title: Evaluating effects of penicillin treatment on the metabolome of rats.
abstract: Penicillin (PEN) V, a well-known antibiotic widely used in the treatment of Gram-positive bacterial infections, was evaluated in this study. LC/MS- and NMR-based metabolic profiling were employed to examine the effects of PEN on the host's metabolic phenotype. Male Sprague Dawley rats were randomly divided into groups that were orally administered either 0.5% methylcellulose vehicle, 100 or 2400mg PEN/kg body weight once daily for up to 14 consecutive days. Urine, plasma and tissue were collected from groups sacrificed at 6h, 24h or 14d. The body fluids were subjected to clinical chemistry and metabolomics analysis; the tissue samples were processed for histopathology. The only notable clinical chemistry observation was that gamma glutamyltransferase (GGT) significantly decreased at 24h for both dose groups, and significantly decreased at 14d for the high-dose groups. Partial least squares discriminant analysis scores plots of the metabolomics data from urine and plasma samples showed dose- and time-dependent grouping patterns. Time- and dose-dependent decreases in urinary metabolites including indole-containing metabolites (such as 3-methyldioxyindole sulfate generated from bacterial metabolism of tryptophan), organic acids containing phenyl groups (such as hippuric acid, phenyllactic acid and 3-hydroxyanthranilic acid), and metabolites conjugated with sulfate or glucuronide (such as cresol sulfate and aminophenol sulfate) indicated that the gut microflora population was suppressed. Decreases in many host-gut microbiota urinary co-metabolites (indole- and phenyl-containing metabolites, amino acids, vitamins, nucleotides and bile acids) suggested gut microbiota play important roles in the regulation of host metabolism, including dietary nutrient absorption and reprocessing the absorbed nutrients. Decreases in urinary conjugated metabolites (sulfate, glucuronide and glycine conjugates) implied that gut microbiota might have an impact on chemical detoxification mechanisms. In all, these results clearly show that metabolic profiling is a useful tool to better understand the effects of the antibiotic penicillin has on the gut microbiota and the host.
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, US FDA, Jefferson, AR 72079, USA. Jinchun.Sun@fda.hhs.gov
authors.forename: Jinchun
authors.initials: J
authors.lastname: Sun
authors.forename: Laura K
authors.initials: LK
authors.lastname: Schnackenberg
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Khare
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: James
authors.initials: J
authors.lastname: Greenhaw
authors.forename: William
authors.initials: W
authors.lastname: Salminen
authors.forename: Donna L
authors.initials: DL
authors.lastname: Mendrick
authors.forename: Richard D
authors.initials: RD
authors.lastname: Beger
mesh_terms: D000596:Amino Acids / Q000652:urine; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000652:urine; D002853:Chromatography, Liquid / Q000379:methods; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000382:microbiology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D055442:Metabolome / Q000187:drug effects*; D009711:Nucleotides / Q000652:urine; D010406:Penicillins / Q000494:pharmacology*; D010949:Plasma / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014556:Urine / Q000737:chemistry
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D009711:Nucleotides; D010406:Penicillins
keywords: Gut microbiota; Host-microbial interaction; LC/MS; Metabolome; NMR; Penicillin