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Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome.
Brain Behav Immun. 2019 11; 82:25-35.BB

Abstract

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.

Authors+Show Affiliations

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.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. Electronic address: prakash@mailbox.sc.edu.Department of Pathology, Microbiology and Immunology. University of South Carolina School of Medicine, Columbia, SC 29208, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

31356922

Citation

Al-Ghezi, Zinah Zamil, et al. "Combination of Cannabinoids, Delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD), Mitigates Experimental Autoimmune Encephalomyelitis (EAE) By Altering the Gut Microbiome." Brain, Behavior, and Immunity, vol. 82, 2019, pp. 25-35.
Al-Ghezi ZZ, Busbee PB, Alghetaa H, et al. Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome. Brain Behav Immun. 2019;82:25-35.
Al-Ghezi, Z. Z., Busbee, P. B., Alghetaa, H., Nagarkatti, P. S., & Nagarkatti, M. (2019). Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome. Brain, Behavior, and Immunity, 82, 25-35. https://doi.org/10.1016/j.bbi.2019.07.028
Al-Ghezi ZZ, et al. Combination of Cannabinoids, Delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD), Mitigates Experimental Autoimmune Encephalomyelitis (EAE) By Altering the Gut Microbiome. Brain Behav Immun. 2019;82:25-35. PubMed PMID: 31356922.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome. AU - Al-Ghezi,Zinah Zamil, AU - Busbee,Philip Brandon, AU - Alghetaa,Hasan, AU - Nagarkatti,Prakash S, AU - Nagarkatti,Mitzi, Y1 - 2019/07/26/ PY - 2019/06/21/received PY - 2019/07/17/revised PY - 2019/07/25/accepted PY - 2019/7/30/pubmed PY - 2020/8/26/medline PY - 2019/7/30/entrez KW - Akkermansia muciniphila KW - CBD KW - EAE KW - Gut microbiome KW - LPS KW - Multiple sclerosis KW - SCFAs KW - THC SP - 25 EP - 35 JF - Brain, behavior, and immunity JO - Brain Behav Immun VL - 82 N2 - 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. SN - 1090-2139 UR - https://www.unboundmedicine.com/medline/citation/31356922/Combination_of_cannabinoids_delta_9_tetrahydrocannabinol__THC__and_cannabidiol__CBD__mitigates_experimental_autoimmune_encephalomyelitis__EAE__by_altering_the_gut_microbiome_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0889-1591(19)30647-6 DB - PRIME DP - Unbound Medicine ER -