Department of Pathology, Microbiology and Immunology. University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Department of Pathology, Microbiology and Immunology. University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Brain Behav Immun. 2019 Nov;82:25-35. doi: 10.1016/j.bbi.2019.07.028. Epub 2019 Jul 26.
Currently, a combination of marijuana cannabinoids including delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is used as a drug to treat muscle spasticity in patients with Multiple Sclerosis (MS). Because these cannabinoids can also suppress inflammation, it is unclear whether such patients benefit from suppression of neuroinflammation and if so, what is the mechanism through which cannabinoids act. In the currently study, we used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to study the role of gut microbiota in the attenuation of clinical signs of paralysis and inflammation caused by cannabinoids. THC + CBD treatment attenuated EAE and caused significant decrease in inflammatory cytokines such as IL-17 and IFN-γ while promoting the induction of anti-inflammatory cytokines such as IL-10 and TGF-β. Use of 16S rRNA sequencing on bacterial DNA extracted from the gut revealed that EAE mice showed high abundance of mucin degrading bacterial species, such as Akkermansia muciniphila (A. muc), which was significantly reduced after THC + CBD treatment. Fecal Material Transfer (FMT) experiments confirmed that THC + CBD-mediated changes in the microbiome play a critical role in attenuating EAE. In silico computational metabolomics revealed that LPS biosynthesis, a key component in gram-negative bacteria such as A. muc, was found to be elevated in EAE mice which was confirmed by demonstrating higher levels of LPS in the brain, while treatment with THC + CBD reversed this trend. EAE mice treated with THC + CBD also had significantly higher levels of short chain fatty acids such as butyric, isovaleric, and valeric acids compared to naïve or disease controls. Collectively, our data suggest that cannabinoids may attenuate EAE and suppress neuroinflammation by preventing microbial dysbiosis seen during EAE and promoting healthy gut microbiota.
目前，大麻素化合物（包括 δ-9-四氢大麻酚（THC）和大麻二酚（CBD））的组合被用作治疗多发性硬化症（MS）患者肌肉痉挛的药物。因为这些大麻素也可以抑制炎症，所以不清楚这些患者是否受益于神经炎症的抑制，如果是，大麻素的作用机制是什么。在目前的研究中，我们使用了实验性自身免疫性脑脊髓炎（EAE）的 MS 小鼠模型，研究了肠道微生物群在减轻大麻素引起的瘫痪和炎症临床症状中的作用。THC+CBD 治疗减轻了 EAE，并显著降低了促炎细胞因子如 IL-17 和 IFN-γ，同时促进了抗炎细胞因子如 IL-10 和 TGF-β的诱导。用细菌 DNA 提取的 16S rRNA 测序揭示了 EAE 小鼠肠道中存在大量黏液降解细菌物种，如阿克曼氏菌（A. muc），THC+CBD 治疗后显著减少。粪便材料转移（FMT）实验证实，THC+CBD 介导的微生物组变化在减轻 EAE 中起着关键作用。计算代谢组学表明，内毒素生物合成（革兰氏阴性菌如 A. muc 的关键成分）在 EAE 小鼠中升高，这通过证明大脑中的 LPS 水平更高得到证实，而 THC+CBD 治疗则逆转了这一趋势。与未治疗或疾病对照组相比，接受 THC+CBD 治疗的 EAE 小鼠还具有显著更高水平的短链脂肪酸，如丁酸、异戊酸和戊酸。总的来说，我们的数据表明，大麻素可能通过防止 EAE 期间出现的微生物失调并促进健康的肠道微生物群来减轻 EAE 和抑制神经炎症。
