Department of Toxicology, School of Public Health, Lanzhou University, Gansu 730000, China.
Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
Sci Total Environ. 2024 Nov 15;951:175681. doi: 10.1016/j.scitotenv.2024.175681. Epub 2024 Aug 22.
Manganese (Mn) is an environmental pollutant, and overexposure can cause neurodegenerative disorders similar to Alzheimer's disease and Parkinson's disease that are characterized by β-amyloid (Aβ) overexpression, Tau hyperphosphorylation and neuroinflammation. However, the mechanisms of Mn neurotoxicity are not clearly defined. In our study, a knockout mouse model of Mn exposure combined with gut flora-induced neurotoxicity was constructed to investigate the effect of gut flora on Mn neurotoxicity. The results showed that the levels of Tau, p-Tau and Aβ in the hippocampus of C57BL/6 mice were greater than those in the hippocampus of control mice after 5 weeks of continuous exposure to manganese chloride (Mn content of 200 mg/L). Transplanted normal and healthy fecal microbiota from mice significantly downregulated Tau, p-Tau and Aβ expression and ameliorated brain pathology. Moreover, Mn exposure activated the cGAS-STING pathway and altered the cecal microbiota profile, characterized by an increase in Clostridiales, Pseudoflavonifractor, Ligilactobacillus and Desulfovibrio, and a decrease in Anaerotruncus, Eubacterium_ruminantium_group, Fusimonas and Firmicutes, While fecal microbiome transplantation (FMT) treatment inhibited this pathway and restored the microbiota profile. FMT alleviated Mn exposure-induced neurotoxicity by inhibiting activation of the NLRP3 inflammasome triggered by overactivation of the cGAS-STING pathway. Deletion of the cGAS and STING genes and FMT altered the gut microbiota composition and its predictive function. Phenotypic prediction revealed that FMT markedly decreased the abundances of anaerobic and stress-tolerant bacteria and significantly increased the abundances of facultative anaerobic bacteria and biofilm-forming bacteria after blocking the cGAS-STING pathway compared to the Mn-exposed group. FMT from normal and healthy mice ameliorated the neurotoxicity of Mn exposure, possibly through alterations in the composition and function of the microbiome associated with the cGAS-STING/NLRP3 pathway. This study provides a prospective direction for future research on the mechanism of Mn neurotoxicity.
锰（Mn）是一种环境污染物，过度暴露可导致类似于阿尔茨海默病和帕金森病的神经退行性疾病，其特征是β-淀粉样蛋白（Aβ）过度表达、Tau 过度磷酸化和神经炎症。然而，锰神经毒性的机制尚不清楚。在我们的研究中，构建了锰暴露联合肠道菌群诱导的神经毒性的敲除小鼠模型，以研究肠道菌群对锰神经毒性的影响。结果表明，连续 5 周暴露于氯化锰（Mn 含量为 200mg/L）后，C57BL/6 小鼠海马中的 Tau、p-Tau 和 Aβ水平高于对照组小鼠。移植正常和健康的粪便微生物群从老鼠身上显著下调 Tau、p-Tau 和 Aβ 的表达，并改善了大脑病理。此外，Mn 暴露激活了 cGAS-STING 通路，并改变了盲肠微生物群谱，特征是梭菌、拟杆菌、Ligilactobacillus 和脱硫弧菌增加，而 Anaerotruncus、Eubacterium_ruminantium_group、Fusimonas 和 Firmicutes 减少，而粪便微生物组移植（FMT）治疗抑制了该通路并恢复了微生物组谱。FMT 通过抑制 cGAS-STING 通路过度激活触发的 NLRP3 炎性小体的激活来缓解 Mn 暴露引起的神经毒性。cGAS 和 STING 基因缺失和 FMT 改变了肠道微生物群落组成及其预测功能。表型预测表明，与 Mn 暴露组相比，阻断 cGAS-STING 通路后，FMT 显著降低了厌氧和应激耐受细菌的丰度，显著增加了兼性厌氧菌和生物膜形成细菌的丰度。来自正常和健康小鼠的 FMT 改善了 Mn 暴露的神经毒性，可能是通过改变与 cGAS-STING/NLRP3 通路相关的微生物群落的组成和功能。本研究为锰神经毒性机制的未来研究提供了一个有前景的方向。
