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Updated: Sep 21, 2025
Cefoperazone-treated Mouse Model of Clinically-relevant Clostridium difficile Strain R20291
Published on: December 10, 2016
Evaluating Cefoperazone-Induced Gut Metabolic Functional Changes in MR1-Deficient Mice
Jinchun Sun1, Zhijun Cao1, Ashley D Smith2
1Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, AR 72079, USA.
Abstract:
Mucosal-associated invariant T cells are activated following the recognition of bacterial antigens presented by the major histocompatibility complex class I-related molecule (MR1). Previous metagenomics data showed that MR1-/- knock-out (KO) mice had distinct microbiota and displayed a resistance to Clostridioides difficile (CDI) colonization vs. wild-type (WT) mice. In the present study, LC/MS-based untargeted metabolomics are applied to evaluate the changes in metabolic activities, in accordance with the changes in gut microbiota caused by cefoperazone (Cef) treatment. Adult C57Bl/6J WT and MR1-/- KO mice were given sterile drinking water or spiked with 0.5 mg/mL Cef ad libitum for five days. Fecal pellets were collected daily, and both small intestinal and cecal contents were harvested at sacrifice. The PLS-DA score plots of the metabolomic data indicate that the microbiota is relatively less disturbed by Cef treatment in KO mice, which is consistent with the metagenomics data. The most noticeable differences in the metabolome of KO and WT mice were the increases in carbohydrates in the WT mice, but not in the KO mice. Metabolic functional biomarkers were identified through the correlation analysis of gamma-aminobutyric acid (GABA) and riboflavin. These detected metabolic functional biomarkers could provide information complementary to metagenomics data.
Insights
Mice lacking MR1 show less gut microbiota disturbance from cefoperazone treatment and resist Clostridioides difficile colonization. Metabolomics reveals distinct carbohydrate metabolism differences between MR1 knockout and wild-type mice.
Area of Science:
- Immunology
- Microbiology
- Metabolomics
Background:
- Mucosal-associated invariant T cells recognize bacterial antigens via MR1.
- MR1 knockout mice exhibit distinct gut microbiota and resistance to Clostridioides difficile infection.
- Antibiotic treatment significantly alters gut microbiota composition and function.
Purpose of the Study:
- To investigate the impact of cefoperazone treatment on gut microbiota and metabolome in MR1 knockout versus wild-type mice.
- To identify metabolic differences associated with altered microbiota in the absence of MR1.
- To explore metabolic biomarkers complementary to metagenomic data.
Main Methods:
- LC/MS-based untargeted metabolomics applied to fecal, small intestinal, and cecal samples.
- Cefoperazone treatment administered to adult C57Bl/6J wild-type and MR1 knockout mice for five days.
- Multivariate statistical analysis (PLS-DA) and correlation analysis used to interpret metabolomic data.
Main Results:
- Cefoperazone treatment caused less disturbance to the gut microbiota in MR1 knockout mice compared to wild-type mice.
- Significant increases in carbohydrate metabolites were observed in wild-type mice but not in MR1 knockout mice post-treatment.
- Gamma-aminobutyric acid (GABA) and riboflavin levels correlated with observed metabolic changes, serving as potential biomarkers.
Conclusions:
- MR1 plays a role in modulating the gut microbiota's response to antibiotic-induced perturbations.
- Metabolomic profiling provides valuable insights into host-microbe-drug interactions, complementing metagenomics.
- Distinct metabolic profiles in MR1 knockout mice suggest a role in resistance to gut dysbiosis and infection.
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