ABSTRACT

Detrimental consequences of antibiotic treatment may include long-lasting disruption of the gut microbiota. Previous studies found no negative effects of antibiotics on metabolic health, although individualized responses were observed. Here, we aimed to investigate the subject-specific response to vancomycin use in tissue-specific insulin sensitivity by stratifying individuals based on the presence of antibiotic resistance genes (ARGs) or opportunistic pathogens (OPs) in the baseline fecal microbiota. Quantitative Polymerase Chain Reaction (qPCR) was used to detect ARGs and OPs in DNA isolated from fecal samples of 56 males with overweight/obesity (Body Mass Index: 25–35 kg/m²) and impaired glucose metabolism (fasting plasma glucose ≥5.6 mmol/L and/or 2-hour glucose 7.8–11.1 mmol/L). A two-step hyperinsulinemic-euglycemic clamp was performed to determine tissue-specific insulin sensitivity. Abdominal subcutaneous adipose tissue (AT) gene expression was assessed using Affymetrix microarray. Gut microbial composition was determined using the Human Intestinal Tract Chip (HITChip) microarray. At baseline, the vancomycin resistance gene vanB was present in 60% of our population. In individuals that were vanB-negative at baseline, AT insulin sensitivity (insulin-mediated suppression of plasma free fatty acids) improved during vancomycin use, while it decreased among vanB-positive individuals (% change post versus baseline: 14.1 ± 5.6 vs. −6.7 ± 7.5% (p = .042)). The vancomycin-induced increase in AT insulin sensitivity was accompanied by downregulation of inflammatory pathways and enrichment of extracellular matrix remodeling pathways in AT. In the vanB-positive group, well-known vanB-carrying bacteria, Enterococcus and Streptococcus, expanded in the gut microbiome. In conclusion, microbiome composition and adipose tissue biology were differentially affected by vancomycin treatment based on fecal vanB carriage.

摘要

抗生素治疗的不利后果可能包括肠道微生物群的长期破坏。先前的研究发现抗生素对代谢健康没有负面影响，尽管观察到了个体化的反应。在这里，我们旨在通过根据基线粪便微生物群中抗生素抗性基因 (ARG) 或机会病原体 (OP) 的存在对个体进行分层，来研究受试者对万古霉素在组织特异性胰岛素敏感性中使用的特异性反应。定量聚合酶链反应 (qPCR) 用于检测从 56 名超重/肥胖男性（体重指数：25–35 kg/m ^{2 ）的粪便样本中分离出的 DNA 中的 ARG 和 OP}) 和糖代谢受损（空腹血糖≥5.6 mmol/L 和/或 2 小时血糖 7.8–11.1 mmol/L）。进行两步高胰岛素-正常血糖钳夹以确定组织特异性胰岛素敏感性。使用 Affymetrix 微阵列评估腹部皮下脂肪组织 (AT) 基因表达。使用人体肠道芯片 (HITChip) 微阵列确定肠道微生物组成。在基线时，万古霉素耐药基因vanB存在于我们 60% 的人口中。在基线时为vanB阴性的个体中，AT 胰岛素敏感性（胰岛素介导的血浆游离脂肪酸抑制）在使用万古霉素期间有所改善，而在vanB中则有所降低- 阳性个体（% 变化后与基线：14.1 ± 5.6 与 -6.7 ± 7.5% ( p = .042)）。万古霉素诱导的 AT 胰岛素敏感性增加伴随着 AT 中炎症通路的下调和细胞外基质重塑通路的富集。在vanB阳性组中，众所周知的携带vanB的细菌肠球菌和链球菌在肠道微生物组中扩增。总之，基于粪便vanB 携带的万古霉素治疗对微生物组组成和脂肪组织生物学有不同的影响。