PMID- 26709835 OWN - NLM STAT- MEDLINE DCOM- 20160706 LR - 20220331 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 12 DP - 2015 TI - Selective Spectrum Antibiotic Modulation of the Gut Microbiome in Obesity and Diabetes Rodent Models. PG - e0145499 LID - 10.1371/journal.pone.0145499 [doi] LID - e0145499 AB - 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. FAU - Rajpal, Deepak K AU - Rajpal DK AD - Computational Biology, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. FAU - Klein, Jean-Louis AU - Klein JL AD - Target and Pathway Validation, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. FAU - Mayhew, David AU - Mayhew D AD - Computational Biology, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. FAU - Boucheron, Joyce AU - Boucheron J AD - Enteroendocrine Discovery Performance Unit, Research and Development, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America. FAU - Spivak, Aaron T AU - Spivak AT AD - Computational Biology, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. FAU - Kumar, Vinod AU - Kumar V AD - Computational Biology, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. FAU - Ingraham, Karen AU - Ingraham K AD - Antibacterial Discovery Performance Unit, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. FAU - Paulik, Mark AU - Paulik M AD - Enteroendocrine Discovery Performance Unit, Research and Development, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America. FAU - Chen, Lihong AU - Chen L AD - Enteroendocrine Discovery Performance Unit, Research and Development, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America. FAU - Van Horn, Stephanie AU - Van Horn S AD - Target and Pathway Validation, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. FAU - Thomas, Elizabeth AU - Thomas E AD - Target and Pathway Validation, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. FAU - Sathe, Ganesh AU - Sathe G AD - Target and Pathway Validation, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. FAU - Livi, George P AU - Livi GP AD - Target and Pathway Validation, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. FAU - Holmes, David J AU - Holmes DJ AD - Antibacterial Discovery Performance Unit, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. FAU - Brown, James R AU - Brown JR AD - Computational Biology, Target Sciences, Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151228 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Anti-Bacterial Agents) RN - 0 (Prebiotics) RN - 9M416Z9QNR (Ceftazidime) SB - IM MH - Animals MH - Anti-Bacterial Agents/*pharmacology MH - Ceftazidime/pharmacology MH - Diabetes Mellitus, Type 2/*microbiology MH - Diet/adverse effects MH - Disease Models, Animal MH - Gastrointestinal Microbiome/*drug effects MH - Male MH - Mice MH - Obesity/etiology/*microbiology MH - Phenotype MH - Prebiotics MH - Rats PMC - PMC4692534 COIS- Competing Interests: We have the following interests: The study was funded by GlaxoSmithKline. Deepak Rajpal, Jean-Louis Klein, David Mayhew, Joyce Boucheron, Aaron Spivak, Vinod Kumar, Karen Ingraham, Mark Paulik, Lihong Chen, Stephanie Van Horn, Elizabeth Thomas, Ganesh Sathe, George P. Livi, David J. Holmes and James R. Brown were employed by GlaxoSmithKline during the time of the study. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. EDAT- 2015/12/29 06:00 MHDA- 2016/07/07 06:00 PMCR- 2015/12/28 CRDT- 2015/12/29 06:00 PHST- 2015/10/15 00:00 [received] PHST- 2015/12/04 00:00 [accepted] PHST- 2015/12/29 06:00 [entrez] PHST- 2015/12/29 06:00 [pubmed] PHST- 2016/07/07 06:00 [medline] PHST- 2015/12/28 00:00 [pmc-release] AID - PONE-D-15-45385 [pii] AID - 10.1371/journal.pone.0145499 [doi] PST - epublish SO - PLoS One. 2015 Dec 28;10(12):e0145499. doi: 10.1371/journal.pone.0145499. eCollection 2015.