Effects of meropenem and amikacin on gut microbiota diversity and structure in a neonatal rat model of necrotizing enterocolitis

ZHANG Chenghuan; CHENG Haiyan; SHEN Leilei; YIN Xianyuan; TAO Min; XU Hedan; CHEN Sheng

doi:10.16016/j.2097-0927.202505056

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Effects of meropenem and amikacin on gut microbiota diversity and structure in a neonatal rat model of necrotizing enterocolitis

Basic Medicine | 更新时间：2025-09-11

- Effects of meropenem and amikacin on gut microbiota diversity and structure in a neonatal rat model of necrotizing enterocolitis
- Journal of Army Medical University Vol. 47, Issue 17, Pages: 2088-2096(2025)
- 作者机构：
  
  陆军军医大学（第三军医大学）第一附属医院儿科，重庆
- 作者简介：
  
  CHEN Sheng， E-mail： chensh129@tmmu.edu.cn
- 基金信息：
  
  the General Program of the National Natural Science Foundation of China(82170565);the Key Project of Natural Science Foundation of Chongqing(2024NSCQ-KJFZZDX0018);the Special Project of Science and Technology Innovation Capacity Promotion of Army Medical University(2019XQY09)
- DOI：10.16016/j.2097-0927.202505056
  CLC： R372;R725.74;R978.1
- Received：23 May 2025，
  
  Revised：2025-08-02，
  
  Accepted：08 August 2025，
  
  Published：15 September 2025
- 稿件说明：
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张成欢，程海燕，沈蕾蕾，等.美罗培南与阿米卡星对新生鼠NEC模型肠道菌群多样性与结构的影响［J］.陆军军医大学学报，2025，47（17）：2088-2096.DOI：10.16016/j.2097-0927.202505056.

ZHANG C H，CHENG H Y，SHEN L L，et al.Effects of meropenem and amikacin on gut microbiota diversity and structure in a neonatal rat model of necrotizing enterocolitis［J］.J Army Med Univ，2025，47（17）：2088-2096.DOI：10.16016/j.2097-0927.202505056.
张成欢，程海燕，沈蕾蕾，等.美罗培南与阿米卡星对新生鼠NEC模型肠道菌群多样性与结构的影响［J］.陆军军医大学学报，2025，47（17）：2088-2096.DOI：10.16016/j.2097-0927.202505056. DOI：

ZHANG C H，CHENG H Y，SHEN L L，et al.Effects of meropenem and amikacin on gut microbiota diversity and structure in a neonatal rat model of necrotizing enterocolitis［J］.J Army Med Univ，2025，47（17）：2088-2096.DOI：10.16016/j.2097-0927.202505056. DOI：

摘要

目的

探究美罗培南与阿米卡星对新生鼠坏死性小肠结肠炎（necrotizing enterocolitis， NEC）模型肠道菌群多样性与结构的影响。

方法

采用新生（出生后1~2 d）SD大鼠（体质量5~10 g，雌雄不限）构建NEC模型。按随机数字表法将大鼠分为4组：对照组（C组，

=12）、NEC组（N组，

=20）、美罗培南干预组（M组，

=20）及阿米卡星干预组（A组，

=20）。NEC模型通过人工配方奶喂养、缺氧冷刺激及脂多糖灌胃联合诱导。M组与A组分别于造模后腹腔注射美罗培南（125 mg/kg）或阿米卡星（468 mg/kg），每日2次，连续3 d；C组与N组给予等体积生理盐水。于干预结束后采集粪便样本，采用16S rDNA高通量测序技术分析肠道菌群结构。使用QIIME2平台进行生物信息学分析，采用Chao1、Shannon及Simpson指数评估菌群α多样性，采用Bray-Curtis距离进行主坐标分析（principal coordinates analysis， PCoA）与非度量多维尺度分析（Non-metric multidimensional scaling analysis， NMDS）以评估β多样性，通过Venn图与UpSet图展示操作分类单元（operational taxonomic unit，OTU）组成与重叠情况。采用线性判别分析效应大小法（linear discriminant analysis effect

size， LEfSe）分析识别组间差异显著的特征菌群。

结果

采用16S rDNA高通量测序技术评估肠道菌群α多样性，与C组比较，N组的3个多样性指标均显著下降（

0.01）：Chao1指数从230降至40，Shannon指数从1.65降至0.85，Simpson指数从0.65降至0.42。经两种抗生素干预后，M组与A组的Chao1指数较N组均显著回升（

0.001），且M组升幅大于A组（

0.05）。然而，2组的Shannon与Simpson指数相较于N组改善不显著。Venn与UpSet分析显示，M组OTU特异性最高（283个），而A组与C组共享OTU最多（63个）。PCoA与NMDS分析中，A组结构趋近C组，聚集性更好。分类组成、关键菌群及LEfSe分析显示，N组富集

Proteobacteria

门（如

Escherichia coli B2、Klebsiella

）等致病菌属，

Firmicutes

门及益生菌属（如

Lactobacillaceae、Bifidobacteriaceae

）显著减少，肠道菌群显著失衡；A组益生菌水平显著上升，微生态结构趋于恢复；M组富集多种条件致病菌及环境相关菌属，菌群构型与健康状态存在明显偏离。

结论

美罗培南与阿米卡星在NEC背景下对肠道菌群调节作用存在差异，阿米卡星在恢复菌群稳定性和益生菌水平方面效果更佳，美罗培南虽适用于早期感染控制但对微生态长期影响需警惕。

Abstract

Objective‍　‍To investigate the effects of meropenem and amikacin on gut microbiota diversity and composition in a neonatal rat model of necrotizing enterocolitis (NEC). Methods‍　‍Neonatal SD rats (1~2 d

weighing 5~10 g

both sexes) were subjected to establish a NEC model through artificial formula feeding

hypoxic-cold stress

and lipopolysaccharide (LPS) gavage. The rats were randomly divided into normal control group (Group C

=12)

NEC group (Group N

=20)

meropenem intervention group (Group M

=20)

and amikacin intervention group (Group A

=20). Following modeling

Group M and Group A received intraperitoneal injections of meropenem (125 mg/kg) or amikacin (468 mg/kg)

twice daily for 3 consecutive days. Groups C and N were administered an equal volume of normal saline. At the end of the intervention

colonic contents or fecal samples were collected. The gut microbiota structure was analyzed using 16S rDNA high-throughput sequencing. Bioinformatics analysis was performed using the QIIME2 platform. Alpha diversity was evaluated using Chao1

Shannon

and Simpson indices. B

eta diversity was assessed based on Bray-Curtis distance through principal coordinate analysis (PCoA) and non-metric multidimensional scaling (NMDS). Venn and UpSet plots were generated to visualize the composition and overlap of operational taxonomic units (OTUs). Linear discriminant analysis effect size (LEfSe) was applied to identify differentially abundant taxa across groups. Results‍　‍High-throughput 16S rDNA sequencing showed that the N group had significantly lower 3 indices of α diversity than the C group (

0.01)

that is

a Chao1 index from 230 to 40

a Shannon index from 1.65 to 0.85

and a Simpson index from 0.65 to 0.42. After antibiotic intervention

both the M group and A group obtained obvious increases in the Chao1 index than the N group (

0.001)

with a greater increase observed in the M group than in the A group (

0.05). However

neither antibiotic group exhibited notable improvements in the Shannon index or Simpson index compared with the N group (

0.05). Venn and UpSet analyses revealed that the M group had the highest number of unique OTUs (283)

while the A group shared the most OTUs (63) with the C group. PCoA and NMDS analyses indicated that the microbial structure of the A group was closer to that of the C group

with better clustering. Taxonomic composition and LEfSe analysis demonstrated that the N group was enriched with potentially pathogenic taxa such as

Escherichia coli B2

and

Klebsiella

under the phylum

Proteobacteria

while beneficial bacteria including

Lactobacillaceae

and

Bifidobacteriaceae

(

phylum Firmicutes

) were significantly reduced

indicating severe dysbiosis. In contrast

the A group exhibited a significant increase in beneficial bacteria and a structural tendency toward ecological recovery. The M group

however

was enriched with various conditionally pathogenic and environmentally associ

ated genera

displaying a microbial configuration notably deviating from a healthy state. Conclusion‍　‍Meropenem and amikacin exhibit differential regulatory effects on the intestinal microbiota in the context of NEC. Amikacin demonstrates superior efficacy in restoring microbial stability and levels of beneficial bacteria

whereas meropenem

although effective for early infection control

warrants caution due to its potential long-term impact on the gut microbiome.

关键词

Keywords

references

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