Wang Xintao, Hui Rongji, Li Qing, Lu Yun, Wang Mengmeng, Shi Yan, Xie Bing, Cong Bin, Ma Chunling, Wen Di
College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei, Shijiazhuang, 050017, PR China; Hebei Medical University Postdoctoral Research Station in Biology, Hebei, Shijiazhuang, 050017, PR China.
College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei, Shijiazhuang, 050017, PR China.
Neuropharmacology. 2025 May 1;268:110339. doi: 10.1016/j.neuropharm.2025.110339. Epub 2025 Jan 31.
Methamphetamine (METH)-provoked psychiatric symptoms are a major health concern, with depression being a prevalent symptom among METH abusers. Recently, gut microbiota-derived metabolites have been involved in various psychosis pathogenesis, but their roles in METH-induced depression remain unclear. This study investigates the implication of gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) in METH-induced depressive-like behaviors (DLBs). We examined the circulating TMAO levels post-METH exposure besides exploring the impacts of TMAO on METH-triggered DLBs. Then, potential causes of TMAO alterations were explored, along with its effects on hippocampal neuronal damage and neuroinflammation. The findings showcased that METH-treated mice displayed DLBs accompanied by increased serum TMAO levels. Similarly, introducing TMAO to the drinking water elevated serum TMAO levels and induced DLBs. Although METH exposure did not notably alter the abundance of the gut microbiota, antibiotic (ABX) therapy suppressed the increased serum TMAO levels and the onset of DLBs. Additionally, choline and L-carnitine levels were elevated following METH exposure, which may be a potential mechanism for TMAO metabolic dysregulation. Elevated TMAO levels resulted in an elevation in Nissl-positive dead cells, the number of microglia, TNF-α, and IL-1β levels, along with TLR-4, NF-κB, and MyD88 expression in the hippocampal CA3 region. Inhibition of TMAO synthesis mitigated METH-provoked neuronal damage and neuroinflammation.
甲基苯丙胺（METH）引发的精神症状是一个主要的健康问题，抑郁症是METH滥用者中普遍存在的症状。最近，肠道微生物群衍生的代谢产物已参与各种精神病的发病机制，但其在METH诱导的抑郁症中的作用仍不清楚。本研究调查了肠道微生物群衍生的代谢产物氧化三甲胺（TMAO）在METH诱导的抑郁样行为（DLB）中的作用。我们检测了METH暴露后循环中TMAO的水平，同时探讨了TMAO对METH引发的DLB的影响。然后，探讨了TMAO改变的潜在原因，以及其对海马神经元损伤和神经炎症的影响。研究结果表明，接受METH治疗的小鼠表现出DLB，同时血清TMAO水平升高。同样，将TMAO引入饮用水中可提高血清TMAO水平并诱导DLB。虽然METH暴露并未显著改变肠道微生物群的丰度，但抗生素（ABX）治疗可抑制血清TMAO水平的升高和DLB的发生。此外，METH暴露后胆碱和左旋肉碱水平升高，这可能是TMAO代谢失调的潜在机制。TMAO水平升高导致海马CA3区尼氏阳性死亡细胞、小胶质细胞数量、TNF-α和IL-1β水平升高，同时TLR-4、NF-κB和MyD88表达增加。抑制TMAO合成可减轻METH引发的神经元损伤和神经炎症。
