间相关性分析的影响
Figure 9 Effect of Weizmannia coagulans BC-G44 on correlation analysis between metabolites and barrier function indices. * indicates P<0.05, and ** indicates P<0.01; Values without an asterisk indicate no significant difference (n=6; P<0.05).
3 讨论
长期使用抗生素会扰乱肠道菌群的平衡,导致菌群失调,并可能诱发AA
在AAD模型中,抗生素处理往往导致结肠发生病理变化,包括黏膜上皮脱落、隐窝结构萎缩和杯状细胞数量的显著减
抗生素的使用常导致肠道菌群失调,进而加剧AAD的发生和发
SCFAs是肠道微生物代谢的关键产物,参与维持肠道稳态、改善结肠功能和调节炎症反
抗生素诱导的AAD模型大鼠表现出肠道屏障通透性的显著增加,这一变化为有害细菌和抗原的入侵提供了机会,进而诱发肠道的炎症反
4 结论
BC-G44能够上调紧密连接蛋白的表达,增强肠道屏障功能,并抑制TLR4/MyD88/NF-κB通路的激活,从而减轻抗生素引发的肠道炎症反应。此外,BC-G44还能调节结肠菌群的组成,提高丙酸和乳酸的水平,这些代谢产物在促进肠道健康恢复方面发挥积极作用。因此,BC-G44能够有效缓解大鼠的腹泻症状,显著改善AAD引起的肠道微生态失衡和炎症反应。
作者贡献声明
夏紫嫣:试验设计、样品分析和初稿撰写;郝占西:论文修改;韩迪:论文修改;赵文轩:试验设计、数据采集;汪晶:实验监督和论文修改。
利益冲突
作者声明不存在任何可能会影响本文所报告工作的已知经济利益或个人关系。
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