Cai Min, Xue Shan-Shan, Zhou Cui-Hong, Feng Yu-Chao, Liu Jiang-Zheng, Liu Rui, Wang Peng, Wang Hua-Ning, Peng Zheng-Wu
Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, 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, China.
J Affect Disord. 2025 Jul 15;381:131-149. doi: 10.1016/j.jad.2025.04.018. Epub 2025 Apr 3.
Intestinal dysbacteriosis is frequently implicated in generalized anxiety disorder (GAD). However, the molecular mechanisms and functional changes of the gut-brain axis in GAD remain largely unexplored.
We investigated anxiety-like behaviors, gut microbiota changes, brain region-specific endocannabinoid (eCB) system alterations, including the expression of cannabinoid type 1 (CB1R), monoacylglycerol lipase (MAGL), and fatty acid amide hydrolase (FAAH) in the hippocampus (Hip), prefrontal cortex (PFC), and amygdala (Amy), as well as plasma medium- and long-chain fatty acids (MLCFAs) in a mouse model of chronic restraint stress (CRS) and antibiotic-treated mice receiving fecal microbiota transplantation from GAD patients (FMT-GAD). Additionally, we assessed the impact of FMT-GAD on anxiety-like behavior in systemic CB1R/FAAH/MAGL knockout mice.
CRS induced anxiety-like behaviors, suppressed eCB signaling in the brain, and altered the gut microbiota and plasma MLCFA composition in mice. FMT-GAD-treated mice exhibited anxiety-like behaviors, increased FAAH expression in the Hip and Amy, and MAGL expression in the Hip, while reducing CB1R expression in the Hip. FMT-GAD was associated with decreased plasma polyunsaturated fatty acids (PUFAs) and reduced microbiome function for fatty acid biosynthesis. Notably, FMT-GAD intensified anxiety-like behaviors in CB1R-KO mice but failed to induce anxiety-like behaviors in MAGL-KO and FAAH-KO mice.
This study demonstrates that the interplay between the gut microbiota and the eCB system modulates GAD-related anxiety-like behaviors.
肠道菌群失调常与广泛性焦虑症（GAD）有关。然而，GAD中肠-脑轴的分子机制和功能变化在很大程度上仍未得到探索。
我们研究了慢性束缚应激（CRS）小鼠模型和接受来自GAD患者粪便微生物群移植的抗生素处理小鼠（FMT-GAD）的焦虑样行为、肠道微生物群变化、脑区特异性内源性大麻素（eCB）系统改变，包括海马体（Hip）、前额叶皮质（PFC）和杏仁核（Amy）中1型大麻素受体（CB1R）、单酰甘油脂肪酶（MAGL）和脂肪酸酰胺水解酶（FAAH）的表达，以及血浆中链和长链脂肪酸（MLCFA）。此外，我们评估了FMT-GAD对全身CB1R/FAAH/MAGL基因敲除小鼠焦虑样行为的影响。
CRS诱导小鼠出现焦虑样行为，抑制大脑中的eCB信号传导，并改变肠道微生物群和血浆MLCFA组成。FMT-GAD处理的小鼠表现出焦虑样行为，海马体和杏仁核中FAAH表达增加，海马体中MAGL表达增加，而海马体中CB1R表达降低。FMT-GAD与血浆多不饱和脂肪酸（PUFA）减少和脂肪酸生物合成的微生物群功能降低有关。值得注意的是，FMT-GAD加剧了CB1R基因敲除小鼠的焦虑样行为，但未能在MAGL基因敲除和FAAH基因敲除小鼠中诱导焦虑样行为。
本研究表明肠道微生物群与eCB系统之间的相互作用调节与GAD相关的焦虑样行为。
