Selective Spectrum Antibiotic Modulation of the Gut Microbiome in Obesity and Diabetes Rodent Models

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.胃肠道菌群（gastrointestinal tract microbiome）被认为是肥胖、2型糖尿病（Type 2 diabetes mellitus, T2DM）等代谢疾病的潜在治疗靶点。然而，微生物群落变化与代谢疾病表型之间的关联仍不甚明晰。本研究采用抗菌谱差异显著的抗生素，对饮食诱导肥胖小鼠模型的肠道菌群进行调控，随后检测肥胖与2型糖尿病相关的生化、激素及表型生物标志物。给高脂饮食小鼠分别采用递增三剂量给药方案的头孢他啶（ceftazidime，主要抗革兰氏阴性菌的抗生素）或万古霉素（vancomycin，主要抗革兰氏阳性菌）进行处理，同时还给予受试动物经典的益生元减重补充剂——10%低聚果糖（10% oligofructose saccharide, 10% OFS）。万古霉素处理组小鼠体重几乎无变化，血糖控制也未得到改善；而头孢他啶与10% OFS处理组均出现了显著的体重下降。但仅头孢他啶可使血糖、胰岛素、蛋白酪氨酸酪氨酸（PYY）及胰高血糖素样肽-1（glucagon-like peptide-1, GLP-1）等关键代谢指标出现显著的剂量依赖性改善。随后，本研究在Zucker糖尿病肥胖（Zucker diabetic fatty, ZDF）大鼠模型中验证了头孢他啶的正向血糖调控效果。对细菌16S rRNA基因V1-V3可变区的宏基因组DNA测序结果显示，头孢他啶处理的小鼠与大鼠的菌群中厚壁菌门（Firmicutes）丰度显著富集，而10% OFS处理组小鼠的拟杆菌门（Bacteroidetes）丰度更高。本研究证实，微生物群落组成的特定变化与肥胖及血糖控制表型密切相关。从更广泛的视角来看，本研究表明体内菌群调控有望作为代谢疾病的潜在治疗策略，值得进一步深入探究。