摘要
      环境因素对肠道微生物群的失调与各种自身免疫和免疫介导的疾病有关。此外，天然存在的细胞外抗生素抗性基因（eARGs）可能通过食物链直接进入肠道。然而，在肠道微生物群暴露于eARGs后，形成微生物群群落的生态过程，以及微生物群组成、代谢功能和免疫反应之间的相互作用，尚不清楚。对“一个健康”方法的日益关注导致迫切需要调查eARGs造成的直接健康损害。在此，我们揭示了eARGs对微生物群群落的显著影响，这是由随机过程强烈驱动的。研究了eARGs如何刺激肠道微生物群组成和代谢组功能的变化，从而导致不同年龄和性别的小鼠产生细胞因子反应。结果显示，细胞因子与免疫调节微生物、代谢产物和ARGs生物标志物显著相关。细胞因子的产生与特定的代谢途径（花生四烯酸和色氨酸代谢途径）有关，这一点已通过离体细胞因子反应和体内恢复实验得到证实。此外，肠道微生物谱可用于准确预测eARGs引起的肠道炎症程度（曲线下面积=0.9166）。本研究全面了解了eARGs对免疫反应和肠道屏障损伤的影响，揭示了eARG、微生物、代谢产物，以及调节人体免疫系统的肠道抗生素耐药性。
ABSTRACT
Dysregulation of the gut microbiota by environmental factors is associated with a variety of autoimmune and immune-mediated diseases. In addition, naturally-occurring extracellular antibiotic resistance genes (eARGs) might directly enter the gut via the food chain. However, following gut microbiota exposure to eARGs, the ecological processes shaping the microbiota community assembly, as well as the interplay between the microbiota composition, metabolic function, and the immune responses, are not well understood. Increasing focus on the One Health approach has led to an urgent need to investigate the direct health damage caused by eARGs. Herein, we reveal the significant influence of eARGs on microbiota communities, strongly driven by stochastic processes. How eARGs-stimulate variations in the composition and metabolomic function of the gut microbiota led to cytokine responses in mice of different age and sex were investigated. The results revealed that cytokines were significantly associated with immunomodulatory microbes, metabolites, and ARGs biomarkers. Cytokine production was associated with specific metabolic pathways (arachidonic acid and tryptophan metabolic pathways), as confirmed by ex vivo cytokine responses and recovery experiments in vivo. Furthermore, the gut microbial profile could be applied to accurately predict the degree of intestinal inflammation ascribed to the eARGs (area under the curve = 0.9616). The present study provided a comprehensive understanding of the influence of an eARGs on immune responses and intestinal barrier damage, shedding light on the interplay between eARGs, microbial, metabolites, and the gut antibiotic resistome in modulating the human immune system.

https://www.tandfonline.com/doi/full/10.1080/19490976.2022.2156764