ABSTRACT
BACKGROUND: Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are serious health concerns, especially in Western populations. Antibiotic exposure and high-fat diet (HFD) are important and modifiable factors that may contribute to these diseases. METHODS: To investigate the relationship of antibiotic exposure with microbiome perturbations in a murine model of growth promotion, C57BL/6 mice received lifelong sub-therapeutic antibiotic treatment (STAT), or not (control), and were fed HFD starting at 13 weeks. To characterize microbiota changes caused by STAT, the V4 region of the 16S rRNA gene was examined from collected fecal samples and analyzed. RESULTS: In this model, which included HFD, STAT mice developed increased weight and fat mass compared to controls. Although results in males and females were not identical, insulin resistance and NAFLD were more severe in the STAT mice. Fecal microbiota from STAT mice were distinct from controls. Compared with controls, STAT exposure led to early conserved diet-independent microbiota changes indicative of an immature microbial community. Key taxa were identified as STAT-specific and several were found to be predictive of disease. Inferred network models showed topological shifts concurrent with growth promotion and suggest the presence of keystone species. CONCLUSIONS: These studies form the basis for new models of type 2 diabetes and NAFLD that involve microbiome perturbation.
Subject(s)
Adiposity , Anti-Bacterial Agents/pharmacology , Diet, High-Fat/adverse effects , Gastrointestinal Microbiome/drug effects , Insulin Resistance , Liver Diseases/etiology , Liver Diseases/metabolism , Adiposity/drug effects , Animals , Biodiversity , Body Composition , Body Weight , Cytokines/blood , Disease Models, Animal , Energy Metabolism/drug effects , Glucose/metabolism , Homeostasis/drug effects , Hormones/blood , Inflammation Mediators/blood , Insulin/metabolism , Lipid Metabolism , Liver Diseases/microbiology , Metagenome , Metagenomics , Mice , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/microbiology , Phenotype , Phylogeny , RNA, Ribosomal, 16S/genetics , Time FactorsABSTRACT
Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects. In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction and identify several taxa consistently linked with metabolic alterations. PAPERCLIP:
Subject(s)
Anti-Bacterial Agents/administration & dosage , Disease Models, Animal , Intestines/microbiology , Microbiota , Obesity/microbiology , Penicillins/administration & dosage , Animals , Bacteria/classification , Bacteria/metabolism , Female , Intestinal Mucosa/metabolism , Male , Mice , Mice, Inbred C57BL , Microbiota/drug effects , Obesity/metabolismABSTRACT
Diet influences host metabolism and intestinal microbiota; however, detailed understanding of this tripartite interaction is limited. To determine whether the nonfermentable fiber hydroxypropyl methylcellulose (HPMC) could alter the intestinal microbiota and whether such changes correlated with metabolic improvements, C57B/L6 mice were normalized to a high-fat diet (HFD), then either maintained on HFD (control), or switched to HFD supplemented with 10% HPMC, or a low-fat diet (LFD). Compared to control treatment, both LFD and HPMC reduced weight gain (11.8 and 5.7 g, respectively), plasma cholesterol (23.1 and 19.6%), and liver triglycerides (73.1 and 44.6%), and, as revealed by 454-pyrosequencing of the microbial 16S rRNA gene, decreased microbial α-diversity and differentially altered intestinal microbiota. Both LFD and HPMC increased intestinal Erysipelotrichaceae (7.3- and 12.4-fold) and decreased Lachnospiraceae (2.0- and 2.7-fold), while only HPMC increased Peptostreptococcaceae (3.4-fold) and decreased Ruminococcaceae (2.7-fold). Specific microorganisms were directly linked with weight change and metabolic parameters in HPMC and HFD mice, but not in LFD mice, indicating that the intestinal microbiota may play differing roles during the two dietary modulations. This work indicates that HPMC is a potential prebiotic fiber that influences intestinal microbiota and improves host metabolism.
Subject(s)
Dietary Fiber/administration & dosage , Intestines/microbiology , Metagenome , Methylcellulose/analogs & derivatives , Animals , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , Biodiversity , Body Weight , Diet, Fat-Restricted , Diet, High-Fat , Hypromellose Derivatives , Metabolome , Metagenome/genetics , Methylcellulose/administration & dosage , Mice , Mice, Inbred C57BL , Phylogeny , Prebiotics , RNA, Bacterial/genetics , RNA, Bacterial/isolation & purification , RNA, Ribosomal, 16S/genetics , RNA, Ribosomal, 16S/isolation & purificationABSTRACT
Antibiotics administered in low doses have been widely used as growth promoters in the agricultural industry since the 1950s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we proposed that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy to young mice and evaluated changes in the composition and capabilities of the gut microbiome. Administration of subtherapeutic antibiotic therapy increased adiposity in young mice and increased hormone levels related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids, increases in colonic short-chain fatty acid levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early-life murine metabolic homeostasis through antibiotic manipulation.
