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.

中文翻译：

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大麻素、delta-9-四氢大麻酚 (THC) 和大麻二酚 (CBD) 的组合，通过改变肠道微生物群来减轻实验性自身免疫性脑脊髓炎 (EAE)

目前，包括 delta-9-四氢大麻酚 (THC) 和大麻二酚 (CBD) 在内的大麻大麻素的组合被用作治疗多发性硬化症 (MS) 患者肌肉痉挛的药物。由于这些大麻素还可以抑制炎症，因此尚不清楚这些患者是否受益于抑制神经炎症，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 MS 小鼠模型，即实验性自身免疫性脑脊髓炎 (EAE)，研究肠道微生物群在减轻由大麻素引起的瘫痪和炎症的临床症状中的作用。THC+CBD治疗减弱了EAE并导致IL-17和IFN-γ等炎症细胞因子显着减少，同时促进IL-10和TGF-β等抗炎细胞因子的诱导。对从肠道中提取的细菌 DNA 进行 16S rRNA 测序表明，EAE 小鼠显示出大量的粘蛋白降解细菌物种，例如 Akkermansia muciniphila (A.muc)，在 THC+CBD 治疗后显着减少。粪便物质转移 (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。计算机计算代谢组学显示 LPS 生物合成是革兰氏阴性菌（如 A.muc）的一个关键成分，在 EAE 小鼠中被发现升高，这通过证明大脑中 LPS 水平升高而得到证实，同时用 THC + CBD 治疗扭转了这一趋势。与幼稚或疾病对照相比，用 THC + CBD 治疗的 EAE 小鼠的短链脂肪酸水平也显着更高，如丁酸、异戊酸和戊酸。