title: Selective Spectrum Antibiotic Modulation of the Gut Microbiome in Obesity and Diabetes Rodent Models.
abstract: The gastrointestinal tract microbiome has been suggested as a potential therapeutic target for metabolic diseases such as obesity and Type 2 diabetes mellitus (T2DM). However, the relationship between changes in microbial communities and metabolic disease-phenotypes are still poorly understood. In this study, we used antibiotics with markedly different antibacterial spectra to modulate the gut microbiome in a diet-induced obesity mouse model and then measured relevant biochemical, hormonal and phenotypic biomarkers of obesity and T2DM. Mice fed a high-fat diet were treated with either ceftazidime (a primarily anti-Gram negative bacteria antibiotic) or vancomycin (mainly anti-Gram positive bacteria activity) in an escalating three-dose regimen. We also dosed animals with a well-known prebiotic weight-loss supplement, 10% oligofructose saccharide (10% OFS). Vancomycin treated mice showed little weight change and no improvement in glycemic control while ceftazidime and 10% OFS treatments induced significant weight loss. However, only ceftazidime showed significant, dose dependent improvement in key metabolic variables including glucose, insulin, protein tyrosine tyrosine (PYY) and glucagon-like peptide-1 (GLP-1). Subsequently, we confirmed the positive hyperglycemic control effects of ceftazidime in the Zucker diabetic fatty (ZDF) rat model. Metagenomic DNA sequencing of bacterial 16S rRNA gene regions V1-V3 showed that the microbiomes of ceftazidime dosed mice and rats were enriched for the phylum Firmicutes while 10% OFS treated mice had a greater abundance of Bacteroidetes. We show that specific changes in microbial community composition are associated with obesity and glycemic control phenotypes. More broadly, our study suggests that in vivo modulation of the microbiome warrants further investigation as a potential therapeutic strategy for metabolic diseases.
authors.affiliation: Computational Biology, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Rajpal
authors.affiliation: Target and Pathway Validation, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Klein
authors.affiliation: Computational Biology, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Mayhew
authors.affiliation: Enteroendocrine Discovery Performance Unit, Research and Development, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Joyce
authors.initials: J
authors.lastname: Boucheron
authors.affiliation: Computational Biology, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Spivak
authors.affiliation: Computational Biology, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Antibacterial Discovery Performance Unit, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Ingraham
authors.affiliation: Enteroendocrine Discovery Performance Unit, Research and Development, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Paulik
authors.affiliation: Enteroendocrine Discovery Performance Unit, Research and Development, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.affiliation: Target and Pathway Validation, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Van Horn
authors.affiliation: Target and Pathway Validation, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thomas
authors.affiliation: Target and Pathway Validation, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Sathe
authors.affiliation: Target and Pathway Validation, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: George P
authors.initials: GP
authors.lastname: Livi
authors.affiliation: Antibacterial Discovery Performance Unit, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Holmes
authors.affiliation: Computational Biology, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Brown
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002442:Ceftazidime / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000382:microbiology*; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D008297:Male; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000382:microbiology*; D010641:Phenotype; D056692:Prebiotics; D051381:Rats
chemical_list: D000900:Anti-Bacterial Agents; D056692:Prebiotics; D002442:Ceftazidime