Abstract
BackgroundThe intestinal microbiota protect the host against enteric pathogens through a defense mechanism termed colonization resistance. Antibiotics excreted into the intestinal tract may disrupt colonization resistance and alter normal metabolic functions of the microbiota. We used a mouse model to test the hypothesis that alterations in levels of bacterial metabolites in fecal specimens could provide useful biomarkers indicating disrupted or intact colonization resistance after antibiotic treatment.MethodsTo assess in vivo colonization resistance, mice were challenged with oral vancomycin-resistant Enterococcus or Clostridium difficile spores at varying time points after treatment with the lincosamide antibiotic clindamycin. For concurrent groups of antibiotic-treated mice, stool samples were analyzed using quantitative real-time polymerase chain reaction to assess changes in the microbiota and using non-targeted metabolic profiling. To assess whether the findings were applicable to another antibiotic class that suppresses intestinal anaerobes, similar experiments were conducted with piperacillin/tazobactam.ResultsColonization resistance began to recover within 5 days and was intact by 12 days after clindamycin treatment, coinciding with the recovery bacteria from the families Lachnospiraceae and Ruminococcaceae, both part of the phylum Firmicutes. Clindamycin treatment caused marked changes in metabolites present in fecal specimens. Of 484 compounds analyzed, 146 (30%) exhibited a significant increase or decrease in concentration during clindamycin treatment followed by recovery to baseline that coincided with restoration of in vivo colonization resistance. Identified as potential biomarkers of colonization resistance, these compounds included intermediates in carbohydrate or protein metabolism that increased (pentitols, gamma-glutamyl amino acids and inositol metabolites) or decreased (pentoses, dipeptides) with clindamycin treatment. Piperacillin/tazobactam treatment caused similar alterations in the intestinal microbiota and fecal metabolites.ConclusionsRecovery of colonization resistance after antibiotic treatment coincided with restoration of several fecal bacterial metabolites. These metabolites could provide useful biomarkers indicating intact or disrupted colonization resistance during and after antibiotic treatment.
Highlights
The gastrointestinal tract of adult mammals is inhabited by a complex microbial community that includes hundreds of distinct bacterial species [1,2,3]
The intestinal microbiota can be classified into 4 principal phyla: Firmicutes and Actinobacteria (Gram-positive) and Bacteroidetes and Proteobacteria (Gram-negative), with Firmucutes and Bacteroidetes typically being dominant in healthy mammals [4]
Antibiotics excreted into the intestinal tract may disrupt colonization resistance, leaving the host vulnerable to infection with pathogens such as Clostridium difficile and vancomycin-resistant enterococci (VRE) [7,8]
Summary
The gastrointestinal tract of adult mammals is inhabited by a complex microbial community that includes hundreds of distinct bacterial species [1,2,3]. The microbiota complement host physiology by providing a rich array of metabolic functions that benefit the host [5]. Key functions provided by intestinal microorganisms include bile salt metabolism, synthesis of vitamins, digestion and fermentation of otherwise non-digestible polysaccharides and proteins, and stimulation of immune function [1,5]. Antibiotics excreted into the intestinal tract may disrupt colonization resistance and alter normal metabolic functions of the microbiota. We used a mouse model to test the hypothesis that alterations in levels of bacterial metabolites in fecal specimens could provide useful biomarkers indicating disrupted or intact colonization resistance after antibiotic treatment
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