title: Metabolomics analysis identifies intestinal microbiota-derived biomarkers of colonization resistance in clindamycin-treated mice.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  Colonization 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.
  
  
  CONCLUSIONS
  Recovery 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.
authors.affiliation: Geriatric Research Education and Clinical Center, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America; Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Robin L P
authors.initials: RL
authors.lastname: Jump
authors.affiliation: Research Service, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Polinkovsky
authors.affiliation: Research Service, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hurless
authors.affiliation: Research Service, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Brett
authors.initials: B
authors.lastname: Sitzlar
authors.affiliation: Research Service, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Eckart
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Myreen
authors.initials: M
authors.lastname: Tomas
authors.affiliation: Research Service, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Deshpande
authors.affiliation: Research Service, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Nerandzic
authors.affiliation: Geriatric Research Education and Clinical Center, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America; Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America; Research Service, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Donskey
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002981:Clindamycin / Q000494:pharmacology*; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology*; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods; D051379:Mice; D064307:Microbiota / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; D002981:Clindamycin