BACKGROUND Exposure to persistent organic pollutants (POPs) and disruptions in the gastrointestinal microbiota have been positively correlated with a predisposition to factors such as obesity, metabolic syndrome, and type 2 diabetes; however, it is unclear how the microbiome contributes to this relationship. OBJECTIVE This study aimed to explore the association between early life exposure to a potent aryl hydrocarbon receptor (AHR) agonist and persistent disruptions in the microbiota, leading to impaired metabolic homeostasis later in life. METHODS This study used metagenomics, nuclear magnetic resonance (NMR)- and mass spectrometry (MS)-based metabolomics, and biochemical assays to analyze the gut microbiome composition and function, as well as the physiological and metabolic effects of early life exposure to 2,3,7,8-tetrachlorodibenzofuran (TCDF) in conventional, germ-free (GF), and Ahr-null mice. The impact of TCDF on Akkermansia muciniphila (A. muciniphila) in vitro was assessed using optical density (OD 600), flow cytometry, transcriptomics, and MS-based metabolomics. RESULTS TCDF-exposed mice exhibited lower abundances of A. muciniphila, lower levels of cecal short-chain fatty acids (SCFAs) and indole-3-lactic acid (ILA), as well as lower levels of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), findings suggestive of disruption in the gut microbiome community structure and function. Importantly, microbial and metabolic phenotypes associated with early life POP exposure were transferable to GF recipients in the absence of POP carry-over. In addition, AHR-independent interactions between POPs and the microbiota were observed, and they were significantly associated with growth, physiology, gene expression, and metabolic activity outcomes of A. muciniphila, supporting suppressed activity along the ILA pathway. CONCLUSIONS These data obtained in a mouse model point to the complex effects of POPs on the host and microbiota, providing strong evidence that early life, short-term, and self-limiting POP exposure can adversely impact the microbiome, with effects persisting into later life with associated health implications. https://doi.org/10.1289/EHP13356.

中文翻译：

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生命早期接触芳基烃受体配体 TCDF 对 C57BL/6J 小鼠肠道微生物群和宿主代谢稳态的影响。


背景 持久性有机污染物 (POP) 的暴露和胃肠道微生物群的破坏与肥胖、代谢综合征和 2 型糖尿病等因素的易感性呈正相关。然而，目前尚不清楚微生物组如何促进这种关系。目的 本研究旨在探讨生命早期接触强效芳烃受体 (AHR) 激动剂与微生物群持续破坏（导致日后代谢稳态受损）之间的关系。方法本研究使用宏基因组学、基于核磁共振 (NMR) 和质谱 (MS) 的代谢组学以及生化分析来分析肠道微生物组的组成和功能，以及生命早期接触 2、传统、无菌 (GF) 和 Ahr-null 小鼠中的 3,7,8-四氯二苯并呋喃 (TCDF)。使用光密度 (OD 600)、流式细胞术、转录组学和基于 MS 的代谢组学评估 TCDF 对 Akkermansia muciniphila (A. muciniphila) 的体外影响。结果暴露于 TCDF 的小鼠表现出较低的 A. muciniphila 丰度、较低的盲肠短链脂肪酸 (SCFA) 和吲哚 3-乳酸 (ILA) 水平以及较低的肠道激素胰高血糖素样肽 1 水平(GLP-1) 和肽 YY (PYY)，这些发现表明肠道微生物群落结构和功能受到破坏。重要的是，在没有 POP 残留的情况下，与生命早期 POP 暴露相关的微生物和代谢表型可以转移给 GF 接受者。此外，还观察到了 POP 和微生物群之间不依赖于 AHR 的相互作用，并且它们与 A. 的生长、生理、基因表达和代谢活动结果显着相关。 muciniphila，支持 ILA 通路受抑制的活性。结论 这些在小鼠模型中获得的数据表明了 POPs 对宿主和微生物群的复杂影响，提供了强有力的证据，表明生命早期、短期和自限性 POP 暴露会对微生物组产生不利影响，其影响会持续到以后的生活中。具有相关的健康影响。 https://doi.org/10.1289/EHP13356。