Dataset Information

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

ABSTRACT:

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 Δ⁹ -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.

SUBMITTER: Mohammed A

PROVIDER: S-EPMC7436585 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:CD8+ T cells can contribute to neuroinflammation by secretion of inflammatory cytokines like interferon γ (IFNγ) and tumor necrosis factor α (TNFα). Astrocytes, a glial cell in the brain, can be stimulated by IFNγ and TNFα to secrete the inflammatory cytokines, monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), and interferon-γ inducible protein 10 (IP-10). Δ9-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in Cannabis sativa, possesses potent anti-inflammatory activity. The objective of this investigation was to assess the effects of THC treatment on CD8+ T cell-mediated activation of astrocytes. CD3/CD28/IFNα- stimulated CD8+ T cells were treated with vehicle (0.03% EtOH) or THC and cocultured with U251 astrocytes. IP-10+, MCP-1+, and IL-6+ astrocytes were quantified by flow cytometry. LegendPlex™ was used to measure cytokine secretion by CD8+ T cells and flow cytometry was employed to quantify IFNγ, TNFα, and lysosomal-associated membrane protein 1 (LAMP-1) expression. Recombinant TNFα and IFNγ were used to stimulate MCP-1, IP-10, IL-6 responses in U251 astrocytes, which were measured by flow cytometry. Treatment with THC reduced CD8+ T cell-mediated induction of IP-10 and IL-6 responses in U251 astrocytes but had no effect on MCP-1. THC treatment differentially affected T cell effector functions such that IFNγ and degranulation responses were sensitive to THC-mediated ablation while TNFα was not. Lastly, THC treatment reduced the IFNγ-induced IP-10 response but had no effect on TNFα-induced MCP-1 response in U251 astrocytes. The results suggest that cannabinoid treatment can selectively reduce certain CD8+ T cell responses that contribute to stimulation of astrocytes. Graphical Abstract Treatment with THC can abate CD8+ T cell-dependent neuroinflammatory processes by inhibiting CD8+ cell differentiation into effector cells, suppressing CD8+ effector cell function, and reducing activation of astrocytes by CD8+ T cell-derived inflammatory cytokines.

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusion and implications

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusion and implications

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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