Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome

Al-Ghezi, Zinah Zamil; Busbee, Philip Brandon; Alghetaa, Hasan; Nagarkatti, Prakash

doi:10.1016/j.bbi.2019.07.028

Cited by 114 publications

(84 citation statements)

References 67 publications

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“…Colonic materials were collected from eight donor mice in each group and used in faecal microbiota transplantation, as described (Al-Ghezi, Busbee, et al, 2019). Briefly, donor mice that were euthanized with an overdose of isoflurane were moved into an anaerobic chamber where the abdominal wall was opened and the colon tissues were collected.…”

Section: Faecal Microbiota Transplantationmentioning

confidence: 99%

Protective effects of Δ⁹‐tetrahydrocannabinol against enterotoxin‐induced acute respiratory distress syndrome are mediated by modulation of microbiota

Mohammed

Alghetaa

Zhou

et al. 2020

British J Pharmacology

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Background and Purpose: Staphylococcal enterotoxin-B (SEB) is one of the most potent bacterial superantigens that exerts profound toxic effects by inducing a cytokine storm. Inhaled SEB can cause acute respiratory distress syndrome (ARDS), which is often fatal and with no effective treatments. Experimental Approach: Efficacy of Δ 9-tetrahydrocannabinol (THC) was tested in a mouse model of SEB-mediated ARDS, in which lung inflammation, alterations in gut/lung microbiota and production of short-chain fatty acids (SCFAs) was measured. Gene dysregulation of lung epithelial cells was studied by transcriptome arrays. Faecal microbiota transplantation (FMT) was performed to confirm the role of microbiota in suppressing ARDS. Key Results: While SEB triggered ARDS and 100% mortality in mice, THC protected the mice from fatality. Pyrosequencing analysis revealed that THC caused significant and similar alterations in microbiota in the lungs and gut of mice exposed to SEB. THC significantly increased the abundance of beneficial bacterial species, Ruminococcus gnavus, but decreased pathogenic microbiota, Akkermansia muciniphila. FMT confirmed that THC-mediated reversal of microbial dysbiosis played crucial role in attenuation of SEB-mediated ARDS. THC treatment caused an increase in SCFA, of which propionic acid was found to inhibit the inflammatory response. Transcriptome array showed that THC up-regulated several genes like lysozyme1 and lysozyme2, β-defensin-2, claudin, zonula-1, occludin-1, Mucin2 and Muc5b while down-regulating β-defensin-1. Conclusion and Implications: The study demonstrates for the first time that THC attenuates SEB-mediated ARDS and toxicity by altering the microbiota in the lungs and the gut as well as promoting antimicrobial and anti-inflammatory pathways.

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Section: Faecal Microbiota Transplantationmentioning

confidence: 99%

Protective effects of Δ⁹‐tetrahydrocannabinol against enterotoxin‐induced acute respiratory distress syndrome are mediated by modulation of microbiota

Mohammed

Alghetaa

Zhou

et al. 2020

British J Pharmacology

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“…Studies from our laboratory over the past 2 decades as well as those from others have shown that cannabinoids including THC and cannabidiol (CBD) act as potent anti-inflammatory agents ( Lombard et al, 2007 ; Hegde et al, 2008 ; Hegde et al, 2010 ; Jackson et al, 2014a ; Rao et al, 2015 ; Sido et al, 2015c ; Sido 2016a ; Elliott et al, 2018 ; Al-Ghezi et al, 2019a ; Al-Ghezi 2019b ; Almogi-Hazan and Or, 2020 ; Mohammed et al, 2020a ; Nichols and Kaplan, 2020 ). In fact, based on our studies ( Hegde et al, 2008 ), CBD has been approved by FDA to treat autoimmune hepatitis as an orphan drug.…”

Section: Cannabinoids As Anti-inflammatory Agents?mentioning

confidence: 96%

“…In fact, based on our studies (Hegde et al, 2008), CBD has been approved by FDA to treat autoimmune hepatitis as an orphan drug. THC, which has been more widely studied, has been shown to act through multiple pathways to attenuate inflammation including: 1) induction of Tregs and myeloid-derived suppressor cells (MDSCs) (Hegde et al, 2010;Jackson et al, 2014a;Sido et al, 2015c;Robinson et al, 2015;Elliott et al, 2018), 2) apoptosis in activated T cells and dendritic cells (Lombard et al, 2007;Rieder et al, 2010), 3) switch from Th1 to Th2 differentiation (Yang et al, 2014), 4) epigenetic alterations including alterations in the expression of miRNA and histone modifications in immune cells (Hegde et al, 2013;Yang et al, 2014;Sido et al, 2015c;Rao et al, 2015;Al-Ghezi et al, 2019b;Yang et al, 2019;Mohammed et al, 2020a), 5) reversal of dysbiosis triggered in the gut and lungs during inflammation (Al-Ghezi et al, 2019a), and 6) inhibition of cytokine storm induced by bacterial superantigens through regulation of suppressor of cytokine signaling 1 (SOCS1) and miRNA (Rao et al, 2015). Recently, we also observed that cannabinoids suppress macrophage-mediated inflammation by shifting myeloid differentiation toward anti-inflammatory MDSCs (Miranda et al, 2020).…”

Section: Cannabinoids As Anti-inflammatory Agents?mentioning

confidence: 99%

Use of Cannabinoids to Treat Acute Respiratory Distress Syndrome and Cytokine Storm Associated with Coronavirus Disease-2019

Nagarkatti

Miranda

2020

Front. Pharmacol.

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Coronavirus disease 2019 (COVID-19) is a highly infectious respiratory disease caused by the severe acute respiratory syndrome coronavirus 2. A significant proportion of COVID-19 patients develop Acute Respiratory Distress Syndrome (ARDS) resulting from hyperactivation of the immune system and cytokine storm, which leads to respiratory and multi-organ failure, and death. Currently, there are no effective treatments against hyperimmune syndrome and ARDS. We propose that because immune cells express cannabinoid receptors and their agonists are known to exhibit potent anti-inflammatory activity, targeting cannabinoid receptors, and endocannabinoids deserve intense investigation as a novel approach to treat systemic inflammation, cytokine storm, and ARDS in patients with COVID-19.

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“…Several preclinical studies have suggested that THC and CBD have protective effects on the gut microbiome. For example, chronic daily THC prevented diet‐induced microbiota changes in obese mice (Cluny et al, ), and a combination of THC and CBD attenuated neuroinflammation and caused alterations in the gut microbiome (e.g., reductions in Akkermansia muciniphila ) in a mouse model of multiple sclerosis (Al‐Ghezi et al, ). The Al‐Ghezi study also conducted fecal transfer experiments, which showed that the THC + CBD‐altered microbiome was associated with reduced disease severity.…”

Section: Role Of the Ecs Within The Mgbamentioning

confidence: 99%

“…Preclinical work suggests that alcohol use has indirect effects on the ECS and that ECS modulation impacts the downstream effects of alcohol (e.g., alcohol consumption and dopamine release in reward‐related brain areas) (Caillé et al, ; Hungund et al, ). Limited existing studies have also shown that THC and CBD confer protective benefits on the gut and immune system in the context of AUD (Cluny et al, ; Al‐Ghezi et al, ) and that these gut and immune changes may impact the clinical features of AUD (Crews et al, ; Engen et al, ; Leclercq et al, , ). It is currently unclear how the effects of alcohol on the ECS and subsequent changes to neural reward pathways may be related to the MGBA‐mediated effects of phytocannabinoids on the clinical features of AUD.…”

Section: Effects Of Cannabinoids On Aud Symptomsmentioning

confidence: 99%

Cannabinoids and the Microbiota–Gut–Brain Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders

Karoly

Mueller

Bidwell

et al. 2019

Alcoholism Clin & Exp Res

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The endocannabinoid system (ECS) has emerged in recent years as a potential treatment target for alcohol use disorders (AUD). In particular, the nonpsychoactive cannabinoid cannabidiol (CBD) has shown preclinical promise in ameliorating numerous clinical symptoms of AUD. There are several proposed mechanism(s) through which cannabinoids (and CBD in particular) may confer beneficial effects in the context of AUD. First, CBD may directly impact specific brain mechanisms underlying AUD to influence alcohol consumption and the clinical features of AUD. Second, CBD may influence AUD symptoms through its actions across the digestive, immune, and central nervous systems, collectively known as the microbiota–gut–brain axis (MGBA). Notably, emerging work suggests that alcohol and cannabinoids exert opposing effects on the MGBA. Alcohol is linked to immune dysfunction (e.g., chronic systemic inflammation in the brain and periphery) as well as disturbances in gut microbial species (microbiota) and increased intestinal permeability. These MGBA disruptions have been associated with AUD symptoms such as craving and impaired cognitive control. Conversely, existing preclinical data suggest that cannabinoids may confer beneficial effects on the gastrointestinal and immune system, such as reducing intestinal permeability, regulating gut bacteria, and reducing inflammation. Thus, cannabinoids may exert AUD harm‐reduction effects, at least in part, through their beneficial actions across the MGBA. This review will provide a brief introduction to the ECS and the MGBA, discuss the effects of cannabinoids (particularly CBD) and alcohol in the brain, gut, and immune system (i.e., across the MGBA), and put forth a theoretical framework to inform future research questions.

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Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome

Cited by 114 publications

References 67 publications

Protective effects of Δ⁹‐tetrahydrocannabinol against enterotoxin‐induced acute respiratory distress syndrome are mediated by modulation of microbiota

Protective effects of Δ⁹‐tetrahydrocannabinol against enterotoxin‐induced acute respiratory distress syndrome are mediated by modulation of microbiota

Use of Cannabinoids to Treat Acute Respiratory Distress Syndrome and Cytokine Storm Associated with Coronavirus Disease-2019

Cannabinoids and the Microbiota–Gut–Brain Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders

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Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome

Cited by 114 publications

References 67 publications

Protective effects of Δ9‐tetrahydrocannabinol against enterotoxin‐induced acute respiratory distress syndrome are mediated by modulation of microbiota

Protective effects of Δ9‐tetrahydrocannabinol against enterotoxin‐induced acute respiratory distress syndrome are mediated by modulation of microbiota

Use of Cannabinoids to Treat Acute Respiratory Distress Syndrome and Cytokine Storm Associated with Coronavirus Disease-2019

Cannabinoids and the Microbiota–Gut–Brain Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders

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Protective effects of Δ⁹‐tetrahydrocannabinol against enterotoxin‐induced acute respiratory distress syndrome are mediated by modulation of microbiota

Protective effects of Δ⁹‐tetrahydrocannabinol against enterotoxin‐induced acute respiratory distress syndrome are mediated by modulation of microbiota