Yu Kristie B, Chandra Franciscus, Coley-O'Rourke Elena J, Paulson Erik T, Novoselov Anna, Zhang David, Finnigan Delanie, Paramo Jorge, Lopez-Romero Arlene, Dong Tien S, Schartup Amina T, Hsiao Elaine Y
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA 92037, USA.
Cell Host Microbe. 2025 May 14;33(5):621-631.e7. doi: 10.1016/j.chom.2025.04.009. Epub 2025 May 1.
Despite efforts to decrease mercury emissions, chronic exposure to the neurotoxicant methylmercury (MeHg) continues to be a global problem that contributes to disparities in risk for neurological and metabolic diseases. Herein we engineer a human commensal gut bacterium, Bacteroides thetaiotaomicron (Bt), to detoxify MeHg by heterologous expression of organomercury lyase (MerB) and mercuric reductase (MerA) genes derived from a resistant bacterium isolated from Hg-polluted mines. We demonstrate that Bt demethylates MeHg both in vitro and within the intestines of mice orally exposed to MeHg or diets containing MeHg-rich fish. In pregnant mice exposed to dietary MeHg, Bt decreases MeHg accumulation in the maternal liver, brain, placenta, and fetal brain, and attenuates the expression of cellular stress genes in the fetal brain. Overall, this work provides foundational proof-of-principle supporting the ability of an engineered gut bacterium to limit MeHg bioaccumulation and reduce adverse effects of chronic MeHg exposure.
尽管人们努力减少汞排放，但长期接触神经毒性物质甲基汞（MeHg）仍是一个全球性问题，它导致了神经和代谢疾病风险的差异。在此，我们对一种人类共生肠道细菌——嗜热栖热放线菌（Bt）进行改造，通过异源表达从汞污染矿山分离出的抗性细菌的有机汞裂解酶（MerB）和汞还原酶（MerA）基因来解毒MeHg。我们证明，Bt在体外以及在口服MeHg或含高汞鱼类饮食的小鼠肠道内均可使MeHg脱甲基。在暴露于膳食MeHg的怀孕小鼠中，Bt可减少母体肝脏、大脑、胎盘和胎儿大脑中的MeHg积累，并减弱胎儿大脑中细胞应激基因的表达。总体而言，这项工作提供了原理验证的基础证据，支持工程化肠道细菌限制MeHg生物累积并减少慢性MeHg暴露不良影响的能力。
