背景:PM2.5,一种已知的公共卫生风险,越来越多地与肠道疾病有关,然而,其影响机制尚未完全了解。
目的:本研究旨在探讨慢性PM2.5暴露对肠屏障完整性的影响,并揭示其潜在的分子机制。
方法:将C57BL/6J小鼠暴露于浓缩的环境PM2.5(CPM)或过滤空气(FA)中六个月,以模拟城市污染条件。我们评估了肠屏障损伤,微生物转移,和代谢变化,使用组织病理学,宏基因组学,和代谢组学。还进行了TLR信号通路的分析。
结果:在整个研究期间,CPM暴露室中PM2.5的平均浓度始终为70.9±26.8μg/m3。我们的研究结果表明,慢性CPM暴露显着损害肠屏障的完整性,如关键紧密连接蛋白Occludin和Tjp1/Zo-1的表达降低所示。宏基因组测序揭示了微生物景观的重大变化,鉴定了35种差异丰富的物种。值得注意的是,促炎非胃螺杆菌的种类增加,有益菌减少,如肠乳酸菌,乳酸杆菌。ASF360和Eubacterium重现。代谢组学分析进一步鉴定了26种通常与肠道疾病相关的显著改变的代谢物。还观察到改变的细菌种类和代谢物之间的强相关性。例如,4种螺杆菌与13种代谢物均呈正相关,包括乳酸,胆汁酸,丙酮酸和谷氨酸。此外,TLR2、TLR5、Myd88和NLRP3蛋白的表达水平升高,它们的表达模式显示出很强的相关性,提示TLR2/5-MyD88-NLRP3信号通路可能参与。
结论:慢性CPM暴露导致肠屏障功能障碍,微生物菌群失调,代谢失衡,和TLR2/5-MyD88-NLRP3炎性体的激活。这些发现强调了迫切需要采取干预策略来减轻空气污染对肠道健康的有害影响,并确定潜在的治疗目标。
BACKGROUND: PM2.5, a known public health risk, is increasingly linked to intestinal disorders, however, the mechanisms of its impact are not fully understood.
OBJECTIVE: This study aimed to explore the impact of chronic PM2.5 exposure on intestinal barrier integrity and to uncover the underlying molecular mechanisms.
METHODS: C57BL/6 J mice were exposed to either concentrated ambient PM2.5 (CPM) or filtered air (FA) for six months to simulate urban pollution conditions. We evaluated intestinal barrier damage, microbial shifts, and metabolic changes through histopathology, metagenomics, and metabolomics. Analysis of the TLR signaling pathway was also conducted.
RESULTS: The mean concentration of PM2.5 in the CPM exposure chamber was consistently measured at 70.9 ± 26.8 μg/m³ throughout the study period. Our findings show that chronic CPM exposure significantly compromises intestinal barrier integrity, as indicated by reduced expression of the key tight junction proteins Occludin and Tjp1/Zo-1. Metagenomic sequencing revealed significant shifts in the microbial landscape, identifying 35 differentially abundant species. Notably, there was an increase in pro-inflammatory nongastric Helicobacter species and a decrease in beneficial bacteria, such as Lactobacillus intestinalis, Lactobacillus sp. ASF360, and Eubacterium rectale. Metabolomic analysis further identified 26 significantly altered metabolites commonly associated with intestinal diseases. A strong correlation between altered bacterial species and metabolites was also observed. For example, 4 Helicobacter species all showed positive correlations with 13 metabolites, including Lactate, Bile acids, Pyruvate and Glutamate. Additionally, increased expression levels of TLR2, TLR5, Myd88, and NLRP3 proteins were noted, and their expression patterns showed a strong correlation, suggesting a possible involvement of the TLR2/5-MyD88-NLRP3 signaling pathway.
CONCLUSIONS: Chronic CPM exposure induces intestinal barrier dysfunction, microbial dysbiosis, metabolic imbalance, and activation of the TLR2/5-MyD88-NLRP3 inflammasome. These findings highlight the urgent need for intervention strategies to mitigate the detrimental effects of air pollution on intestinal health and identify potential therapeutic targets.