Department of Occupational and Environmental Health, School of Public Health, Soochow University, 199 Renai Road, Suzhou, Jiangsu 215123, China.
Food Funct. 2024 Mar 18;15(6):3060-3075. doi: 10.1039/d3fo05148j.
Lead (Pb) is a widespread toxic endocrine disruptor that could cause liver damage and gut microbiota dysbiosis. However, the causal relationship and underlying mechanisms between the gut microbiota and Pb-induced liver injury are unclear. In this study, we investigated the metabolic toxicity caused by Pb exposure in normal chow (Chow) and high-fat diet (HFD) mice and confirmed the causal relationship by fecal microbial transplantation (FMT) and antibiotic cocktail experiments. The results showed that Pb exposure exacerbated HFD-induced hepatic lipid deposition, fibrosis, and inflammation, but it had no significant effect on Chow mice. Pb increased serum lipopolysaccharide (LPS) levels and induced intestinal inflammation and barrier damage by activating TLR4/NFκB/MLCK in HFD mice. Furthermore, Pb exposure disrupted the gut microbiota, reduced short-chain fatty acid (SCFA) concentrations and the colonic SCFA receptors, G protein-coupled receptor (GPR) 41/43/109A, in HFD mice. Additionally, Pb significantly inhibited the hepatic GPR109A-mediated adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway, resulting in hepatic lipid accumulation. FMT from Pb-exposed HFD mice exacerbated liver damage, disturbed lipid metabolic pathways, impaired intestinal barriers, and altered the gut microbiota and metabolites in recipient mice. However, mice exposed to HFD + Pb and HFD mice had similar levels of these biomarkers in microbiota depleted by antibiotics. In conclusion, our study provides new insights into gut microbiota dysbiosis as a potential novel mechanism for human health related to liver function impairment caused by Pb exposure.
铅（Pb）是一种广泛存在的有毒内分泌干扰物，可能导致肝脏损伤和肠道微生物群落失调。然而，肠道微生物群落与 Pb 诱导的肝损伤之间的因果关系和潜在机制尚不清楚。在本研究中，我们研究了 Pb 暴露对正常饲料（Chow）和高脂肪饮食（HFD）小鼠引起的代谢毒性，并通过粪便微生物移植（FMT）和抗生素鸡尾酒实验证实了因果关系。结果表明，Pb 暴露加剧了 HFD 诱导的肝脂肪沉积、纤维化和炎症，但对 Chow 小鼠没有显著影响。Pb 通过激活 TLR4/NFκB/MLCK 在 HFD 小鼠中增加血清脂多糖（LPS）水平并诱导肠道炎症和屏障损伤。此外，Pb 暴露破坏了肠道微生物群落，降低了短链脂肪酸（SCFA）浓度和结肠 SCFA 受体 G 蛋白偶联受体（GPR）41/43/109A，在 HFD 小鼠中。此外，Pb 显著抑制了肝脏 GPR109A 介导的腺苷 5'-单磷酸激活蛋白激酶（AMPK）途径，导致肝脏脂质堆积。来自 Pb 暴露的 HFD 小鼠的 FMT 加剧了肝脏损伤，扰乱了脂质代谢途径，损害了肠道屏障，并改变了受体小鼠的肠道微生物群落和代谢物。然而，在抗生素耗尽的微生物群中，暴露于 HFD+Pb 和 HFD 的小鼠具有相似水平的这些生物标志物。总之，我们的研究为肠道微生物群落失调作为 Pb 暴露导致肝功能损害相关的人类健康的潜在新机制提供了新的见解。
