Lead (Pb) toxicity has been widely studied, but its dose-dependent toxic effects on the gut remain unclear, therefore, the aim of this study was to evaluate the effects of different doses of Pb exposure on the gut microbiota and gut barrier in vitro and in vivo. The HT-29 cell model was used to determine the Pb-induced effects on cell viability, reactive oxygen species (ROS), and tight junction proteins (TJPs) in vitro, and C57BL/6 mice models exposed to 0, 20, 100, 500, and 1000 mg/kg Pb were used to investigate the Pb-induced dose-dependent effects on the gut microbiota, TJP expression, and colon histopathology. Our results showed that the exposure of HT-29 cells to 8 mM Pb decreased cell viability by 50%, elevated ROS levels by 200%, and suppressed the expression of the TJPs, zonula occludens-1 (ZO-1) and occludin by 23% and 35%, respectively. Consistently, Pb-exposed mice showed significant increases in colon tissue damage and inflammation and reductions in ZO-1 mRNA levels in a dose-dependent manner. The occludin mRNA levels decreased in the 500 and 1000 mg/kg groups. At the genus level, the relative abundance of Coprococcus and Oscillospira decreased and that of Lactobacillus increased in linear manner with the Pb exposure dose. PICRUSt analysis based on 16S rRNA sequencing revealed Pb dose-dependent alterations in metabolism through the gut microbiota. These findings suggest that Pb exposure can not only disrupt the barrier by generating oxidative stress, but can also induce gut dysbiosis, colon tissue damage, and gut inflammation in a dose-dependent manner.

铅（Pb）毒性已被广泛研究，但其对肠道的剂量依赖性毒性作用仍不清楚，因此，本研究的目的是在体外评估不同剂量的Pb暴露对肠道微生物群和肠道屏障的影响以及体内。HT-29 细胞模型用于确定 Pb 诱导的体外细胞活力、活性氧 (ROS) 和紧密连接蛋白 (TJP) 的影响， C57BL/6 小鼠模型暴露于 0、20、100、使用 500 和 1000 mg/kg Pb 来研究 Pb 诱导的对肠道微生物群、TJP 表达和结肠组织病理学的剂量依赖性影响。我们的结果表明，HT-29 细胞暴露于 8 mM Pb 会使细胞活力降低 50%，ROS 水平升高 200%，并将 TJP、zonula occlusionns-1 (ZO-1) 和 occludin 的表达抑制 23%分别为 % 和 35%。一致的是，暴露于 Pb 的小鼠表现出结肠组织损伤和炎症显着增加，并且 ZO-1 mRNA 水平以剂量依赖性方式降低。500 和 1000 mg/kg 组的 occludin mRNA 水平下降。在属水平上，随着Pb暴露剂量的增加，粪球菌和颤螺菌的相对丰度下降，而乳杆菌的相对丰度呈线性增加。基于 16S rRNA 测序的 PICRUSt 分析揭示了肠道微生物群代谢中铅的剂量依赖性变化。这些发现表明，铅暴露不仅可以通过产生氧化应激来破坏屏障，而且还可以以剂量依赖的方式诱发肠道菌群失调、结肠组织损伤和肠道炎症。