A Targeted Metabolomics Analysis Identifies Intestinal Microbiota-Derived Urinary Biomarkers of Colonization Resistance in Antibiotic-Treated Mice [PublishAheadOfPrint]

Antibiotics excreted into the intestinal tract may disrupt the microbiota that provide colonization resistance against enteric pathogens and alter normal metabolic functions of the microbiota. Many of the bacterial metabolites produced in the intestinal tract are absorbed systemically and excreted in urine. Here, we used a mouse model to test the hypothesis that alterations in levels of targeted bacterial metabolites in urine specimens could provide useful biomarkers indicating disrupted or intact colonization resistance. To assess in vivo colonization resistance, mice were challenged with oral Clostridium difficile spores at 3, 6, and 11 days after completion of 2 days of treatment with piperacillin/tazobactam, aztreonam, or saline. For concurrent groups of antibiotic-treated mice, urine samples were analyzed using liquid chromatography mass spectrometry (LC-MS/MS) to quantify 11 compounds targeted as potential biomarkers of colonization resistance. Aztreonam did not affect colonization resistance, whereas piperacillin/tazobactam disrupted colonization resistance 3 days after piperacillin/tazobactam treatment with complete recovery by 11 days after treatment. Three of the 11 compounds exhibited a statistically significant and greater than 10-fold increase (tryptophan metabolite N-acetyltryptophan) or decrease (plant polyphenyl derivatives cinnamoylglycine and enterodiol) in urinary concentration 3 days after piperacillin/tazobactam treatment followed by recovery to baseline that coincided with restoration of in vivo colonization resistance. These urinary metabolites could provide useful and easily accessible biomarkers indicating intact or disrupted colonization resistance during and after antibiotic treatment.

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