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Prolonged antibiotic use induces intestinal injury in mice that is repaired after removing antibiotic pressure: implications for empiric antibiotic therapy

Abstract

Metabolic profiling of urine and fecal extracts, histological investigation of intestinal ilea, and fecal metagenomics analyses were used to investigate effects of prolonged antibiotic use in mice. The study provides insight into the effects of extended empiric antibiotic therapy in humans. Mice were administered a broad-spectrum antibiotic for four consecutive days followed by oral gavage with Clostridium butyricum, an opportunistic gram-positive pathogenic bacteria commonly isolated in fecal and blood cultures of necrotizing enterocolitis patients. Metagenomics data indicated loss of bacterial diversity after 4 days on antibiotics that was restored after removing antibiotic pressure. Histological analyses indicated damage to ileal villi after antibiotic treatment that underwent repair after lifting antibiotic pressure. Metabolic profiling confirmed intestinal injury in antibiotic-treated mice indicated by increased urinary trans-4-hydroxy-l-proline, a breakdown product of collagen present in connective tissue of ileal villi that may serve as a biomarker for antibiotic-induced injury in at risk populations.

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Abbreviations

BCAAs:

Branched-chain amino acids

DM :

Mahalanobis distance

ELBW:

Extremely low birth weight

NEC:

Neonatal necrotizing enterocolitis

NMR:

Nuclear magnetic resonance

OTU:

Operational taxonomic units

PCA:

Principal components analysis

T4HP:

Trans-4-hydroxy-l-proline

TSP:

Trimethylsilyl propionate

UC:

Ulcerative colitis

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Acknowledgments

The authors would like to acknowledge support of Miami University and the Ohio Board of Regents for funding to establish the Ohio Eminent Scholar Laboratory where the work was performed. MAK acknowledges Miami University start-up funds that, in part, supported this study. The authors would also like to acknowledge support from Bruker Biospin, Inc that enabled development of the statistical significance analysis software used in the analysis of the data reported in this paper. ALM was supported by R01 HD 059140/HD/NICHD. MAK was supported by a grant from the NIH/NCI (1R15CA152985).

Competing Interests

The authors have declared that no competing interests exist. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Michael A. Kennedy.

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Romick-Rosendale, L.E., Legomarcino, A., Patel, N.B. et al. Prolonged antibiotic use induces intestinal injury in mice that is repaired after removing antibiotic pressure: implications for empiric antibiotic therapy. Metabolomics 10, 8–20 (2014). https://doi.org/10.1007/s11306-013-0546-5

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Keywords

  • Antibiotic
  • Metabolomics
  • Mouse model
  • Necrotizing enterocolitis
  • NMR
  • PCA