Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome.
Animals
Cannabidiol
/ therapeutic use
Cannabinoids
/ therapeutic use
Cannabis
/ metabolism
Cytokines
/ metabolism
Disease Models, Animal
Dronabinol
/ therapeutic use
Dysbiosis
/ complications
Encephalomyelitis, Autoimmune, Experimental
/ drug therapy
Female
Gastrointestinal Microbiome
/ drug effects
Inflammation
/ complications
Interferon-gamma
/ immunology
Interleukin-17
/ metabolism
Mice
Mice, Inbred C57BL
Multiple Sclerosis
RNA, Ribosomal, 16S
/ genetics
Akkermansia muciniphila
CBD
EAE
Gut microbiome
LPS
Multiple sclerosis
SCFAs
THC
Journal
Brain, behavior, and immunity
ISSN: 1090-2139
Titre abrégé: Brain Behav Immun
Pays: Netherlands
ID NLM: 8800478
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
21
06
2019
revised:
17
07
2019
accepted:
25
07
2019
pubmed:
30
7
2019
medline:
26
8
2020
entrez:
30
7
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31356922
pii: S0889-1591(19)30647-6
doi: 10.1016/j.bbi.2019.07.028
pmc: PMC6866665
mid: NIHMS1538381
pii:
doi:
Substances chimiques
Cannabinoids
0
Cytokines
0
Interleukin-17
0
RNA, Ribosomal, 16S
0
Cannabidiol
19GBJ60SN5
Dronabinol
7J8897W37S
Interferon-gamma
82115-62-6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
25-35Subventions
Organisme : NIAID NIH HHS
ID : R01 AI129788
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH094755
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103641
Pays : United States
Organisme : NCCIH NIH HHS
ID : P01 AT003961
Pays : United States
Organisme : NCCIH NIH HHS
ID : R01 AT006888
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI123947
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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