Protective Effects ofΔ9-Tetrahydrocannabinol Against Enterotoxin-induced Acute Respiratory Distress Syndrome is Mediated by Modulation of Microbiota.
Br J Pharmacol. 2020 Aug 4. Epub 2020 Aug 4. PMID: 32754917
BACKGROUND: Staphylococcal enterotoxin-B (SEB) is one of the most potent bacterial superantigens that exerts profound toxic effects by inducing cytokine storm. When SEB is inhaled, it can cause Acute Respiratory Distress Syndrome (ARDS), which is often fatal and currently there are no effective treatment modalities.
EXPERIMENTAL APPROACH: We used mouse model of SEB-mediated ARDS to test the efficacy ofΔ9-tetrahydrocannabinol (THC). These mice were monitored for lung inflammation, alterations in gut and lung microbiota and production of short-chain fatty acids (SCFA). Gene dysregulation of lung epithelial cells was studied by transcriptome arrays. Fecal 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 effects. 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 also led to increase in SCFA, of which propionic acid was found to inhibit the inflammatory response. Transcriptome array showed that THC up-regulated several genes like lysozyme-1&2,β-defensin-2, claudin, zonula-1, occludin-1, Mucin2 and Muc5b while downregulating β-defensin-1.
CONCLUSIONS: Current 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 anti-microbial and anti-inflammatory pathways.