The oral uptake of nanoparticles is an important route of human exposure and requires solid models for hazard assessment. While the systemic availability is generally low, ingestion may not only affect gastrointestinal tissues but also intestinal microbes. The gut microbiota contributes essentially to human health, whereas gut microbial dysbiosis is known to promote several intestinal and extra-intestinal diseases. Gut microbiota-derived metabolites, which are found in the blood stream, serve as key molecular mediators of host metabolism and immunity. Gut microbiota and the plasma metabolome were analyzed in male Wistar rats receiving either SiO2 (1000 mg/kg body weight/day) or Ag nanoparticles (100 mg/kg body weight/day) during a 28-day oral gavage study. Comprehensive clinical, histopathological and hematological examinations showed no signs of nanoparticle-induced toxicity. In contrast, the gut microbiota was affected by both nanoparticles, with significant alterations at all analyzed taxonomical levels. Treatments with each of the nanoparticles led to an increased abundance of Prevotellaceae, a family with gut species known to be correlated with intestinal inflammation. Only in Ag nanoparticle-exposed animals, Akkermansia, a genus known for its protective impact on the intestinal barrier was depleted to hardly detectable levels. In SiO2 nanoparticles-treated animals, several genera were significantly reduced, including probiotics such as Enterococcus. From the analysis of 231 plasma metabolites, we found 18 metabolites to be significantly altered in Ag-or SiO2 nanoparticles-treated rats. For most of these metabolites, an association with gut microbiota has been reported previously. Strikingly, both nanoparticle-treatments led to a significant reduction of gut microbiota-derived indole-3-acetic acid in plasma. This ligand of the arylhydrocarbon receptor is critical for regulating immunity, stem cell maintenance, cellular differentiation and xenobiotic-metabolizing enzymes. The combined profiling of intestinal microbiome and plasma metabolome may serve as an early and sensitive indicator of gut microbiome changes induced by orally administered nanoparticles; this will help to recognize potential adverse effects of these changes to the host.

中文翻译：

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口服管饲纳米颗粒后大鼠肠道微生物组和血浆代谢组的变化：可能对健康产生不利影响的敏感指标

纳米颗粒的口服摄取是人类暴露的重要途径，需要可靠的模型来进行危害评估。虽然全身利用率通常较低，但摄入可能不仅会影响胃肠道组织，还会影响肠道微生物。肠道微生物群基本上对人类健康有贡献，而众所周知，肠道微生物菌群失调会促进几种肠道和肠外疾病。在血液中发现的肠道微生物群衍生代谢物是宿主代谢和免疫的关键分子介质。在为期 28 天的口服管饲研究中，对接受 SiO2（1000 mg/kg 体重/天）或 Ag 纳米颗粒（100 mg/kg 体重/天）的雄性 Wistar 大鼠的肠道微生物群和血浆代谢组进行了分析。综合临床，组织病理学和血液学检查未显示纳米颗粒诱导的毒性迹象。相比之下，肠道微生物群受到两种纳米颗粒的影响，在所有分析的分类水平上都有显着变化。用每种纳米颗粒进行治疗导致普氏菌科的丰度增加，该科的肠道物种已知与肠道炎症相关。只有在暴露于 Ag 纳米颗粒的动物中，Akkermansia，一种以其对肠道屏障的保护作用而闻名的属，被消耗到几乎无法检测到的水平。在 SiO2 纳米粒子处理的动物中，几个属显着减少，包括肠球菌等益生菌。通过对 231 种血浆代谢物的分析，我们发现 18 种代谢物在 Ag 或 SiO2 纳米颗粒处理的大鼠中发生了显着变化。对于大多数这些代谢物，先前已经报道了与肠道微生物群的关联。引人注目的是，两种纳米颗粒处理都导致血浆中肠道微生物群衍生的吲哚-3-乙酸显着减少。芳烃受体的这种配体对于调节免疫、干细胞维持、细胞分化和外源代谢酶至关重要。肠道微生物组和血浆代谢组的组合分析可以作为口服纳米粒子诱导的肠道微生物组变化的早期和敏感指标；这将有助于识别这些变化对宿主的潜在不利影响。芳烃受体的这种配体对于调节免疫、干细胞维持、细胞分化和外源代谢酶至关重要。肠道微生物组和血浆代谢组的组合分析可以作为口服纳米粒子诱导的肠道微生物组变化的早期和敏感指标；这将有助于识别这些变化对宿主的潜在不利影响。芳烃受体的这种配体对于调节免疫、干细胞维持、细胞分化和外源代谢酶至关重要。肠道微生物组和血浆代谢组的组合分析可以作为口服纳米粒子诱导的肠道微生物组变化的早期和敏感指标；这将有助于识别这些变化对宿主的潜在不利影响。